Treatment of VEGFR-Mediated Diseases Using Circadian Administration of VEGFR Inhibitors

Abstract

Methods of treating vascular endothelial growth factor receptor (VEGFR)-mediated diseases are provided. The methods described herein involve performing a circadian trajectory assessment for a patient based at least in part on one or more patient inputs, determining a circadian administration window for the VEGFR mediated disease and the amount of the VEGFR inhibitor to be administered to the patient, and administering the VEGFR inhibitor to the patient during the circadian administration window.

Description

PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)Treatment of VEGFR-Mediated Diseases Using Circadian Administration of VEGFR InhibitorsCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of the filing date of U.S. Provisional Application Serial No. 63 / 755,961, filed on February 7, 2025, entitled “Treatment Of Vascular Endothelial Growth Factor Receptor (VEGFR)-Mediated Diseases Using Circadian Administration of Regorafenib” the disclosure of which is incorporated by reference herein in its entirety. This application also claims priority’ benefit of the filing date of U.S. Provisional Application Serial No. 63 / 796,955, filed on April 29, 2025, entitled “Treatment Of Vascular Endothelial Growth Factor Receptor (VEGFR)-Mediated Diseases Using Circadian Administration of VEGFR Inhibitors” the disclosure of which is incorporated by reference herein in its entirety. This application also claims priority- benefit of the filing date of U.S. Provisional Application Serial No. 63 / 942,230, filed on December 16, 2025, entitled “Treatment of VEGFR-Mediated Diseases Using Circadian Administration of VEGFR Inhibitors” the disclosure of which is incorporated by reference herein in its entirety.FIELD

[0002] The present disclosure concerns the use of vascular endothelial growth factor receptor (VEGFR) inhibitors in the treatment of vascular endothelial growth factor receptor (VEGFR)- mediated diseases. The methods described herein involve performing a circadian trajectory assessment for a patient based at least in part on one or more patient inputs, determining a circadian administration window for the VEGFR mediated disease and the amount of the VEGFR inhibitor to be administered to the patient, and administering the VEGFR inhibitor to the patient during the circadian administration w indow7.BACKGROUND

[0003] Vascular endothelial growth factor receptors (VEGFRs) are involved in many diseases, including cancer, cardiovascular disease, and neurodegenerative diseases. These receptors play important roles in mediating the formation of new blood vessels under various pathological conditions and processes, including wound healing and many others.

[0004] It is well-established in the scientific literature that circadian rhythms have a fundamental influence on nearly every7biological process in the body. Circadian rhythms are responsible forPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) sleep / wake cycles, digestive functions, hormone production, thermoregulation, cognitive function, cell regeneration, immune function, blood pressure, liver function, and gene expression, among other processes.

[0005] Three key properties of a circadian trajectory representing circadian rhythms might be:period, phase, and amplitude. A Midline Estimating Statistic of Rhythm (MESOR) may also be used as a measurement of circadian rhythm. Circadian rhythms are the rhythmic changes in the body which repeat roughly every 24 hours. The circadian intrinsic period is the duration of a single cycle of a circadian trajectory in the absence of external inputs (e.g., 24.4 hours). Circadian phases are the specific time points within a circadian rhythm where a physiological event or behavioral event occurs. Circadian amplitude is the relative strength or weakness of the “peaks and troughs” of biological rhythms. A circadian amplitude of a circadian trajectory need not be strictly the maxima and minima of circadian states of the circadian trajectory but might be some measure that is representative of how pronounced or unpronounced the circadian trajectory happens to be. If a circadian trajectory is exactly a sinewave, then the maxima / minima of the sinewave can be good to use as the circadian amplitude, but a circadian trajectory is typically not exactly a sinewave. A MESOR may also be referred to as the equilibrium point. A MESOR represents the average value around which a biological variable oscillates over a circadian period and can help to quantify rhythmic paterns. A MESOR minus amplitude can be the lowest point in a circadian rhythm.

[0006] A circadian trajectory may pass through phases, and the passage of time between a particular phase and a return to that phase might be referred to as one “circadian cycle.” It could be that a circadian cycle duration is constant, and a circadian trajectory might be described as periodic in that it repeats the same cycle. However, one circadian cycle might not have exactly the same duration as the next circadian cycle (and there might be variations in the amplitude and phase from cycle to cycle). It also could be the case that, even in a single organism, there are multiple circadian trajectories each with their own cycle durations, which might vary from cycle to cycle and as between the multiple circadian trajectories.

[0007] In any given patient, there is expected to be more than one aspect of the patient having its own circadian trajectories and states. A circadian state might represent a state of a circadian trajectory and be represented at least by values for a phase and an amplitude of the circadian trajectory. A given circadian trajectory might be associated with some aspect of the patient,PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) such as the patient’s nervous system, some particular tissue, some biological process, etc. As used herein, a circadian state might be assumed to be tissue-specific, but it should be understood that a circadian state of a circadian trajectory might be specific to some biological process that is not typically associated with a specific tissue.

[0008] As used herein, a whole-body circadian state is an assemblage of the circadian states of each tissue or aspect. A whole-body circadian trajectory might represent the assemblage of the circadian states of each tissue over a circadian period. Circadian rhythms may be defined by the brain, or ‘'central pacemaker,” or other tissues, “peripheral pacemakers.” Two tissues with different circadian states can have circadian desynchrony where they batle for “true time.” One example of this is tissues specific to the brain receiving light signals and tissues specific to digestion receiving signals from meal timing. In some instances, these two signals may be aligned, but in some cases, one tissue-specific signal will overcome the other. In the example where light cues and food cues are only misaligned by several hours, the brain generally leads, but introducing food into the body may change the timing of some genes (e.g., PER2) and glucose regulation, as described in [Wehrens].

[0009] Circadian rhythms may be impacted by factors such as: light exposure, temperature, diet, caffeine, alcohol, melatonin supplementation, exercise, stress, age, shift work, jet lag and medical conditions, such as neurodegenerative disease and mental health disorders. At the cellular level, circadian rhythms can be impacted by molecules including, but not limited to, glucocorticoids (dexamethasone), CK15 / e kinase inhibitors like PF-670462, HD AC inhibitors, REV-ERB agonists, AMPK activators (metformin), CRY stabilizers, and cAMP activators (forskolin). Understanding circadian rhythms plays a crucial role in understanding human health and optimizing one’s schedule.

[0010] Circadian rhythms also have an influence on a drug’s efficacy and metabolism. It has long been known that the time of day a drug is taken can affect its efficacy and / or toxicity. More generally, a treatment applied to a human patient or another animal might be done at a particular time of day to maximize efficacy and minimize toxicity. A treatment might be the administration of a drug, administration of a nutrient, administration of a supplement, administration of a behavioral modification or behavioral therapy, or administration of another substance, such as orally, intravenously, intramuscularly, cutaneously, or via other pathways. Furthermore, a treatment could be providing an individual with guidance about how to managePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) stress, how to schedule tasks in their day to optimize cognitive performance, or when to exercise, eat, or perform other tasks. A biological treatment might be more than, or instead of, administering a substance. For example, a biological treatment might be the application of kidney dialysis, a surgical procedure, or another medical procedure. The terms “chronomedicine” and “chronomedical” might be used in the literature to refer to considering time of day effects of biological treatments and “chronomodulation” and “chronomodulated” might refer to scheduling the timing of biological treatments based on time of day and the process might be referred to as “chronotherapy.”

[0011] Examples in the literature of chronomedicine and chronomodulation include [Levi2010], which reported on rodent trials wherein more than forty anticancer drugs were shown to have differing toxicities, depending on the time of administration and / or different efficacy profiles over the course of the day. [HrusheskyJ and |Levil990] found that the toxicity of cancer treatments in humans varies by time of day: doxorubicin is best tolerated in the morning, whereas cisplatin show s greater tolerability in the afternoon. [Levi 1997] reported up to a fivefold reduction in grade 3-4 mucositis and half the occurrence of neuropathy when drugs are given in a chronomodulated way. More recently, time-of-day effects for overall treatment efficacy have been reported for temozolomide, a glioblastoma treatment [Damato], and immunotherapy [Qian], with morning dosing shown to be more effective in both cases. While cancer has received the most atention in chronomedical research, it is far from being the only area where chronomodulation has proven effective: morning versus evening effects have also been reported for treatments for conditions such as asthma, diabetes, and hypertension, as well as differences in immune response as in [Wangl] and [Wang2],

[0012] [Sato] describes how7local and systemic metabolic responses to exercise can vary7based on time of day.

[0013] While most work to date has focused on the contributions of circadian period and circadian phase, circadian amplitude is also an important aspect to consider for understanding circadian rhythms. Despite this, the impact of circadian amplitude on chronomedicine and chronotherapy has been under-researched. [Gutu] described a simulated mathematical model of in vitro human cancer cells treated with common chemotherapeutic drugs, which showed that increasing the amplitude of the circadian clock enhanced the maximum range of the time-of-day drug response. [Cui] reported that “circadian activity rhythm energy (CARE),” a measure correlatedPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) with melatonin amplitude, was significantly correlated with reasoning abi 1 i ty, short-term and prospective memory. [Roodbandi] found that shift workers with higher amplitudes had higher rates of sleepiness at work and perceived higher stress on the night shift.

[0014] Circadian amplitude can vary across organ systems. For instance, circadian amplitude can be higher in the suprachiasmatic nucleus, while rhythms in the digestive system can have lower amplitude rhythms.

[0015] Circadian amplitude can also vary between healthy and diseased cells. For instance, healthy cells can have higher amplitudes than cancer cells, and vice versa.

[0016] Interventions, such as light exposure or drug exposure, can alter the amplitude, period, or more broadly, the trajectory7of circadian rhythms at the whole-body level, the organ level, and the cellular level.

[0017] Cunent methods of chronomedicine and chronomodulation are quite limited and improvements are needed.

[0018] VEGFR inhibitors are a family of receptor protein kinases that are used in treating cancers, tumors, and other vascular diseases. VEGF is one of the primary molecules involved in angiogenesis, along with platelet-derived growth factor (PDGF), basic fibroblast growth factors (bFGF), and angiopoietin molecules. The VEGF family consists of VEGF-A, VEGF- B, VEGF-C, and VEGF-D. VEGF-A, VEGF-B, and VEGF-C primarily bind the VEGF receptor VEGF1, which is primarily located on blood vascular endothelial cells. VEGF-A and VEGF-C / D are ligands for VEGFR2, which is expressed on both blood and lymphatic vessels. VEGF-C and VEGF-D bind to the VEGFR3 receptor which is expressed on blood vascular and lymphatic endothelial cells. When VEGF family members bind to VEGFR, this activates downstream signaling pathways. VEGFR inhibitors have been developed to target multiple receptors, which grants these inhibitors higher anticancer activity compared to single-target agents. VEGFR inhibitors are often used alongside chemotherapy and immunotherapies.[Patel], Despite VEGFR inhibitors being used regularly^ in the treatment of numerous types of cancer and solid tumors, they are not without their drawbacks, and can have negative side effects such as vasoconstriction, elevated blood pressure, thromboembolic events, cardiac toxicity, and proteinuria. [Santorsola],

[0019] Without being bound to theory7, the applicant has determined that certain pathological processes involving VEGFRs vary in their activity over a circadian trajectory7, being morePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) active during certain times of day, and less active during others. The methods described herein relate to determining one or more circadian trajectories for a patient and optionally administering an intervention to the patient to modulate the patient’s circadian trajectories; then administering a VEGFR-inhibitor during a determined circadian administration window. References

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[0057] Aspects of the invention relate to methods of treating a vascular endothelial growth factor receptor (VEGFR)-mediated disease in a patient in need thereof, the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; and administering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

[0058] Aspects of the invention address this by administering a VEGFR inhibitor in a manner that aligns the peak serum concentration of the VEGFR inhibitor with a portion of the patient’s circadian cycle such that the VEGFR inhibitor can have maximal effect. Among other things, this can reduce the maximum dose of the VEGFR inhibitor required to achieve a therapeutic effect, thereby reducing unwanted side effects.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0059] According to aspects described herein, a treatment, such as drug administration to a patient, can be simulated to determine probability and / or risk of failure of the treatment, and a modified treatment plan devised, based on timing of treatment administration and circadian trajectories of the patient.

[0060] The circadian trajectory might represent a measure of a circadian phase over time, where a circadian phase indicates where in a circadian rhythm cycle the patient is. The circadian phase at any given time might be based on circadian phases determined at other times. For example, a person with a daily cycle that is long - may be referred to as having a 25-hour intrinsic circadian period in the absence of any other entraining signals - would have a circadian cycle with a measured circadian phase at a time, to, and would be around 4% further along in their circadian trajectory one hour later. A circadian phase might be determined from sensors, measurements, etc. of functioning of the patient. If the patient receives light exposure or other entraining signals, the patient’s circadian phase might move faster or slower relative to wallclock time.

[0061] Without being bound to theory, the applicant has determined that circadian rhythms play an important role in the development and progression of certain diseases. Similarly, circadian rhythms play an important role in the biological processes involved in treating these diseases. Genes which control circadian rhythms, called clock genes, coordinate the expression and regulation of downstream target genes that are responsible for hormone regulation, metabolic processes, body temperature, and DNA repair. [Partch] Clock gene overexpression may lead to an increase in transcriptional activation of pro-angiogenic factors such as VEGF, transforming growth factor beta3 (TGF-(33), and epidermal growth factor (EGF) through the activation of transcription factor HIF-1. Furthermore, certain repair processes and drug metabolism processes may vary according to the circadian phase. It is therefore important to understand and target both disease processes and treatment plans with circadian phases in mind.[Munteanu] .

[0062] Patients might be human beings or non-human animals known to have circadian rhythms.The treatment might comprise administering a drug, such as a VEGFR inhibitor, wherein at least an approximate drug administration time at which the drug is administered is determined.

[0063] A treatment plan might be modified in response to a simulation and a variance in likely effectiveness and / or the failure probability. Modification might include revising anPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) administration time for the administration of the treatment, and applying the treatment to the patient based on a revised treatment plan. Modification might instead, or also, include revising an administration time to be specific to the patient’s circadian rhythms, which can change daily (e.g., instructions to administer the treatment five hours after peak cortisol).

[0064] In some implementations, biomolecule expression and / or concentration in the patient is measured over time and the treatment relates to the biomolecule expression and / or concentration, such as where the treatment is the administration of a drug that dampens effectiveness of a protein or molecule in the body that is produced when the biomolecule is expressed. The expression might be that of a gene, a protein, or some other biomolecule that has some effect in the body of a patient, such as VEGFRs.

[0065] In other implementations, a more general bodily activity is considered instead of, or in addition to, biomolecule expression and / or concentration, such as the activity of some gene, protein, and / or other bodily material.

[0066] Aspects of the invention include methods for treating a VEGFR-mediated disease in a human patient, which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; and administering the dose of a VEGFR inhibitor to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor is selected from the group consisting of: apatinib (rivoceranib), axitinib. brivanib, cediranib, chiauranib, dovitinib, enzastaurin, famitinib, foretinib, fruquintinib, linifanib, lucitanib, motesanib, nintedanib, orantinib, pexidartinib, ponatinib, regorafenib, semaxanib, sitravatinib, surufatinib, telatinib, vadimezan, vatalanib, and vorolanib. In some embodiments, the method further comprises administering an anti-cancer therapy to the patient. In some embodiments, the method further comprises determining a second circadian administration window based on the circadian trajectory assessment and a dose of the anti-cancer therapy to be administered to the patient, and administering the anti-cancer therapy to the patient during the second circadian administration window. In some embodiments, the anti-cancer therapy comprises a chemotherapeutic agent, a radiotherapy, an immunotherapy, or any combination thereof.

[0067] Aspects of the invention include methods for treating a VEGFR-mediated disease in a human patient, which additionally comprises: performing a circadian trajectory assessment onPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; and administering the dose of a VEGFR inhibitor to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor is selected from the group consisting of: a polymorphic cry stalline form of apatinib (rivoceranib), a polymorphic crystalline form of axitinib, a polymorphic crystalline form of brivanib, a polymorphic crystalline form of cediranib. a polymorphic crystalline form of chiauranib, a polymorphic crystalline form of dovitinib, a polymorphic crystalline form of enzastaurin, a polymorphic cry stalline form of famitinib, a polymorphic crystalline form of foretinib, a polymorphic cry stalline form of fruquintinib, a poly morphic cry stalline form of linifanib, a polymorphic crystalline form of lucitanib, a polymorphic crystalline form of motesanib, a polymorphic crystalline form of nintedanib, a polymorphic crystalline form of orantinib, a polymorphic crystalline form of pexidartinib, ponatinib, a polymorphic crystalline form of regorafenib, a polymorphic crystalline form of semaxanib, a polymorphic crystalline form of sitravatinib, a polymorphic crystalline form of surufatinib, a poly morphic crystalline form of telatinib, a polymorphic crystalline form of vadimezan. a polymorphic crystalline form of vatalanib, and a polymorphic crystalline form of vorolanib. In some embodiments, the methods further comprise administering an anti-cancer therapy to the patient. In some embodiments, the methods further comprise determining a second circadian administration window for the VEGFR-mediated disease based on the circadian trajectory assessment and a dose of the anticancer therapy to be administered to the patient, and administering the anti-cancer therapy to the patient during the second circadian administration window. In some embodiments, the anticancer therapy comprises a chemotherapeutic agent, a radiotherapy, an immunotherapy, or any combination thereof.

[0068] In some embodiments, the VEGFR-mediated disease is cancer, retinopathy, or preeclampsia. In some embodiments, the disease is cancer, and the cancer was initially sensitive to a KIT tyrosine kinase inhibitor and acquired resistance to the KIT ty rosine kinase inhibitor. In some embodiments, the cancer has acquired resistance to one of the following KIT inhibitors: imatinib mesylate, salts of imatinib mesylate; PPl(4-Amino-5-(4-methylphenyl)-7- (t-butyl)pyrazolo[3,4-d]pyrimidine); MLN518 (CT53518); PD180970; SU112481 SU5416; SU5414; SU6597; SU6663 or SU6561. In some embodiments, the cancer is one or more of aPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) malignant gastrointestinal stromal tumor (GIST), a benign gastrointestinal stromal tumor (GIST), a mesenchymal tumor of the intestinal tract, chronic myelogenous leukemia (CML), a mast cell tumor, SCLC, a germ cell tumor, breast cancer, and / or neuroblastoma.

[0069] In some embodiments, the cancer has acquired resistance to imatinib mesylate. In some embodiments, the acquired resistance of the cancer is associated with a secondary mutation in a KIT gene mutated in a primary tumor. In some embodiments, the secondary' mutation is in a kinase catalytic domain of the KIT gene. In some embodiments, the secondary’ mutation is in Exon 13, 14, and / or 17. In some embodiments, the secondary mutation is at residues 654, 670, 716, 816, 820, 822, and 823. In some embodiments, the secondary' mutation is at residues 650- 654. In some embodiments, the secondary' mutation is at residues 670-674. In some embodiments, the secondary mutation is at residues 816-824. In some embodiments, the secondary mutation is one or more of V654A (Exon 13), T670I (Exon 14), T670E, D716N, S709F (Exon 14), D816G, D816E (Exon 17), D820E, D820Y, D820GN822K, Y823D (Exon 17), or deletions and other amino acid substitutions at such positions or adjacent positions.

[0070] In some embodiments, the secondary mutation is one or more of: i) deletion of amino acid residues 557-558; ii) deletion of amino acid residues 551-555; iii) deletion of amino acid residues 550-558; iv) deletion of amino acid residues 559-560; v) deletion of amino acid residues 557-561; vi) deletion of amino acid residues 554-558; vii) deletion of amino acid residues 552-557; viii) mutations at residue 559. including V559D, V559A, or V559G; ix) mutations at residue 560. including V560D, V560E, or V560G; x) W557S, alone, or in combination with a deletion of amino acids 552-556; xi) mutations at amino acid residue 557, including W557R; and xii) mutations at amino acid residue 576, including L576P. In some embodiments, the secondary mutation is deletion of residues 557-558 and at least one of the following mutations: V654A, T670I, D820Y, N822K, or Y823D.

[0071] Aspects of the invention include methods of treating a VEGFR-mediated cancer in a patient in need thereof, the cancer having a primary and / or secondary KIT gene mutation in the primary' tumor, the methods comprising: performing a circadian traj ectory assessment on the patient: determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory’ assessment and a dose of regorafenib to be administered to the patient; and administering the dose of regorafenib to the patient during the circadian administration window.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0072] Aspects of the invention include methods of treating a VEGFR-mediated cancer in a patient in need thereof, the cancer having a primary and / or secondary KIT gene mutation in the primary tumor, the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of a cry stalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

[0073] In some embodiments, the primary and / or secondary KIT gene mutation in the primary tumor is associated with acquired resistance of the cancer to KIT tyrosine kinase inhibitors. In some embodiments, the secondary mutation is in a kinase catalytic domain of a KIT gene. In some embodiments, the secondary mutation is in Exon 13, 14, and / or 17. In some embodiments, the secondary mutation is at residues 654, 670, 716, 816, 820, 822, and 823. In some embodiments, the secondary mutation is at residues 650-654. In some embodiments, the secondary mutation is at residues 670-674. In some embodiments, the secondary mutation is at residues 816-824. In some embodiments, the secondary mutation is one or more of V654A (Exon 13). T670I (Exon 14), T670E, D716N, S709F (Exon 14). D816G, D816E (Exon 17), D820E, D820Y, D820G N822K, Y823D (Exon 17), or deletions and other amino acid substitutions at such positions or adjacent positions.

[0074] In some embodiments, the secondary mutation is one or more of: i) deletion of amino acid residues 557-558; ii) deletion of amino acid residues 551-555; iii) deletion of amino acid residues 550-558; iv) deletion of amino acid residues 559-560; v) deletion of amino acid residues 557-561; vi) deletion of amino acid residues 554-558; vii) deletion of amino acid residues 552-557; viii) mutations at residue 559, including V559D, V559A, or V559G; ix) mutations at residue 560. including V560D, V560E, or V560G; x) W557S, alone, or in combination with a deletion of amino acids 552-556; xi) mutations at amino acid residue 557, including W557R; and xii) mutations at amino acid residue 576, including L576P. In some embodiments, the secondary' mutation is deletion of residues 557-558 and at least one of the following mutations: V654A, T670I, D820Y, N822K, or Y823D.

[0075] Aspects of the invention include methods of treating a VEGFR-mediated cancer in a patient in need thereof, the cancer having a primary and / or secondary KIT gene mutation associated with resistance or acquired resistance to imatinib mesylate or salts of imatinibPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) mesylate, the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; and administering the dose of regorafenib to the patient during the circadian administration window.

[0076] Aspects of the invention include methods of treating a VEGFR-mediated cancer in a patient in need thereof, the cancer having a primary and / or secondary KIT gene mutation associated with resistance or acquired resistance to imatinib mesylate or salts of imatinib mesylate, the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

[0077] Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient with imatinib mesylate or salts of imatinib mesylate, which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; and administering the dose of regorafenib to the patient during the circadian administration window.

[0078] Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient with imatinib mesylate or salts of imatinib mesylate, which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

[0079] Aspects of the invention include methods of treating a VEGFR-mediated cancer in a patient who has acquired resistance to imatinib, the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose ofPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) regorafenib to be delivered to the patient; and administering the dose of regorafenib to the patient during the circadian administration window.

[0080] Aspects of the invention include methods of treating a VEGFR-mediated cancer in a patient who has acquired resistance to imatinib, the methods comprising: performing a circadian trajectory' assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian traj ectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

[0081] Aspects of the invention include methods of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST) in a patient who has been treated with imatinib, salts of imatinib mesylate, PPl(4-Amino-5-(4-methylphenyl)-7-(t- butyl)pyrazolo[3,4-d]pyrimidine); MLN518 (CT53518); PD180970; SU112481; SU5416; SU5414; SU6597; SU6663 or SU6561, the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; and administering the dose of regorafenib to the patient during the circadian administration window.

[0082] Aspects of the invention include methods of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST) in a patient who has been treated with imatinib, salts of imatinib mesylate, PPl(4-Amino-5-(4-methylphenyl)-7-(t- butyl)pyrazolo[3,4-d]pyrimidine); MLN518 (CT53518); PD180970; SU112481; SU5416; SU5414; SU6597; SU6663 or SU6561, the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

[0083] Aspects of the invention include methods of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST) in a patient who has been treated with imatinib, the methods comprising: performing a circadian trajectory assessmentPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) on the patient; determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; and administering the dose of regorafenib to the patient during the circadian administration window.

[0084] Aspects of the invention include methods of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST) in a patient who has been treated with imatinib, the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

[0085] Aspects of the invention include methods of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST), the methods comprising: performing a circadian trajectory7assessment on the patient; determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; and administering the dose of regorafenib to the patient during the circadian administration window.

[0086] Aspects of the invention include methods of treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST), the methods comprising: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

[0087] In some embodiments, the patient has not been treated with imatinib. In some embodiments, the patient has not acquired resistance to a cKit inhibitor. In some embodiments, performing the circadian trajectory assessment on the patient and determining the circadian administration window comprises performing a computer-implemented method under the control of one or more computer systems configured with executable instructions for: estimating a circadian trajectory7of the patient using, at least in part, a set of patient inputs; determining one or more circadian-mapping profiles; determining, from the circadian trajectoryPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) and the one or more circadian-mapping profiles, and the dose of regorafenib or the crystalline polymorphic form of regorafenib to be administered to the patient, the circadian administration window; and alerting the patient that the circadian administration window is occurring or is to occur.

[0088] In some embodiments, the VEGFR-mediated disease is refractory metastatic colorectal cancer. Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient who has received previous fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and an anti-VEGF therapy, which additionally comprises: performing a circadian trajectory' assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of fruquintinib; and administering the dose of fruquintinib to the patient during the circadian administration window. In some embodiments, the anti-VEGF therapy is bevacizumab, aflibercept, or ramucirumab. In some embodiments, the anti-EGFR therapy is cetuximab or panitumumab. In some embodiments, fruquintinib comprises a cry stalline polymorphic form of fruquintinib.

[0089] In some embodiments, the VEGFR-mediated disease is RAS wild-type refractory metastatic colorectal cancer. Aspects of the invention include methods for treating a VEGFR- mediated cancer in a human patient who has received previous fluoropyrimidine-, oxaliplatin- , and irinotecan-based chemotherapy, an anti-VEGF therapy, and anti-EGFR therapy, which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of fruquintinib; and administering the dose of fruquintinib to the patient during the circadian administration window. In some embodiments, the anti-VEGF therapy is bevacizumab. aflibercept, or ramucirumab. In some embodiments, the anti-EGFR therapy is cetuximab or panitumumab. In some embodiments, fruquintinib comprises a crystalline polymorphic form of fruquintinib.

[0090] In some embodiments, the VEGFR-mediated disease is advanced gastric cancer. Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient, which additionally comprises: performing a circadian trajectory’ assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of apatinib (rivoceranib) plus camrelizumab; andPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) administering the dose of apatinib (rivoceranib) plus camrelizumab to the patient during the circadian administration window. In some embodiments, the method further comprises administering paclitaxel to the patient. In some embodiments, apatinib comprises a crystalline polymorphic form of apatinib.

[0091] In some embodiments, the VEGFR-mediated disease is ovarian cancer. Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient, which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of apatinib (rivoceranib) plus camrelizumab; and administering the dose of apatinib (rivoceranib) plus camrelizumab to the patient during the circadian administration window. In some embodiments, the method further comprises administering fluzoparib to the patient. In some embodiments, apatinib comprises a crystalline polymorphic form of apatinib.

[0092] In some embodiments, the VEGFR-mediated disease is unresectable hepatocellular carcinoma. Aspects of the invention include methods for treating a VEGFR-mediated cancer in ahuman patient, which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of apatinib (rivoceranib) plus camrelizumab; and administering the dose of apatinib (rivoceranib) plus camrelizumab to the patient during the circadian administration window. In some embodiments, apatinib comprises a crystalline polymorphic form of apatinib.

[0093] In some embodiments, the VEGFR-mediated disease is advanced renal cell carcinoma.Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient who has previously failed tyrosine kinase inhibitor treatment, which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of vorolanib; and administering the dose of vorolanib to the patient during the circadian administration window. In some embodiments, the method further comprises administering a dose of vorolanib with everolimus. In some embodiments, vorolanib comprises a crystalline polymorphic form of vorolanib.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0094] In some embodiments, the VEGFR-mediated disease is advanced renal cell carcinoma.Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient who has previously failed tyrosine kinase inhibitor treatment, which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of vorolanib plus everolimus; and administering the dose of vorolanib plus everolimus to the patient during the circadian administration window. In some embodiments, vorolanib comprises a cry stalline polymorphic form of vorolanib.

[0095] In some embodiments, the VEGFR-mediated disease is advanced pancreatic neuroendocrine tumors. Aspects of the invention include methods for treating a VEGFR- mediated cancer in a human patient which additionally comprises: performing a circadian trajectory- assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of surufatinib; and administering the dose of surufatinib to the patient during the circadian administration window. In some embodiments, surufatinib comprises a crystalline polymorphic form of surufatinib.

[0096] In some embodiments, the VEGFR-mediated disease is late-stage, well-differentiated extrapancreatic neuroendocrine tumors. Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient which additionally comprises: performing a circadian trajectory- assessment on the patient; determining a circadian administration window for the VEGFR-mediated disease based on the circadian trajectory- assessment and a dose of surufatinib; and administering the dose of surufatinib to the patient during the circadian administration window. In some embodiments, surufatinib comprises a crystalline polymorphic form of surufatinib.

[0097] In some embodiments, the VEGFR-mediated disease is Philadelphia chromosomepositive acute lymphoblastic leukemia. Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient which additionally comprises: performing a circadian trajectory- assessment on the patient; determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of ponatinib; and administering the dose of ponatinib to the patient during the circadian administration window. In some embodiments, the method further comprises aPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) chemotherapeutic agent. In some embodiments, the method further comprises administering the chemotherapeutic agent during the circadian administration window. In some embodiments, the method further comprises determining a second circadian administration win ow for the Philadelphia chromosome-positive acute lymphoblastic leukemia based on the circadian trajectory assessment and a dose of the chemotherapeutic agent to be administered to the patient, and administering the chemotherapeutic agent to the patient during the second circadian administration window. In some embodiments, ponatinib comprises a crystalline polymorphic form of ponatinib.

[0098] In some embodiments, the VEGFR-mediated disease is advanced renal cell carcinoma. In some embodiments, the VEGFR-mediated disease is advanced renal cell carcinoma, in a patient who has failed one prior systemic therapy. Aspects of the invention include methods for treating a VEGFR-mediated cancer in a human patient which additionally comprises: performing a circadian trajectory assessment on the patient; determining a circadian administration window^ for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of axitinib; and administering the dose of axitinib to the patient during the circadian administration window. In some embodiments, axitinib is N-methyl-2-[3-((E)-2- pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering a combination therapy which comprises an antagonist of a Programmed Death 1 protein (PD-1) inhibitor. In some embodiments, the PD-1 agonist is a PD-1 monoclonal antibody. In some embodiments, the method further comprises administering pembrolizumab to the patient. In some embodiments, axitinib comprises a crystalline polymorphic form of axitinib.

[0099] In some embodiments, the VEGFR-mediated disease is an interstitial lung disease. In some embodiments, the interstitial lung disease is chronic fibrosing interstitial lung disease with a progressive phenotype. In some embodiments, the interstitial lung disease is systemic sclerosis. In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis. Aspects of the invention include methods for treating a VEGFR-mediated disease in a human patient which additionally comprises: performing a circadian trajectory assessment on the patient: determining a circadian administration window for the VEGFR-mediated disease based on the circadian trajectory assessment and a dose of nintedanib; and administering thePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) dose of nintedanib to the patient during the circadian administration window. In some embodiments, nintedanib comprises a crystalline polymorphic form of nintedanib.

[0100] In some embodiments, the VEGFR-mediated disease that is treated is: Accelerated Phase Chronic Myelogenous Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Lymphocytic Leukemia; Acute Monoblastic and Acute; Monocytic Leukemia; Acute Myelogenous Leukemia; Acute Myeloid Leukemia; Adenocarcinoma of the Prostate; Adenoid Cystic Carcinoma of the Head and Neck; Advanced Gastrointestinal Stromal Tumor; Agnogenic Myeloid; Metaplasia; Anaplastic Oligodendroglioma; Astrocytoma; B-Cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Bone Metastases; Brain Tumor; Breast Cancer; Cancer; Central Nervous System Cancer; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Central Nervous System Germ Cell Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Soft Tissue Sarcoma; Chordoma; Chronic Eosinophilic Leukemia (CEL); Chronic Idiopathic Myelofibrosis; Chronic Myelogenous Leukemia; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Colon Cancer; Colorectal Cancer; Dermatofibrosarcoma; Dermatofibrosarcoma Protuberans (DFSP); Desmoid Tumor; Eosinophilia; Epidemic Kaposi's Sarcoma; Essential Thrombocythemia; Ewing's Family of Tumors; Extensive Stage Small Cell Lung Cancer; Fallopian Tube Cancer; Familiar Hypereosinophilia; Fibrosarcoma; Gastric Adenocarcinoma; Gastrointestinal Neoplasm; Gastrointestinal Stromal Tumor; Glioblastoma; Glioma; Gliosarcoma; Grade I Meningioma; Grade II Meningioma; Grade III Meningioma; Hematopoietic and Lymphoid Cancer; High-Grade Childhood Cerebral Astrocytoma; Hypereosinophilic Syndrome; Idiopathic Pulmonary Fibrosis; LI Adult Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; Leukemia, Lymphocytic, Acute L2; Leukemia, Myeloid, Chronic; Leukemia, Myeloid, Chronic Phase; Liver Dysfunction and Neoplasm; Lung Disease; Lymphoid Blastic Phase of Chronic Myeloid Leukemia; Male Breast Cancer; Malignant Fibrous Histiocytoma; Mastocytosis: Meningeal Hemangiopericytoma; Meningioma; Meningioma; Meningioma; Metastatic Cancer; Metastatic Solid Tumors; Myelofibrosis; Myeloid Leukemia, Chronic; Myeloid Leukemia, Chronic Accelerated-Phase; Myeloid Leukemia, Chronic, Chronic-Phase; Myeloid Metaplasia; Myeloproliferative Disorder (MPD)PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) with Eosinophilia; Neuroblastoma; Non-T, Non-B Childhood Acute Lymphoblastic Leukemia; Oligodendroglioma; Osteosarcoma; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Ovarian Neoplasms; Pancreatic Cancer; Pelvic Neoplasms; Peritoneal Cavity Cancer; Peritoneal Neoplasms; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Philadelphia Positive Acute Lymphoblastic Leukemia; Philadelphia Positive Chronic Myeloid Leukemia in Myeloid Blast Crisis; Polycythemia Vera; Pulmonary Fibrosis; Recurrent Adult Brain Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Breast Cancer; Recurrent Colon Cancer; Recunent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Glioblastoma Multiforme (GBM); Recurrent Kaposi's Sarcoma; Recurrent Melanoma; Recurrent Merkel Cell Carcinoma; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Tumors of the Ewing's Family; Recurrent Uterine Sarcoma; Relapsing Chronic Myelogenous Leukemia; Rheumatoid Arthritis; Salivary Gland Adenoid Cystic Carcinoma; Sarcoma; Small Cell Lung Cancer; Stage II Melanoma; Stage II Merkel Cell Carcinoma; Stage III Adult Soft Tissue Sarcoma; Stage III Esophageal Cancer; Stage III Merkel Cell Carcinoma; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Salivary Gland Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage W Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Melanoma; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer; Systemic Mastocytosis; T-Cell Childhood Acute Lymphoblastic Leukemia; Tenosynovial Giant Cell Tumor, Testicular Cancer; Thyroid Cancer; Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumor (GIST); Unspecified Adult Solid Tumor; Untreated Childhood Brain Stem Glioma; Uterine Carcinosarcoma, and Uterine Sarcoma.

[0101] In some embodiments, a duration of the circadian administration window varies according to an uncertainty measure of the circadian traj ectory. with the length being longer when the uncertainty measure is higher and the length being shorter when the uncertainty measure is lower. In some embodiments, the circadian administration window has a duration that ranges from 30 minutes to 12 hours, such as 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours,PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, or 12 hours. In some embodiments, the circadian administration window has a duration that ranges from 4-8 hours, such as 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6.5 hours, 7 hours, 7.5 hours, or 8 hours. In some embodiments, the set of patient inputs comprises data derived from signals received of a patient from wearing a wearable data system. In some embodiments, the circadian trajectory is derived by a scheduler using at least one biophysics model of a human circadian clock and at least one statistical model of the human circadian clock. In some embodiments, the circadian administration window is optimized based on associating a circadian time with a time for taking regorafenib or a cry stal I ine polymorphic form of regorafenib for generating a raw model output.

[0102] Aspects of the invention include non-transitory computer-readable storage media storing instructions, which when executed by at least one processor of a computer system, causes the computer system to carry out one or more of the methods described herein.

[0103] Aspects of the invention include computer systems comprising: one or more processors;and a storage medium storing instructions, which when executed by the at least one processor, cause the system to implement one or more of the methods described herein.

[0104] These and further aspects will be further explained in the rest of the disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Various embodiments in accordance with the present disclosure will be described with reference to the drawings, in which:

[0106] FIG. 1 is an illustration of a biological trajectory.

[0107] FIG. 2 is an illustration of a circadian trajectory.

[0108] FIG. 3 is an illustration of a circadian trajectory’ and interaction with drug concentration .

[0109] FIG. 4 is an illustration of a circadian trajectory' bundle.

[0110] FIG. 5 illustrates a set of trajectories for clock gene expression given a light exposure history’. FIG. 5 comprises FIGS. 5A-5H.[OHl] FIG. 6 illustrates trajectory bundles, one for light histories, such as those shown in FIG. 5, and one for clock gene expression circadian trajectories, such as those shown in FIG. 5.

[0112] FIG. 7 illustrates an example of a trajectory having some uncertainty’ built in.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0113] FIG. 8 illustrates an example circadian-mapping profile, an efficacy profile, that maps between circadian states to efficacy of a drug.

[0114] FIG. 9 illustrates another example circadian-mapping profile, a toxicity profile, that maps between circadian states to toxicity of a drug.

[0115] FIG. 10 illustrates tailoring the dose of a drug based on the amplitude of the drug target;FIG. 10 comprises FIGS. 10A-10F.

[0116] FIG. 11 is a diagram of a patient treatment system, according to various embodiments.

[0117] FIG. 12 is a diagram of a treatment assignment and coordination system, according to various embodiments.

[0118] FIG. 13 is a diagram of a treatment scheduling feedback system, according to various embodiments.

[0119] FIG. 14 illustrates components that might be used in a control system to change environmental cues and behavioral triggers in response a fixed treatment time and user data, according to various embodiments.

[0120] FIG. 15 illustrates components that might be used for a digital twin simulation, according to various embodiments.

[0121] FIG. 16 illustrates components that might be used for a profile identification system, according to various embodiments.

[0122] FIG. 17 illustrates components that might be used for a treatment mapping module, according to various embodiments.

[0123] FIG. 18 illustrates components that might be used for a treatment system module, according to various embodiments.

[0124] FIG. 19 illustrates components that might be used for a control system, according to various embodiments.

[0125] FIG. 20 illustrates components that might be used for a treatment assignment and coordination system, according to various embodiments.

[0126] FIG. 21 illustrates examples of a trajectory’ uncertainty and differences, according to various embodiments; FIG. 21 comprises FIGS. 21A and 21B.

[0127] FIG. 22 illustrates an example computer system memory structure as might be used in performing methods described herein, according to various embodiments.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0128] FIG. 23 is a block diagram illustrating an example computer system upon which the systems illustrated in FIGS. 1 and 22 may be implemented, according to various embodiments.

[0129] FIG. 24 shows circadian gene expression of genes involved in angiogenesis. FIG. 24 comprises FIG. 24A, 24B, and 24C.

[0130] FIG. 25 shows an example of administering a VEGFR inhibitor in the preferred circadian administration window versus at standard time for the treatment of glioblastoma. FIG. 25 comprises FIG. 25A. 25B, and 25C, which show comparative data for tumor volume.

[0131] FIG. 26 shows an example of administering a VEGFR inhibitor in the preferred circadian administration window versus at a standard time for the treatment of non-small cell lung cancer. FIG. 26 comprises FIG. 26A, which shows reduced tumor grow th, and FIG. 26B, which show s reduced mortalit .DETAILED DESCRIPTION

[0132] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmaceutical formulation and administration of therapeutic agents.

[0133] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, betw een the upper and low er limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0134] In the following description, numerous specific details are set forth to provide a more thorough understanding of the present invention. However, it will be apparent to one of skill in the art that the present invention may be practiced without one or more of these specific details. In other instances, well-known features and procedures well known to those skilled in the art have not been described in order to avoid obscuring the invention.

[0135] All references cited throughout the disclosure, including patent applications and publications, are incorporated by reference herein in their entirety.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)Definitions

[0136] By "comprising” it is meant that the recited elements are required in the composition / method / kit, but other elements may be included to form the composition / method / kit etc. within the scope of the claim.

[0137] By “consisting essentially of’, it is meant a limitation of the scope of composition or method described to the specified materials or steps that do not materially affect the basic and novel characteristic(s) of the subject invention.

[0138] By “consisting of’, it is meant the exclusion from the composition, method, or kit of any element, step, or ingredient not specified in the claim.

[0139] The terms “treatment”, “treating” and the like are used herein to generally mean obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment” as used herein covers any treatment of a disease in a mammal and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; or (c) relieving the disease, i.e., causing regression of the disease. The therapeutic agent may be administered before, during or after the onset of disease or injury. The treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest. Such treatment is desirably performed prior to complete loss of function in the affected tissues. The subject therapy may be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease.

[0140] A “therapeutically effective amount” is intended for an amount of active agent which is necessary to impart therapeutic benefit to a subject. For example, a “therapeutically effective amount” is an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with a disease or which improves resistance to a disorder.

[0141] The terms “subject,” “individual.” and “patient” are used interchangeably herein to refer to a mammal being assessed for treatment and / or being treated. In an embodiment, the mammalPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) is a human. Subjects may be human, but also include other mammals, particularly those mammals useful as laboratory models for human disease, e.g., mouse, rat, etc.

[0142] The term ‘‘pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile. “Pharmaceutically acceptable” excipients (vehicles, additives) are those which can reasonably be administered to a subject to provide an effective dose of the active ingredient employed.

[0143] A “sterile” formulation is aseptic or free or essentially free from all living microorganisms and their spores. A “frozen” formulation is one at a temperature below 0 °C.

[0144] A “stable” formulation is one in which the protein therein essentially retains its physical stability and / or chemical stability and / or biological activity upon storage. Preferably, the formulation essentially retains its physical and chemical stability’, as well as its biological activity' upon storage. The storage period is generally selected based on the intended shelf-life of the formulation. Various analytical techniques for measuring protein stability are available in the art and are reviewed in [Dekker], for example. Stability can be measured at a selected temperature for a selected time period. Stability can be evaluated qualitatively and / or quantitatively in a variety7of different ways.

[0145] The term “VEGFR-mediated disease” broadly refers to any disease or disorder in which VEGFR is associated with or involved in the pathological processes that are characteristic of the disease or disorder. Such disorders include, but are not limited to cancers, tumors, autoimmune diseases, cardiovascular diseases, and neurovascular diseases.

[0146] Without being bound to theory', the applicant has determined that certain pathological processes involving VEGFRs vary in their activity’ over a circadian trajectory, being more active during certain circadian time periods, and less active during others. As such, treatment protocols in accordance with the methods described herein involve timing the administration of a therapeutic agent to coincide with the correct portion of the circadian cycle, during a given day. In the case of treatments geared toward reducing the activity' of VEGFRs, a treatment is administered such that the peak effect of the therapeutic intervention coincides with the portion of the circadian cycle when the VEGFR activity is highest. This means timing the administration of the therapeutic agent so that its maximum concentration in the patient’sPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) system coincides with the portion of the circadian cycle when VEGFR activity is highest. For example, in drugs with short half-lives that pass through a patient's system quickly, this means timing the administration of the drug so that its presence in the patient’s system coincides with the portion of the circadian cycle during which the VEGFR activity is highest.Circadian Trajectory Assessment and Circadian Administration Window7Determination

[0147] Systems and methods for performing a circadian trajectory assessment on a patient are known in the art and include, for example, those described in U.S. Patent Application Publication No. 2024 / 0153607; U.S. Patent Application Publication No. 2025 / 0037878; and U.S. Patent Application No. 63 / 889,072, the disclosure of which is incorporated by reference herein in its entirety7.

[0148] As used herein, a circadian trajectory assessment consists of estimating one or more circadian trajectories of the patient using, at least in part, a set of patient inputs; determining one or more circadian-mapping profiles; based on the circadian trajectories and the one or more circadian-mapping profiles determining a preferred circadian administration window7for the patient; and administering a treatment to the patient during the circadian administration window. In some embodiments, a circadian trajectory of the patient may be modified before the treatment is administered. In some embodiments, a circadian rhythm of a patient may be modified with a circadian rhythm modulating protocol, including, but not limited to: behavioral therapy, light therapy, pharmacological protocols, sleep schedule modifications, or dietary modifications.

[0149] In some embodiments, the methods described herein involve performing a circadian trajectory7assessment on a patient and determining a circadian administration window for treatment of a VEGFR-mediated disease, where the circadian administration window7is determined based on the circadian trajectory assessment and a dose of a drug to be administered to the patient. In some embodiments, the drug is apatinib (rivoceranib), axitinib, brivanib, cediranib, chiauranib, dovitinib, enzastaurin, famitinib, foretinib, fruquintinib, linifanib, lucitanib, motesanib, nintedanib, orantinib, pexidartinib, ponatinib, regorafenib, semaxanib, sitravatinib, surufatinib, telatinib, vadimezan, vatalanib, or vorolanib. In some embodiments, the drug is a crystalline polymorphic form of apatinib (rivoceranib), axitinib, brivanib, cediranib, chiauranib, dovitinib, enzastaurin, famitinib, foretinib, fruquintinib, linifanib, lucitanib, motesanib, nintedanib, orantinib, pexidartinib, ponatinib, regorafenib, semaxanib,PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) sitravatinib, surufatinib, telatinib, vadimezan, vatalanib, or vorolanib. In the following description, various embodiments will be described. For purposes of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the embodiments. However, it will also be apparent to one skilled in the art that the embodiments may be practiced without the specific details. Furthermore, well-known features may be omited or simplified in order not to obscure the embodiment being described.

[0150] A circadian trajectory assessment may consist of estimating a circadian trajectory of the patient using, at least in part, a set of patient inputs; determining circadian-mapping profiles; and determining a circadian administration window for one or more drugs or interventions. In a patient treatment system, various inputs are obtained, such as wearable device data from a wearable device worn by a patient, other sensor data from the patient, calendar data from a calendar program of the patient, location, travel, environmental, etc. inputs. From some or all of those inputs, as explained herein, and possibly also from precomputed machine-learning models and stored data that is not necessarily specific to that patient, a circadian trajectory that maps between wall-clock time and a circadian state (containing at least phase and amplitude) is determined. As used herein, the circadian trajectory refers to at least a circadian phase, a circadian amplitude, a circadian period, and a MESOR, and as such, a circadian trajectory might correspond to changes of a circadian state over time with the circadian state having a value at a point in time. The circadian trajectory might have varying degrees of uncertainty from patient to patient and / or from time to time for a given patient, such as when fewer inputs are available, inputs are inconsistent, and / or for other reasons. For example, the stability of the amplitude may be considered. An amplitude’s stability might be based on how high a “peak” or “trough” is in relation to previous measurements from the same patient. If a patient’s amplitude is very unstable, this might introduce more uncertainty. Amplitude can also be used as a point of comparison to other patients. Individuals with a high amplitude will show very clear differences between their day and night states, whereas individuals with a low amplitude will show weaker fluctuations with less-pronounced differences between the peak and trough values. Individuals with high amplitude may have more to gain from chronomedicine at the correct timing, and more to lose from chronomedicine at the incorrect timing. Individuals with low' amplitude may have little to gain from chronomedicine approaches, as all times for dosing may be essentially equally effective and / or toxic.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0151] In some embodiments, a patient’s circadian state might be characterized by unusually high or low amplitudes. If a patient’s circadian states are characterized by high amplitudes, and are thus associated with increased sleepiness during shift or night work, the patient treatment system might indicate a treatment to the patient, perhaps on a wearable device, and perhaps some time in advance, to provide guidance to the patient on when to sleep before beginning a shift work schedule to prevent this sleepiness. In some embodiments, the guidance provided to a patient only modifies the patient’s amplitude.

[0152] In some embodiments, a patient treatment system can determine, from the circadian trajectory, and circadian-mapping profiles for a given treatment, what wall-clock time, times, and / or time ranges, to administer a treatment, and how a treatment should be administered to modulate circadian amplitude. In some embodiments, the methods comprise determining the circadian trajectory of the patient prior to administering a treatment. In some embodiments, the methods comprise modifying the circadian trajectory of the patient prior to administering a treatment. In some embodiments, the methods comprise administering a circadian rhythm modulating protocol to the patient.

[0153] A highly accurate measurement of a circadian state of a patient at a given point in time can be obtained with great inconvenience to the patient and a considerable delay in processing. For example, multiple saliva samples can be taken while the patient resides in a dark room for many hours but that is typically impractical and the circadian states and the circadian trajectory of the patient over those hours might only be known after lab results are complete, perhaps days later and therefore of limited use. Using the methods and apparatus described herein, a good estimate of a patient’s circadian trajectory can be obtained in near real-time with minimal effort and inconvenience to the patient. In some instances, the methods and apparatus described herein might not be able to determine the circadian state with great accuracy at some times (such as when the patient is involved in travel or irregular activities) while being able to be more accurate at other times.

[0154] In some embodiments, the circadian trajectory is modified prior to treatment with a circadian rhythm modulating protocol, intended to adjust circadian-relevant behaviors toward a target-constrained time. A circadian rhythm modulating protocol may comprise one or more of a behavioral therapy, a light therapy, a pharmaceutical protocol, a sleep schedule modification, or a dietary modification. In some embodiments, the circadian trajectory isPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) modified by one or more of: increasing or decreasing the circadian amplitude, shifting, or maintaining the circadian phase, and increasing or decreasing the MESOR. A non-exhaustive list of treatments includes an IV infusion, an injection, an orally administered drug, or a surgery, wherein a circadian rhythm modulating protocol is administered to a patient to adjust circadian-relevant behaviors toward a target-constrained time prior to the treatment. In some embodiments, the treatment may impact angiogenesis, including but not limited to VEGFR inhibitors.

[0155] In some embodiments, the time, or time ranges, for administering a treatment or signaling for the administration to occur, might be determined based on circadian-mapping profiles that indicate, for example, what circadian states relate to high efficacy and / or low toxicity. In a specific example, if a patient’s circadian state’s phase at a snapshot in time is represented in memory by a value between 0.0 and 1.0 and the patient treatment system determines that efficacy for a drug D is highest at a phase value of 0=0.4 and toxicity of drug D is lowest at that phase value as well, and further that the patient treatment system determines that 0=0.4 corresponds to a best time of 10 AM with an uncertainty of three minutes, the patient treatment system might send guidance to the patient, perhaps on a wearable device and perhaps some time in advance, to the effect of "Please take your pill D sometime between 9:57 and 10:30 AM for best results.”

[0156] In another example, a best time may depend on both the phase and amplitude of the circadian state. For instance, the best time may occur at 0=0.4 for an amplitude R = 1.0 and at 0=0.6 for amplitude R = 0.5. If this is the case, and the patient treatment system determines that 0=0.4 corresponds to 10 AM with an uncertainty of three minutes and that 0=0.6 corresponds to 2 PM with an uncertainty of three minutes, the patient treatment system might send guidance to the patient, perhaps on a wearable device and perhaps some time in advance, to the effect of "Please take your pill D sometime between 9:57 and 10:03 AM for best results” if the patient has an amplitude R = 1.0, while sending “Please take your pill D sometime between 1 :57 and 2:30 PM for best results” to a patient with amplitude R = 0.5.

[0157] In another example, the patient’s amplitude could change the uncertainty window. For instance, a patient with low amplitude might see a wider window (“Please take your pill D sometime between 11:00 AM and 5:00 PM for best results”) than a patient with higherPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) circadian amplitude R = 1.0 (“Please take your pill D sometime between 1:57 and 2:30 PM for best results”).

[0158] In another example, the patient could be guided to increase the amplitude of their rhythms to make a drug more effective at the time being dosed. A patient treatment system might send a message to the patient, perhaps on a wearable device, and perhaps some time in advance, to provide guidance on when to eat, seek light, and be active, in order to increase the amplitude of their circadian rhythms.

[0159] In another example, the patient could be guided to decrease the amplitude of their rhythms.This could result in greater minimum value over the 24-hour day, as a low amplitude rhythm may not dip as much as a high amplitude rhythm, and dips may be highly undesirable. As an example, a lower circadian amplitude could prevent an immune response from dropping below a baseline value, allowing greater protection against external threats to the body. A patient treatment system might send a message to the patient, perhaps on a wearable device, and perhaps some time in advance, to provide guidance on when to eat, seek light, and be active, in order to decrease the amplitude of their circadian rhythms.

[0160] Other scales are possible for circadian state, such as circadian state being considered like a circular phase and continuously varying from 0 through to 2*TT (units of radians), which the patient treatment system could consider to be the same as 0. A circadian traj ectory can represent past circadian state changes as a function of wall-clock time and / or anticipated or predicted future circadian state changes as a function of wall-clock time. Wall-clock time could be represented by a clock circuit, a computer circuit that keeps time, and / or a computer element that receives signals representing a time measured independent of bodily activity or details such as a local time, which might have vary ing resolutions, such as from {morning, daytime, noon, afternoon, evening, late night}, to HH o'clock, to HH:MM on day DD, to HH:MM:SS on day DD of month M in year Y.

[0161] Wall-clock time can be represented in anumber of ways, such as a stored value of between 0.0 and 1.0 representing a time of day, perhaps in resolutions of seconds or some other interval, a stored value of between 0:00 and 23:59:59 representing a time of day, an epoch time, such as a number of elapsed seconds since some specified time and date. Epoch time may’ be a Unix measurement for the number of seconds that have elapsed since January 1, 1970, at midnight UTC minus leap seconds. As an example of epoch time, a stored time value, t, wherePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 1=1642724939 might represent a wall-clock time of 12:28:59 AM UTC on January 21, 2022. In some embodiments, time may be represented as Zeitgeber Time (ZT), which is a standardized 24-hour notation of the phase in a circadian cycle, where ZTO indicates the beginning of day or light phase, and ZT12 indicates the beginning of night, or dark phase.

[0162] In some instances, a patient treatment system might maintain multiple circadian trajectories for a patient and use one or more of those maintained circadian trajectories for particular treatment management. Examples of multiple maintained circadian trajectories might include a central circadian trajectory that maps a body’s central circadian state to wallclock time where the central circadian state corresponds to the body’s suprachiasmatic nucleus (SCN), such as a representation in memory of instantaneous firing paterns in the suprachiasmatic nucleus, corresponding to how neuronal firing paterns change over time, and / or paterns in changes of concentration of clock genes within cells.

[0163] A peripheral circadian state might reflect circadian-relevant molecular concentrations in a body and a peripheral circadian trajectory representing changes in that peripheral circadian state over a period of wall-clock time. For example, one particular peripheral circadian state might represent the concentration of sodium-proton exchanger (NHE3) in the intestinal lumen of a patient at a given time. The measure of the daily variation in concentration over time may be represented by the amplitude.

[0164] Examples of treatments might include administering a medicine to the patient, outputing a message to be received by the patient for them to take the medicine, and / or indicating an optimal time, or estimate thereof, for some other treatment, therapy, or behavioral guidance. Where the treatment has a fixed wall-clock time, such as a surgery scheduled for November 18 at 2:00 PM, the patient treatment system could compute which inputs could affect the circadian trajectory and provide the patient with inputs, and / or administer some pre-surgery treatment, to cause a modulation of the patient’s circadian amplitude for a desired outcome.

[0165] In some embodiments, the treatments may comprise amplitude-boosting interventions.Amplitude-boosting interventions, as used herein, comprise increasing the height or depth of peaks and troughs. Examples of amplitude-boosting interventions comprise, but are not limited to, consistent mealtimes and consistent times / duration / brightness of light, as well as light during hours predicted to boost amplitude which may occur during the middle of the day, when light has limited effects on phase. In some embodiments, the treatment consists of amplitude-PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) decreasing interventions. Amplitude-decreasing interventions, as used herein, comprise decreasing the height or depths of peaks and troughs. Examples of amplitude-decreasing interventions comprise, but are not limited to, dim light during the day for day workers, bright light exposure during the middle of the night for day workers, inconsistent light, and inconsistent mealtimes.

[0166] Amplitude boosting and decreasing interventions can apply at the cellular level, as well as to both healthy and diseased cells. Molecules including but not limited to glucocorticoids (dexamethasone), CK15 / e kinase inhibitors like PF-670462, HDAC inhibitors, REV-ERB agonists, AMPK activators (metformin), CRY stabilizers, and cAMP activators (forskolin) can act to increase or decrease amplitude when delivered at the correct time. In some cases, a dramatic amplitude shift can look like a phase shift (e.g., if the amplitude is made negative by the application of the drug).

[0167] In one embodiment, a drug intervention is given to boost the amplitude of healthy cells and improve their robustness.

[0168] In another embodiment, a drug intervention is given to boost the amplitude of cancer cells to make them vary more over the course of the day, causing them to be more vulnerable to a treatment at the correct circadian phase.

[0169] In another embodiment, a drug intervention is given to suppress the amplitude of healthy cells to prevent dips below an undesirable threshold.

[0170] In another embodiment, a drug intervention is given to suppress the amplitude of cancer cells to make them less viable and less robust to treatment.

[0171] In another embodiment, a drug intervention is given to boost amplitude in both healthy and cancer cells, with the goal of the benefits of higher amplitude in the healthy cells outweighing the benefits of higher amplitude to the cancer cells.

[0172] In another embodiment, a drug intervention is given to suppress amplitude in both healthy and cancer cells, with the goal of the benefits of lower amplitude in the cancer cells outweighing the costs of lower amplitude in the healthy cells.

[0173] In one embodiment, a behavioral intervention can be given to a patient to boost their circadian amplitude in healthy cells, while a drug intervention is given to the patient to suppress amplitude in their cancer cells.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0174] In another embodiment, a behavioral intervention can be given to a patient to suppress their circadian amplitude in healthy cells, while a drug intervention is given to the patient to boost amplitude in their cancer cells and make them more vulnerable to damage at the right time.

[0175] Determining the circadian trajectory can be an involved process, since some input data might be missing and / or there might be some disruptions in the patient’s schedule, such as travel over several time zones. In some cases, a circadian trajectory might need to be computed on the fly, in real time, or near real time and therefore some optimizations in the processing of data might be required. Furthermore, some of the computations might be done on a low- powered device. In some implementations, part of the computation is done remotely, perhaps on more powerful servers, and part of the computation is done on a low-power, local, wearable and / or portable device with communications capability.

[0176] In a typical configuration, a circadian trajectory is continuous in that two nearby points on a circadian trajectory’ map to nearby wall-clock times. While a circadian trajectory' could map exactly to wall-clock time, e.g., a linear mapping, more typically a circadian trajectory will compress or expand units of circadian time relative to wall-clock time, which might be treated as a circadian clock and a wall clock running at different rates and the ratio of the different rates varying over a day or other measurement period. A patient’s circadian state may therefore differ from the wall-clock time, and may vary' over a given period of time. In general, a complete circadian trajectory can provide a mapping from a circadian state of the patient to a wall-clock time as well as providing a mapping from a wall-clock time to a circadian state. A circadian trajectory is also recurrent in nature with the previous estimate being fed into the prediction over the next timestep. Circadian trajectories also produce estimates on a time scale significantly shorter than the period of the oscillator (approximately 24 hours). For example, the circadian trajectory could estimate the state of the oscillator every 6 minutes, producing 240 predicted or forecasted states for each day. In some embodiments, a circadian trajectory could be shifted to correspond a certain state with the wall-clock time.

[0177] Whereas some treatments might be prescribed strictly on wall-clock times (e.g., ‘‘take one pill early in the morning and a second one at noon local time”), other treatments might rely on circadian time that represents some circadian state on a circadian trajectory. Such other treatments might benefit a patient more if that circadian trajectory' and / or a current circadianPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) state is more accurately and / or precisely determined. In some embodiments, the circadian trajectory is therefore tailored to the patient’s individual circadian rhythms, rather than consistently associated with a given wall-clock time. In some embodiments, a patient’s individual circadian phase is not modified. In some embodiments, a treatment is aligned with an individual’s circadian trajectory. In some embodiments, a patient’s circadian trajectory is shifted with a circadian rhythm modulating protocol to match a target circadian trajectory. In some embodiments, a circadian trajectory comprises a circadian phase, a circadian amplitude, a circadian period, and a MESOR over time.

[0178] The circadian trajectory can be represented and stored in computer memory' as a lookuptable, possibly corresponding to a piecewise linear plot of circadian time versus wall-clock time. The patient treatment system might store the circadian traj ectory as a vector data structure that can be manipulated by computer instructions created for performing vector operations or hardware capable of vector operations. The resolution of such a plot of circadian time versus wall-clock time might be on the order of seconds or minutes. For example, a 24-hour plot of circadian time versus wall-clock time might be stored as a vector of 288 values each corresponding to a circadian state at five-minute intervals.

[0179] A patient’s body has biological states that might vary' over time. For example, a stored biological state value might reflect a concentration of melatonin in the patient’s saliva, the concentration of caffeine in the patient’s bloodstream, the concentration of the BMAL1 gene in the patient’s cells, the current firing rate in the patient’s suprachiasmatic nucleus, etc. For nonhuman patients, some biological states might not have human counterparts. A circadian state is one particular example of a biological state. A circadian state captures both the amount to which a rhythm has completed one cycle (phase), as well as the strength of the rhythm at that time (i.e., the amplitude at a given point in time.)

[0180] A patient’s circadian state is a biological state corresponding to where the patient is in a circadian cycle. As explained herein, a given body might have multiple circadian cycles, not all of which need be aligned, such as a central circadian cycle and peripheral circadian cycles. Melatonin concentrations, BMAL1 gene concentrations, firing rate of the SCN, and other biological states might be circadian states or proxies therefore. The amplitude of each of these circadian states can be measured by, for example, the concentration of a molecule or gene expression. In some embodiments, the circadian trajectory is tissue-specific. In somePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) embodiments, the circadian trajectory may pertain to skeletal muscle tissue. In some embodiments, the circadian trajectory may pertain to vascular tissue. In some embodiments, the circadian trajectory may pertain to epithelial tissue. In some embodiments, the circadian trajectory may pertain to nervous tissue. In some embodiments, the circadian trajectory may pertain to connective tissue.

[0181] In some embodiments, the circadian trajectory encompassing the circadian state (containing at least phase and amplitude) is organ-specific or tissue-specific. In some embodiments, the circadian trajectory may pertain to the stomach. In some embodiments, the circadian trajectory may pertain to the liver. In some embodiments, the circadian trajectory may pertain to the lungs. In some embodiments, the circadian trajectory7may pertain to the colon. In some embodiments, the circadian trajectory may pertain to the heart.

[0182] In some embodiments, the circadian trajectory encompassing the circadian state (containing at least phase and amplitude) may be specific to one or more types of tissue and / or one or more organs. In some embodiments, the target trajectory7for one type of tissue may be different from the target trajectory for another type of tissue. In some embodiments, the circadian trajectory is whole-body.

[0183] A time sequence of a biological state can be stored and / or represented in memory as a time series of state values, or a trajectory7for the biological state. The representation of a trajectory in computer memory can be in the form of a listing of records each indicating a state value and a time, a piecewise linear plot, coefficients of a fited curve, or other form of data structure usable for representing state values and specified times.

[0184] An example biological state might be that a melatonin concentration is 4.3 picograms / ml at epoch time / =I642724939. Another example biological state might be that core body temperature is 97.3° F at epoch time 1=1642724939. A value, R, might be stored in memory7as a representation of some unitless or unit-specific quantity corresponding to a biological state’s amplitude. For example, it might be a value of a biological oscillator such as melatonin concentration in saliva in units picogram per milliliter. Another example is a unitless quantity corresponding to a measure of cohesion of neurons firing in a suprachiasmatic nucleus and might be such that R=0 represents a state wherein the neurons are completely out of sync with each other and 7?=1 represents a state wherein the neurons are firing perfectly in sync with each other.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0185] As an example of a circadian state, it might be represented as a point from a sinusoidal curve defined by having an amplitude of Aa=0.4 and at an epoch time of t= 1642724939 having a phase of T^TI / 4. A period of a trajectory, which might correspond with a circadian cycle, might not be constant and can change from period to period (e.g., a 24.75-hour circadian cycle followed by a 25.4-hour circadian cycle then followed by a 24.9-hour circadian cycle. The effective period of a trajectory, the rate of change of the state might also change dynamically over the course of a trajectory as time shrinks and expands.

[0186] In some cases, an intrinsic period might be present and / or measured, which might correspond to a circadian cycle that a body experiences in the absence of external time-marking signals, such as light variations throughout the day. A patient treatment system might store a value for the intrinsic period that can be used as a parameter that can be tuned to improve estimates of a person’s circadian state, along with other parameters that might really mater to the circadian phenotype, like light sensitivity’, in defining a trajectory. Varying such parameters can be used to generate a trajectory' bundle, and the range of parameters can be narrowed or made wider if other information about them is available, such as by giving a person a test to see how much their pupil constricts to assess light sensitivity, or demographic correlations are discovered which impart information about the parameters under consideration.

[0187] In another example, a circadian state might be stored as a representation of multiple gene expressions, such as a vector value [32.242, 484.23, 4994.2 ...] for t=l 6427249 representing expression levels for genes [Genei, Gene2, Genes, ...]. For some such circadian states, there might be hundreds of genes represented. The expression levels may fluctuate over time and be stored as an amplitude relating to gene expression, wherein the amplitude varies at different circadian states.

[0188] FIG. 1 is an illustration of a biological trajectory 100. In this example, the biological state is a body’s concentration of a drug over time following the intake of the drug at time t=0. In the plot show n, the scale of drug concentration ranges from A (which can be 0, or not) through A+B, which can be an arbitrary' scale or a stored trajectory' could include specific scales. In this example, A is the base concentration, and B is the addition of a drug. In other examples, A might be a base example, B may be the addition of one drug or treatment, and a further C might be a further example of a drug or treatment, such that there is an additive effect. In this particular example, the drug concentration appears to decline with exponential decay. For somePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) trajectories, the biological state might be measured at a few points in time and then fited to a curve that assumes certain behaviors, such as linear or exponential decay.

[0189] A trajectory maps between wall-clock time and a biological state, as a time series, either in the past or future, of biologically relevant data. An example might be a trajectory of adenosine concentrations over time, a trajectory' of temozolomide (TMZ) concentration over time, etc., wherein the concentration of the drug is a biological trajectory'. A trajectory' might reflect a half-life of a drug concentration in the body, interactions between drugs and other molecules in the body over time, etc.

[0190] FIG. 2 is an illustration of a circadian trajectory 200, yvhich represents a time series of circadian states. An example might be a biological state representing changes in melatonin in saliva over the course of a day, levels of firing paterns in the brain over the course of weeks, or expression rates of clock genes over either time scale. While the example of circadian trajectory' 200 suggests a sinusoidal patern with a period of around twenty -four hours, that need not be the case for all circadian trajectories. The initial amplitude 210 is also shoyvn.

[0191] In addition to storing and manipulating a traj ectory of a biological state, a patient treatment system might store, manipulate, and / or operate on a bundle of multiple related trajectories. Different trajectories in a trajectory bundle might be created with different starting conditions and / or assumptions. A trajectory' bundle may comprise a sampling of circadian trajectories, which should be considered a finite representation taken from a continuous trajectory probability distribution function (TPDF) or may encapsulate a representation of the full distribution function (TPDF) or an approximation of this function. Therefore, bundles may also be represented or obtained by the expression of the TPDF and the dynamics may' be described by the evolution of any representation of this function. In some embodiments, the treatment may involve modulating the trajectory by changing the circadian amplitude (as shown by doted line 220), which has a lower amplitude 230 than the initial amplitude.

[0192] FIG. 3 is an illustration of three circadian trajectories (Rhythm A, Rhythm B, Rhythm C) that could be in a trajectory' bundle 300 and could be used to capture three different ways the same drug could interact with a circadian target (Interaction A, Interaction B, Interaction C). The different trajectories might represent different individuals, different measurements from one person (or multiple people), and / or one set of measurements yvith differing assumptions or initial conditions applied. For example, the value A+B shoyvn in the plot in FIG. 3 could be aPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) normalized starting concentration for different amounts of drug intake to illustrate the probability of various biological states (‘“fuzziness'’) of the trajectory over multiple samples and over multiple drug intake amounts. In other examples of trajectory bundles, a trajectory bundle might represent trajectories for differing average concentrations of adenosine receptors in the brain. For example, a trajectory bundle for four different coffee sizes that were ingested by a patient might be stored as a traj ectory bundle of four traj ectories, while a traj ectory bundle for adenosine receptors might contain a sampling of ten trajectories, and a trajectory bundle of one trajectory for each combination of ingestion size and receptor concentration might contain forty trajectories.

[0193] FIG. 4 is an illustration of three trajectories that could be part of a circadian trajectory bundle 400. In this example, each trajectory corresponds to a clock gene expression level ranging from Expmin to Expmax. For each trajectory, an expression level at time t=0 is the same or is normalized to be the same, as illustrated but that is not necessarily required for circadian trajectory bundles. The circadian amplitude, phase, and period are different for each possible example within the bundle, demonstrating how the different aspects of a circadian rhythms may be used to understand a circadian trajectory.

[0194] A trajectory bundle can be used to quantify uncertainty in a wearable signal. A digital twin simulation can be carried out for 100,000 slight modifications of a wearable history, where each wearable history corresponds to a different trajectory. The spread of biological states shown across the trajectory bundle at every time point can provide the uncertainty for that time point.

[0195] A trajectory bundle can be used to quantify uncertainty in a user’s circadian phenotype, such as their light sensitivity or intrinsic Tau. A digital twin simulation can be carried out with 10,000 choices of circadian parameter Tau, where each choice of Tau corresponds to a different trajectory. The spread of trajectories at every time point can again provide the uncertainty for that time point. The uncertainty can be used to set the width of the administration window. A high uncertainty with regard to either the phase or the amplitude will correspond to a wide administration window, while low uncertainty with regard to the phase or amplitude corresponds to a narrow administration window.

[0196] A trajectory bundle can be used to patch missing data. In the absence of wearable data, for instance, a digital twin simulation can be carried out over a distribution of possible wearablePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) data histories. These wearable data histories can be chosen from a uniform distribution or one informed by historical data from the user (e.g.. “typical days”). The trajectory bundle can patch the gap during the missing data period, reducing the uncertainty in the circadian trajectory when the wearable data resumes. For instance, the circadian state at the moment the wearable data returns can be taken from the average state of the trajectory bundle, and the uncertainty at that moment can also be taken from the trajectory bundle.

[0197] A trajectory bundle can be used to quantify the risk of drug interactions. For instance, a trajectory bundle can be used to calculate the risk of two drugs interacting, based on either the amplitude of a certain characteristic impacted by a drug or based on where the different trajectories include different effective half-lives of the drugs in the system. For example, the best dosing time for a stimulant or a sleep aid may be impacted by a circadian rhythm modulating protocol, such as a caffeine or melatonin regimen. The risk of drug interactions, calculated from a trajectory bundle, can be used to inform the treatment mapping. An administration window might not be recommended if the risk of drug interactions is too high.

[0198] A trajectory bundle can be used to quantify uncertainty in a user's circadian phenotype, such as their light sensitivity or intrinsic Tau. A digital twin simulation can be carried out with 10,000 choices of circadian parameter Tau, where each choice of Tau corresponds to a different trajectory’. The spread of trajectories at every time point can again provide the uncertainty7for that time point. The uncertainty can be used to set the width of the administration window. A high uncertainty with regard to either the phase or the amplitude will correspond to a wide administration window, while low uncertainty with regard to the phase or amplitude corresponds to a narrow administration window.

[0199] A trajectory bundle can be used to patch missing data. In the absence of wearable data, for instance, a digital twin simulation can be carried out over a distribution of possible wearable data histories. These wearable data histories can be chosen from a uniform distribution or one informed by historical data from the user (e g., “typical days”). The trajectory bundle can patch the gap during the missing data period, reducing the uncertainty7in the circadian trajectory when the wearable data resumes. For instance, the circadian state at the moment the wearable data returns can be taken from the average state of the trajectory bundle, and the uncertainty at that moment can also be taken from the trajectory bundle.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0200] A trajectory bundle can be used to quantify the risk of drug interactions. For instance, a trajectory bundle can be used to calculate the risk of two drugs interacting, based on either the amplitude of a certain characteristic impacted by a drug or based on where the different trajectories include different effective half-lives of the drugs in the system. For example, the best dosing time for a stimulant or a sleep aid may be impacted by a circadian rhythm modulating protocol, such as a caffeine or melatonin regimen. The risk of drug interactions, calculated from a trajectory bundle, can be used to inform the treatment mapping. An administration window might not be recommended if the risk of drug interactions is too high.

[0201] Trajectory bundles can be used to speed up the work of an expensive trajectory mapping.Optimization operations can often become prohibitively slow as complexity increases. For instance, a trajectory bundle can be calculated for the next two days using probabilistic wearable histories ("typical days”). The treatment mapping can then be applied to this hypothetical data in advance of a user request for an administration window. The treatment mapping will yield administration windows for each trajectory' in the bundle. When the user next asks for an administration window, the trajectory most closely resembling their actual trajectory will be identified and the administration window corresponding to it will be presented.

[0202] A circadian administration window is a dosage amount or treatment with an affiliated period of time recommended for the dose or treatment, calculated from a circadian trajectory', where states might have affiliated uncertainties, and one or more circadian-mapping profiles, such as efficacy profiles and / or toxicity profiles. A patient treatment system might generate an administration window' by taking into account other biological trajectories as inputs, such as a trajectory of caffeine leaving the body. An administration window might be represented by a data structure that indicates a timing window and a dosage amount or other treatment suggestions and / or details, such as the amplitude of the expression of a gene known to interact with a treatment, or the amplitude of the production of a molecule in the body.

[0203] An example of an administration window' might be data indicating an administration window' for M mg of drug D between 2:00 and 2:30 PM based on the patient treatment system determining that a computation of the expected circadian state in that time period would have low' uncertainty and the expected circadian state maps, via a circadian-mapping profile, to a high efficacy and / or low toxicity for drug D. Another example might be data indicating anPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) administration window for M mg of drug D sometime in the afternoon based on the patient treatment system determining that a computation of the expected circadian state in that time period would have low uncertainty and the expected circadian state maps, via a circadian- mapping profile, to a high efficacy and / or low toxicity for drug D where the expected circadian state has a larger uncertainty. In some embodiments, the duration of the circadian administration window varies from 30 minutes up to 12 hours, such as 30 minutes, 1 hour, 1.5 hours, 2 hours. 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours. 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, or 12 hours. In one embodiment, a circadian administration window has a duration of 30 minutes. In one embodiment, a circadian administration window has a duration of 4 hours. In one embodiment, a circadian administration window has a duration of 8 hours. In one embodiment, a circadian administration window has a duration of 12 hours.

[0204] The patient treatment system might provide messages to the patient that reflect the uncertainty7. For example: (a) “Take one pill between 8:00 AM and 8:15 AM tomorrow’’ (low uncertainty), (b) “Take 45 mg of your drug tomorrow afternoon” (high uncertainty), and (c) “Take your pill tomorrow” (extremely high uncertainty).

[0205] FIGS. 5 A-5G illustrate two distinct trajectories for circadian targets and interactions with a drug given a wearable history7. The wearable histories might be obtained from a wearable device that periodically measures the amount of light or characteristics of light that the wearer is experiencing. The corresponding circadian target levels illustrated in FIG. 5 might be determined from actual measurements of the wearer, or might be determined or estimated based on a precomputed volatile or mapping from light histories to clock gene expressions. For the same drug intake, as shown by the biological trajectories in FIG. 5 A and FIG. 5E, different circadian trajectories (FIG. 5C and FIG. 5G) are produced by the different wearable streams (FIG. 5B and FIG. 5F) which yield different interactions (FIG. 5D and FIG. 5H)

[0206] FIG. 6 illustrates trajectory bundles, one for wearable histories, such as those shown in FIGS. 5B and FIG. 5F, and one for circadian trajectories representing circadian targets, such as those shown in FIG. 5C and FIG. 5G. A trajectory bundle might bundle 10,000 trajectories, each representing a trajectory7of a patient being exposed to a particular constant light level over an exposure period. The 10,000 trajectories might be distinct trajectories. The exposure period might be one hour, or some other period. These trajectories can be from actual exposures thatPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) are measured or from a model of such exposures. A circadian trajectory' bundle might include representations of circadian trajectories over a population of patients. The population of patients might be 50 patients, or some other number of patients. Among the population of patients, they might have differing levels of light sensitivity and the data representing the circadian trajectory bundle might have indicators of each patient’s light sensitivity and those might be different, or not, for each patient. Thus, a circadian trajectory bundle might include a circadian traj ectory for each combination of the levels of light sensitivity per patient and 10,000 light levels, for a total of 500,000 circadian trajectories within the circadian trajectory bundle. As illustrated by FIG. 6, the timing of wearable signals can affect the amplitude and phase of the resulting circadian trajectory. In general, greater differences between daytime light / activity and nightime light / activity yield higher amplitude circadian trajectories. The amplitude of clock gene expression may vary by patient or even in the same patient over a period of time.

[0207] A trajectory bundle might be stored as a data structure in computer-readable form. A trajectory bundle might comprise circadian trajectories or other biological trajectories. In the presence of missing data, a trajectory bundle can be created by propagating forward from a last tracked circadian state and its affiliated uncertainty with inputs drawn from a distribution. The distributions can be uniform (e.g., sample uniformly across all possible inputs) or informed by historical data (e.g., sample from the space of ‘'typical” days for this person, or sample from the space of likely chronotypes). The inputs can be wearable data inputs such as a hypothetical lighting or activity history. The inputs can be parameters capturing the way the circadian system works or is expected to work, such as greater light sensitivity or reduced light sensitivity affecting state. These can be averaged together to yield the most likely trajectory during the period of missing data.

[0208] In the presence of an expensive optimization problem, such as the case of multiple interacting drugs and inputs, trajectory bundles can be precomputed to save time for a patient. For example, if a treatment decision is to be made or a message communicated to a patient and that needs to be done relatively quickly after the patient has made a request (e.g., the patient presses a buton on their wearable device and expects a message shortly thereafter), trajectory bundles can be precomputed with probabilistic future paths. Expensive optimization problems can thus be carried out over the set of trajectories ahead of time so that the moment the patient makes a request, the data can be accessed. An updated traj ectory' can be compared againstPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) precomputed trajectories, and if one matches sufficiently well, that one is used. Otherwise, a relatively computationally expensive optimization might take place.

[0209] Additionally, the trajectory bundle could be expressed using the full trajectory density function or equivalently coordinates for this density function which can be used to recover the probability density function. For example, through using the observable coordinates defined through Koopman operator theory, the moments of the probability distribution, Fourier coefficients, etc. The optimization problem under consideration may be more efficiently and / or accurately solved when framed under these coordinate transformations.

[0210] The patient treatment system might use digital twin modeling for generating trajectories or presumed trajectories from input data. With digital twin modeling, the patient treatment system operates on a virtual model of the patient given some inputs. The inputs might be from body sensors, wearable devices, internal measurements, etc. that might have varying degrees of accuracy and / or precision and some inputs might have time gaps or missing data. Input data can also be physiological parameters, such as light sensitivity. Input data can also be demographics data, like age. The digital twin modeling might include some simulations run to estimate what the actual trajectories might be under certain conditions. The input data can be prerecorded or past obtained data, or might be real-time data. Digital twin modeling might also involve feedback of simulation results. Examples of hardware that might be used for digital twin modeling are described herein elsewhere.

[0211] A particular model for generating an optimal time (preferred circadian administration time or preferred circadian administration window) for taking a drug by associating a circadian time with a time for taking a drug might include a raw model output with a model of a core circadian pacemaker connected to another model, such as a blood-brain barrier model and / or a liver model.

[0212] State values that result in a trajectory can have affiliated uncertainties thus making the trajectory have some uncertainty. Uncertainty might relate to a confidence level that a state at a given time is correct. High uncertainty might result when the data used to arrive at the state - for instance, wearable data used to predict circadian states - is sparse or highly irregular. Efficacy and toxicity profiles may look very different. The efficacy and / or toxicity profile identification system may identify efficacy profiles with very different peaks from toxicity profiles.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0213] A computer-implemented method for administering a treatment can be provided, perhaps under the control of one or more computer systems configured with executable instructions, for determining a set of patient inputs, determining a treatment, estimating a circadian trajectory of the patient, determining one or more circadian-mapping profiles, determining, from the circadian trajectory and the one or more circadian-mapping profiles, a preferred treatment time period, and then administering the treatment in response to an alert that the preferred treatment time period is occurring or is to occur. The circadian trajectory might be represented in a computer-readable data structure, such as sample values, curve approximations, piece-wise linear representations, etc. and might be represented such that a circadian phase and a circadian amplitude might be determined at a given time point in the circadian trajectory. The circadian trajectory might be represented such that a circadian period, a MESOR, and other characteristics of the circadian trajectory can also be derived. The circadian trajectory might be represented in a computer-readable data structure in part, with missing parts inferred or extrapolated. In some embodiments, for characterization of a circadian trajectory, it might be sufficient to have data from which circadian phase and circadian amplitude can be derived. The periods and trajectories can vary. The treatment can be an administration of a substance, wherein the substance is one or more of a drug, nutrient, or medicament. The set of patient inputs can comprise data derived from signals received of a patient from wearing a wearable data system. The circadian trajectory might be derived by a scheduler using at least one biophysics model of a human circadian clock and at least one statistical model of the human circadian clock. The preferred treatment time period might be optimized based on associating a circadian time with a time for taking a drug for generating a raw model output.

[0214] A model output might be used by an environmental controller to adjust an environment such that the circadian trajectory is adjusted to match a target trajectory. The trajectory may be adjusted in order to meet a target-constrained times. Such target-constrained times might correspond to but are not limited to treatments administered at an infusion clinic or a scheduled surgery.

[0215] FIG. 7 illustrates an example of a trajectory 700 having some uncertainty built in.Uncertainty for each state in a trajectory can be calculated with a trajectory bundle. In FIG. 7,PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) the uncertainty is illustrated by the lines of varying inputs with different trajectories in the uncertainty region 702.

[0216] The digital twin simulation can be carried out for varying inputs, with different trajectories generated for each input. The distribution of the trajectories at a given time can be used to define the uncertainty for each circadian state. The different inputs given can be different wearable inputs (e.g., assuming the sensors on a wearable device were inaccurate or incomplete) or different model parameters (e.g., light sensitivity). The inputs can be chosen randomly or systematically from a distribution. This distribution can be the uniform distribution, or it can be a distribution based on historical data from a user or a population of users.

[0217] Uncertainty might be due to wide variances among trajectories. For example, where a patient treatment system might have trajectories for several different input values, but lacks the input value or certainty over the input value, the trajectory might be uncertain, as reflected in the plot shown in FIG. 7. Uncertainty might relate to, for each circadian state, central or peripheral, a reflection of how confident an estimation of that state is. For example, at time lx, a concentration of a particular molecule could be between 3 and 4 picograms / ml and that variance might contribute some level of uncertainty for time tx. On the other hand, if the concentration were only known to be between 3 and 300 picograms / ml at time tx, that would be a higher uncertainty. In other embodiments, the concentration might be varied and yet has no impact on the time t of a certain state. Circadian uncertainty might increase in light of jet lag and travel, as the effects of jet lag / travel on circadian patterns for a specific individual might not be well-known. Uncertainty can increase in the presence of missing data and can decrease in the presences of large volumes of input data.

[0218] Circadian-mapping profiles that map efficacy, toxicity, etc. variances to circadian state can be developed by collecting examples from a large number of patients and processing that data into circadian-mapping profiles. These circadian-mapping profiles can be stored as data structures that are processable by the patient treatment system and might be used with trajectory data to make treatment timing decisions and / or recommendations.

[0219] FIG. 8 illustrates an example circadian-mapping profile, an efficacy profile, that maps between circadian states to efficacy of a drug. The circadian-mapping profile can be represented and stored in memory using various data structures that a processor can use toPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) determine, for a given circadian state, what an efficacy value might be or conversely, for a given efficacy value or range of values, which circadian state or range of states correspond to the given efficacy value or range of values. In the example of FIG. 8, R is a value that corresponds to how synchronized neurons in the SCN are and can range in this example from R=0 to 7?=1 (the amplitude), while is a value that corresponds to a circadian phase that might range from -n to +71 and represent a state at a point in time within a circadian cycle or trajectory.

[0220] Efficacy is shown in 10% ranges from 0% to 80%. with different shades of gray corresponding to particular ranges. Other ranges are possible. In this example of FIG. 8, at a point 802, corresponding to a circadian state of 'P=+ n / 3 and an SCN neuron synchronization value of R=0.5, the efficacy would be between 10% and 20%. At another point 804, at a circadian state of =-271 / 3 and an SCN neuron synchronization value of / =().84. the efficacy would be between 40% and 50%. While FIG. 8 is a representation of what might be a circadian- mapping profile stored in computer memory, the computer representation might have more resolution and the value represented in the circadian-mapping profile for point 802 might be 14%. All other things being equal, this might indicate that the treatment might benefit from being adjusted closer to ¥=+71 and A=0.98.

[0221] While FIG. 8 illustrates a two-dimensional (2D) profile, a circadian-mapping profile might have more than one dimension, with one or more of the dimensions being components of the circadian state, or components of tissue-specific or organ-specific circadian states. For example, an efficacy profile might have one dimension for circadian state that is a central circadian state of an expression level of the BMAL1 gene, another dimension for drug efficacy for a given drug, a peripheral circadian state of an expression level of NHE3, a biological state of concentrations of drugs already in the system, etc. An A-dimensional circadian-mapping profile stored in memory as a data structure might provide a processor with indications of what an efficacy of the drug would be at a point or region of an A'-dimensional space corresponding to a current expression level of the BMAL 1 gene, a current expression level of NHE3, current concentrations of drugs already in the system, etc.

[0222] FIG. 9 illustrates another example circadian-mapping profile, this one a toxicity profile, that maps circadian states to a toxicity measure of a drug. The toxicity profile can be represented and stored in memory using various data structures that a processor can use to determine, for a given circadian state, what a toxicity value might be or conversely, for a givenPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) toxicity value or range of values, which circadian state or range of states correspond to the given toxici ty value or range of values. This might be used by a patient management system to prompt a patient to initiate a treatment, such as the taking of a prescribed medication. As illustrated in FIGS. 8 and 9, some circadian states might be preferred over others for the initiation of a treatment and the methods described herein for inferring a current or future circadian state can be useful.

[0223] In the example of FIG. 9. R is a value that corresponds to how synchronized neurons in the SCN are (corresponding to circadian amplitude) and is a value that corresponds to a circadian phase, as with FIG. 8. For various values of those two axes, a range of adverse events is indicated, which can represent an indication of toxicity. The circadian-mapping profile can be represented and stored in memory using various data structures that a processor can use to determine, for a given circadian state, what an adverse event count value might be or conversely, for a given adverse event count value or range of values, which circadian state or range of states correspond to the given adverse event count value or range of values. In the example of FIG. 9, R (amplitude) can range from R=0 to R=l, while circadian phase, , can range from n to +71 and represent a state at a point in time within a circadian cycle or trajectory.

[0224] The number of adverse events is shown in ranges of five events from 0 events to 40 events, with different shades of gray corresponding to particular ranges. Other ranges are possible. In this example of FIG. 9, at a point 902, corresponding to a circadian phase of '+'= I m / 3 and an SCN neuron synchronization value (amplitude) of R=0.5, the number of adverse events would be indicated in the circadian-mapping profile as being between 10 to 15. At another point 904, at a circadian phase of T'=-27i / 3 and an SCN neuron synchronization value of R=0.84, the number of adverse events w ould be indicated in the circadian-mapping profile as being between 30 to 35. All other things being equal, this might indicate that the treatment might benefit from being adjusted closer to =+71 / 3 and / or R=0.95.

[0225] A treatment might be more effective when R is higher. A behavioral intervention can be used to increase R while still dosing at the same phase.

[0226] While FIG. 9 is a representation of what might be a circadian-mapping profile stored in computer memory, the computer representation might have more resolution and the value represented in the circadian-mapping profile for point 904 might be 32.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0227] In some implementations, selection of T and R might be optimized by taking into account multiple circadian-mapping profdes, such as one or more efficacy profile and one or more toxicity profile to find a best fit when an optimal region of each circadian-mapping profile is not all at the same values of and R.

[0228] While FIG. 9 illustrates a two-dimensional (2D) profile, a circadian-mapping profile might have more than one dimension, with one or more of the dimensions being circadian components of the circadian state, or components of central and peripheral circadian states. For example, a toxicity profile might have one dimension for circadian state that is an expression level (reflecting phase and amplitude) of the BMAL1 gene, another dimension for drug toxicity for a given drug, a peripheral circadian state of an expression level (reflecting phase and amplitude) of NHE3, a biological state of concentrations of drugs already in the system, etc. An N- dimensional profile stored in memory as a data structure might provide a processor with indications of what a toxicity of the drug would be at a point or region of an A-dimensional space corresponding to a current expression level of the BMAL1 gene, a current expression level of NHE3. current concentrations of drugs already in the system, etc.

[0229] As explained herein elsewhere, the patient treatment system might convert large numbers of circadian trajectories and clinical outcome data into efficacy and / or toxicity7profiles. Such processing to generate circadian-mapping profiles might also take as inputs demographics data and other trajectories and output a circadian-mapping profile that maps circadian states (and possibly other inputs) to efficacy values, toxicity’ values, or other profile type values.

[0230] As show n in FIGS. 10A through 10F, the timing of a drug may be altered in order to beter match atarget trajectory and improve treatment outcomes. FIGS. 10A and 10B show dosing of a certain amount of drug and the amount of target. In FIG. 10A, the dose is given to a subject 10 hours after the concentration of a target compound reaches the minimum concentration. With a beter time for dosing, the amount of interaction reaches a higher peak, and the total interaction of the drug’s concentration in the subject lasts at a high concentration for a longer period of time. In contrast, as show n in FIG. 10B, dosing two hours before the target minimum results in a decreased amount of interaction, and a decreased interaction. FIGS. 10C and 10D show the same dose times, but for a subject whose target has a lower MESOR, and therefore, an overall lower amount of interaction and a lower total interaction occur, as shown in FIGS.10C and 10D. FIGS. 10E and 10F show a lower amplitude target with a higher relativePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) MESOR. For such a target, because the amplitude of the target is lower, the impact of the drug dosing time is less significant than it is for a subject with a higher amplitude, and the amount of interaction is both lower at its peak and lower over time.

[0231] A treatment mapping can be represented in a data structure that provides a rule for converting a circadian trajectory with affiliated uncertainty and a circadian -mapping profile into a set of administration windows. An administration window can be narrower (e.g., “take a drug between 5:00 PM and 5:30 PM”) when the uncertainty is low, such as, for example, in a patient with a higher amplitude target. An administration window can be wider (e.g., “take a drug in the afternoon”) when the uncertainty is high, such as, for example, in a patient with a lower amplitude target. The treatment mapping can be computed from a patient's circadian trajectory, which in turn can be derived from wearable data. For instance, wearable data can be used to arrive at both a circadian trajectory and uncertainties for each point by simulating a digital twin of the suprachiasmatic nucleus (SCN). In this example, a circadian state can be represented by the firing rate and firing cohesion of the neurons in the SCN, or by the expression of genes in SCN cells in a moment of time.

[0232] A fixed treatment window might exist for a period of time when a treatment is scheduled that is out of the user’s control. This can be a surgery or an infusion. Fixed treatment windows might be dealt with by instituting controls that can result in altering the mapping of circadian state to wall-clock time. A control might be a behavior or activity that affects biological states. A control might be represented in memory as a data structure that comprises an action and a time period. A control might be a pulse of light at a specific time to alter a light exposure history or a suggestion to do so (e.g., “Get 10,000 lux of light exposure for 45 minutes starting at 2:45 PM on October 3rd”), a signal to suggest exercising during a window of time (e.g., “Do a moderate work out from 11:45 AM to 12:45 PM”), a signal to take a drug during a window of time, etc., in order to modify circadian amplitude and / or circadian phase.

[0233] A control system might consider a current circadian state, with affiliated uncertainty, as well as a fixed treatment window, and prescribe a set of controls to move a recommended administration window, which corresponds to a future circadian trajectory and an efficacy and / or toxicity profile, to overlap as much as possible with the fixed treatment window.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0234] Accurately determining an individual patient’s circadian time so that it can be used in the treatment mapping might include wearable data augmented by a data structure such as a work calendar data table. Inclusion of this data structure can reduce uncertainty.

[0235] The digital twin simulation for converting inputs into trajectories can address problems with masking caused by external factors that obscure true circadian signals to allow for accurate, personalized treatment timing recommendations. For instance, the digital twin simulation can address the problems caused by noise and outliers in a signal, which confound the estimation of true circadian time, by imposing realistic bounds on how much of an effect any time period of signal can have on the output circadian state. Without steps to address masking, administration window times can become highly volatile and inaccurate.

[0236] The administration windows may be presented as only timing recommendations for doses with a fixed amount, such as pills (e.g., “there is a good time of day to take this pill and for you specifically, that time of day is between around 10 AM to 11 AM local time tomorrow”), or they can be presented as both dosing and timing recommendations (e.g., “your morning dose should be X mg between around 10 AM to 11 AM local time and X+Y mg between around 12 PM and 1 PM”).

[0237] Inputs to a digital twin simulation used to arrive at a trajectory might be wearable device data streams, demographic data stored in a user data record, or demographic details (e.g., gender, age, geographic residence location, etc.).

[0238] Inputs to a circadian-mapping profile can include known optimal timings for the individual based on self-report or other records, a set of timing restrictions represented in a restrictions table or stored restrictions rule set (e.g., restrictions on time intervals between doses), and the like.

[0239] A user interface might be provided to inform the patient of administration windows and alerts at wall-clock times (corresponding to the circadian trajectory) that correspond to administration windows.

[0240] A digital twin simulation may also incorporate environmental factor input and outputs and use those to modify a trajectory. This in turn can change the inputs to the treatment mapping, resulting in new administration windows. For instance, a hospital room could include known lighting levels in a digital twin simulation, reducing uncertainty for a trajectory and narrowing the administration window-s presented to the user.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0241] Environmental controls can also integrate with a control system. For example, a control system may interact with environmental controls to change an environment based on a set of rules or data that move future administration windows to overlap as much as possible with fixed treatment times. As an example, the environmental control system might alter light levels, light colors, heating, cooling, etc. in ways that would alter a patient’s circadian trajectory' so that the resulting treatment mapping recommends an administration window near or overlapping a fixed treatment time.

[0242] FIGS. 11-13 illustrate a hardware structure and examples that could be used to implement the patient treatment system described herein.

[0243] A treatment system can gather inputs, apply a treatment mapping, and provide a user interface to indicate, possibly at or near certain wall-clock times, computed administration windows. The administration window's may initially cover long windows of time (e.g., "all afternoon”) and then become more specific as uncertainty is reduced (“between 8 and 8:30 PM”).

[0244] As described herein, a treatment system can take in patient inputs, and other inputs, process a treatment mapping that intakes biological states and at least one circadian state, along with a circadian-mapping profile, producing administration windows which correspond to wall-clock times. The display of the administration w indow s can be triggered near the time of the start of the administration w indow, and this display can be provided through a user interface that would issue a treatment administration message, such as a reminder to a patient or caregiver to administer the corresponding treatment.

[0245] FIG. 11 is a diagram of a patient treatment system 1100, according to various embodiments. Patient treatment system 1100 can be used for producing optimal administration windows related to a biological process and provide patient information related to treatments and timing of treatments.

[0246] In one example of the treatment mapping to determine best timing, a best time for taking a drug can be seven hours after the circadian state corresponding to melatonin onset. In another example, the treatment mapping can include a complicated molecular model that has equations capturing how different molecules in the drug bind to the body and interact with each other in order to select the best administration window given these drug interactions. In another example, the treatment mapping can take demographics information such as ethnicity, sex, age,PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) and other drugs as parameters for input. Logical gating may be used and in one example, the treatment mapping ensures drugs are spaced at least twenty-four hours apart. In a further example, where molecules bind and interact in the equations, the variables represent molecular equations and parameters represent binding rates. In many cases, indicating to a patient an optimal timing to take a drug or perform other treatments might depend on a determination of a circadian state and possibly also an uncertainty about the patient’s circadian state. As with the example above, if the optimal time for taking a drug is seven hours after the patient has experienced melatonin onset, a patient system 1102 of patient treatment system 1100 might send a message around the time determined to be seven hours after melatonin onset. If there is uncertainty about when that is, the patient might be messaged around the start of a window of uncertainty and provided an indication of the uncertainty (e.g., “The best time to take drug A, for you, is 7 hours after melatonin onset. Based on an analysis of data measured from you and data input by you, melatonin onset today for you would have been at 11:25 AM with an uncertainty7of around + / - 35 minutes. You should therefore take Drug A, in the indicated dose, at 6:25 PM and given the uncertainty, the actual optimal time to take Drug A might be between 5:50 PM and 7:00 PM.”). In other instances, indicating to a patient an optimal timing for treatment might occur based on the amplitude of the circadian trajectory'. For example, the best time could be earlier or later depending on the amplitude of the rhythm. The determination of the correct phase at which to dose may depend on knowledge of the circadian amplitude.

[0247] An effect could be enhanced if circadian amplitude is high. Interventions to increase circadian amplitude include, but are not limited to: consistency of lighting, sleep, and meal time; pulses of light during the circadian “dead zone” when phase shifting does not occur (ty pically in the middle of the day), restricted hours of meal timing (e.g., circadian time restricted eating), and drug interventions delivered at the correct time (e.g., melatonin pills at night).

[0248] An effect could be enhanced if circadian amplitude is low. Interventions to decrease circadian amplitude include, but are not limited to: inconsistency of lighting, sleep, and meal time; pulses of light near core body temperature minimum (ty pically in the middle of the night), expanded hours of meal timing (e.g.. eating around the clock), and drug interventions delivered at the correct time (e.g., melatonin pills during the day).PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0249] For example, this could be based on melatonin amplitude, corresponding to the highest or lowest amplitude of melatonin concentration over a circadian trajectory. If a patient is trying to determine what time to go to bed, the patient may be messaged around the start of a window of uncertainty and provided an indication of the uncertainty (e g., “Your melatonin levels will be lowest at 4:00 AM with an uncertainty of around + / - 20 minutes. You should therefore aim to go to sleep around 11:00 PM, and given the uncertainty, the actual optimal time to go to sleep might be between 10:40 PM and 11 :20 PM?)

[0250] As illustrated in FIG. 11, a user / patient 1106 might provide a user interface 1008 with user data 1010 that is stored in user data storage 1112. User data 1110 might include data received from user 1106 via user interface 1108, such as user demographics, user work information, user travel information, indications of other medications or treatments, user sentiment (how the user is feeling, how the user has reacted to past treatments, etc.) and the like, as well as selfreported manually entered data, such as historical mealtimes, light exposure, exercise times, or lists of drugs the patient is currently taking. Other user-related data might be obtained by wearable sensors 1120 converting sensor signals 1122 into digitized sensor data 1124 that is provided to user data storage 1112. That user data can be provided to a treatment processing unit 1130. Digitized sensor data 1124 might include steps taken, heart rate, temperature, etc.

[0251] Treatment processing unit 1130 might comprise a processor 1132 and program code / logic 1134 that can be used to take in user-specific data to determine a current circadian state of the user, as well as state interaction information from molecular stimulations and data about efficacy and / or toxicity profiles of various drugs to determine an optimal or preferred circadian state for administering a treatment. Data provided to treatment processing unit 1130 can be used to modify a statistical 1140 and / or a biophysics model 1142 to track circadian state. User details, such as a list of drugs the patient has reported as taking, can be used to determine which circadian-mapping profile to use from among a set of profiles.

[0252] The circadian state of the user can be passed on as a circadian-mapping profile for that patient and then an administration window can be passed to the user as an output. For example, as illustrated in FIG. 11, treatment processing unit 1130 can receive, from a drug data set 1144, data 1146 related to efficacy, toxicity, other drug facts, etc. of a particular treatment such as the administration of “Drug A”. Considering also the user-specific data about user / patient 1106, treatment processing unit 1130 can output a record 1152 representing a relative timePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) optimization that would indicate a best time or time range for treatment for user / patient 1106 expressed in circadian relative time. For example, the best time might be represented as a number of hours before or after a defined circadian state, such as the circadian state corresponding to melatonin onset. A model converter 1154 could convert data in record 1152 into a wall-clock optimization data record 1156, which in turn can be provided to user interface 1108 to present a message or a signal to user / patient 1106 indicating the best, preferred, and / or optimal wall-clock time for administering a treatment.

[0253] As explained in detail herein, circadian cycles might pass through various circadian states and the patern of circadian states can be referred to as a circadian trajectory. A circadian trajectory might correspond to a particular physical state of a person’s body (or perhaps over a population of people or other organisms that exhibit circadian cycles). While commonly represented as a simple sinewave having a frequency of around one day or slightly longer and thus circadian states that can be thought of as corresponding to phases of the simple sinewave, circadian states and circadian trajectories are often not so simply modeled. To account for this, apparatus and methods described herein can be used to predict or estimate a circadian trajectory of an organism and a mapping of circadian states along that circadian trajectory onto wall-clock time. This can be useful for timing treatments in which optimal circadian states along circadian trajectory’ for administering the treatments are known when a current circadian state of a user / patient and / or a future wall-clock time corresponding to a future circadian state of the user / patient needs to be determined.

[0254] Circadian trajectories might be reflected in concentrations of molecules that rise and fall with a circadian pattern. These trajectories might be called “peripheral circadian trajectories” when they occur in peripheral clocks, such as the biological clock mechanisms related to the stomach or the liver. These trajectories might be called “central circadian trajectories” when they occur in the central clock, the SCN. These trajectories, or estimates thereof, can be generated using digital twin simulations as they are often not easily determined from direct measurement of an organism. In one instance, digital twin simulations of circadian trajectories are generated by a processor according to a differential equation describing the concentration of the molecule, enabling the concentration to rise and fall in a dynamical, physiological manner.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0255] Concentrations of molecules external to the body can be described by trajectories. These trajectories can be generated by digital twin simulations. In one instance, digital twin simulations of external molecule trajectories are generated by a processor according to a differential equation describing the concentration of the molecule, enabling the concentration to rise and fall in a dynamical, physiological manner. For instance, an impulse of caffeine to the system can be captured by a digital twin simulation in which the caffeine slowly drains from the bloodstream at a rate expressed as a differential equation.

[0256] The information provided to the treatment mapping can include data on pill consumption, such as a pill that automatically tracks that it has been collected, or detection of wrist motion via an accelerometer that is predicted to match the wrist motion of taking a pill. In this example, the treatment mapping can use the pill timing information to arrive at more accurate trajectories for the pill concentration in the body. It can also use this information to apply logical gating rules, such as spacing between the intake of two consecutive doses.

[0257] In yet another example, a treatment assignment and coordination system can be used to assist in scheduling for a clinic or hospital. In a treatment assignment and coordination system, a treatment mapping is repeatedly applied across a number of individuals to assist a clinic or hospital schedule people for appointments (infusions, surgeries) to arrive at recommendations for fixed treatment windows (e.g., clinical or surgery time slots for appointments) that best align with the individuals' administration windows. For instance, the treatment mapping can be applied to determine the administration windows for all people at a clinic, and the people with the earlier administration windows can be assigned to earlier fixed treatment windows. The collective raw' treatment mapping output is converted into a human interpretable form being a display of best time for surgery or clinic visit amongst available time slots.

[0258] FIG. 12 is a diagram of a circadian-mapping profile identification system. As shown there, circadian-mapping profiles, such as efficacy and / or toxicity profiles, are generated from circadian trajectories and outcomes data from multiple individuals, who either self-report such data or have such data automatically detected. As shown in FIG. 12, there might be several patient systems 1202 for multiple patients. Each patient system 1202(z) might provide, to a timing profile determining module 1204, circadian trajectories and outcomes data that is maintained for patient z, such as patient-specific data 1206 from each of patient systems 1202. Timing profile determining module 1204 can then supply a drug profile data record 1210 to aPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) treatment system 1208. An example of patient-specific data might be “Adverse events for Patient ABC12 include incident IN0045371 in which the patient dosed at 7:34 PM, their circadian state at the time of dosing was 0.243813 (along a trajectory that is scaled from 0.0 to 1.0), and the patient self-reported two headaches the next day.” If, for example, a large number of patients reported next-day headaches and a large number did not and a significant distinguishing factor between the two groups is that those who dosed having a circadian state of between 0.2 and 0.3 at the time of dosing are in the first group (the group having the adverse effect) and those who dosed having a circadian state of between 0.6 and 0.7 at the time of dosing are in the second group (the group reporting no adverse effect), then it might be expected that drug profile data record 1210 would indicate for Drug A that a circadian state of 0.6 to 0.7 is preferred for administering Drug A.

[0259] Patient-specific data 1206 passed into timing profile determining module 1104 could be circadian state data over time, as well as efficacy and / or toxicity outcomes. These could include efficacy outcomes, like remission rate, tumor shrinkage, overall survival or changes in blood pressure, lipid profiles, or other biological outcomes. These could also be toxicity outcomes, such as the number of adverse events or side-effects reported. Timing profile determining module 1104 can aggregate the data from multiple patients to arrive at a tool for converting circadian states and other inputs into efficacy and toxicity.

[0260] The cumulative data generates an efficacy and / or toxicity profile that takes circadian states, as well as other possible inputs, and yields efficacy and / or toxicity. For instance, a circadian-mapping profile identification system could identity' that the reason an 8 AM dosing reduces blood pressure for one person while having no effect for a different person is because the two individuals are at different circadian states at 8 AM of wall-clock time. The system could then leam a relationship between circadian states, taken from computed trajectories, and efficacy, and in doing so reveal trends that are not obvious from the wall-clock time of administration. For example, the system could produce an efficacy profile that converts a circadian state (such as peak BMAL1 expression) into an efficacy fraction (80% of peak efficacy at peak BMAL1 expression).

[0261] This circadian-mapping profile identification system could identify gender differences and include them as optional inputs in the circadian-mapping profile. For instance, peak BMAL1 expression could correspond to 80% efficacy for men and 70% efficacy for women. It couldPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) also identify age-related effects and include them as optional inputs in the resulting circadian- mapping profile. It could also identify demographics effects and include them as optional inputs in the resulting circadian-mapping profiles.

[0262] This circadian-mapping profile identification system could identify the effects of meal interactions and include them as optional inputs to the circadian-mapping profile. The circadian-mapping profile identification system can build circadian-mapping profiles from self-report data or from signals directly extracted from the user. For instance, the system could identify circadian states affiliated with lower blood pressure without user manual input. The circadian-mapping profile identification system could also be used to extract the best circadian timing for a treatment to reduce self-reported side-effects of the treatment.

[0263] In addition to, or instead of, administering a treatment, the treatment system can include a control system, a trigger from which might be an indicator of a control. A control can be an action the patient is to take, such as performing an exercise routine at a specific time, to assist the individual to move their administration window7to overlap with a fixed treatment window. A control can also be used to reduce uncertainty, which can narrow the width of an administration window.

[0264] An efficacy profile can be generalized to include non-drug and non-medical treatment activities. For instance, an efficacy profile could relate exercise at different circadian states to efficacy at reducing diabetes risk.

[0265] An administration window can be generalized to include non-drug and non-medical treatment activities. For example, an administration window could recommend exercise, meal timing and composition at a specific time to target lowering diabetes risk, according to an efficacy profile. A different efficacy profile could yield administration windows for exercise at different times if one’s goals relate to improving hypertension, for instance.

[0266] An administration window can also be generalized to include times to eat or to avoid eating, as well as the composition and / or size of the meal. For example, for the control of blood sugar the administration window could give a meal timing window and / or the protein, fats, and carbohydrate composition for the meal.

[0267] An administration window can be large, such as six to twelve hours in duration. In such a case, the specific timing of the administration window might be of most significance to shiftPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) workers, recent travelers, and others who have recently experienced significant shifts in their circadian trajectories, for whom concepts like biological morning and night are poorly defined.

[0268] This system’s applications are not limited to timing pill consumption. The system can used to identify the best fixed treatment windows for a user, e.g., for an infusion, or the best time for surgery7. The system can instruct a person the best time to go into a clinic out of all the times the clinic is available, or from amongst the available appointment times at the clinic.

[0269] The system can inform people the best time for scheduling a surgery. On the other hand, the system can inform people on what controls are best for them in the lead up to surgery in order to allow for better recovery times from surgery7. These controls can be actions the user should take. For example, if a toxicity profile indicates that the patient will recover more easily if surgery occurs during circadian states that habitually happen for this patient during the night, but the surgery is scheduled for the day, that person’s circadian trajectory can be shifted by the controls recommended by the control system to make the circadian states that habitually happen during the night shift earlier or later, to beter overlap with the fixed treatment window during daytime hours.

[0270] In another example, the treatment system can interface with digital therapeutics in pharmaceuticals. The treatment system may be integrated into a feedback loop system in which sensors embedded in the drug or in the pill botle can track drug consumption. The sensors can provide information about what wall-clock time patients are taking the drug. This information can be provided to the treatment mapping to inform logical gating rules for spacing drug consumption, changing the recommended administration windows. This information can also be used to inform trajectories calculated using a digital twin simulation which express how much of the drug is present in the body over time. These trajectories in turn can be used as inputs to the treatment mapping to carry out more sophisticated determination of administration windows.

[0271] In yet another example, the system serves as a tool for pharmaceutical companies to identify circadian-mapping profiles in their assets. Drug timing information can be retrieved directly from the drug or a patient’s self-report timing in combination with a circadian-mapping profile identification system such as described herein, can generate circadian-mapping profiles for new assets, thereby enabling more new drugs to emerge from early-stage drug trials. ThesePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) circadian-mapping profiles would map circadian states, and possibly other inputs such as biological states or demographic information, to efficacy and / or toxicity.

[0272] FIG. 13 is a diagram of a control system 1300, according to various embodiments. In an example, control system 1300 can be used to adjust someone’s circadian trajectory through environmental controllers, such as light exposure via an LED device or behavioral nudges via a graphical user interface (GUI), so their recommended administration windows overlap as much as possible with the fixed treatment windows. Control system 1300 might comprise a patient system 1302 that provides patient-specific data 1314 to a feedback controller 1310. Feedback controller 1310 might obtain constraints data 1312 from a treatment schedule constraints table 1316 to determine what timing constraints there might be on treatments. Patient-specific data 1314 might include the patient’s current circadian trajectory and state, their current prescriptions, etc.

[0273] Treatment schedule constraints table 1316 could be used to provide a list of times for light exposure and other environmental controls for a given cl'ficacy / toxicity profile and circadian state, as well as constraints data 1312, such as when a particular surgery has to happen. Patient system 1302 might provide a predicted circadian state. Feedback controller 1310 can then combine light exposure instructions, as well as the circadian state from patient system 1302, and trigger changes in the environmental control to move the patient’s circadian state to beter align with what is prescribed by the treatment schedule constraints schedule. Feedback controller 1310 might provide control data 1308 to an environmental controller system 1306 that can control an environment so as to influence a circadian trajectory.

[0274] Control system 1300 can identify information such as a phase response curve. In a phase response curve, “phase advance” and “phase delay” regions are identified during which light either pushes the clock forward or pushes the clock backwards. Control system 1300 can identify’ phase advance and phase delay regions for an individual and can provide light during the periods that beter align the recommended administration windows with the fixed treatment time. Control data 138 might be specific instructions, such as “turn on lights at 4:45 AM” in order to shift the patient into an earlier portion of their circadian trajectory.

[0275] The timing system can be integrated into a smart drug delivery system. For instance, it can be integrated into a time-lock pill system. The pill system could automatically release drugs each data according to the administration windows produced by the treatment mapping.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0276] The timing system can be integrated into an artificial organ. The treatment system could identify administration windows for optimal compound release from the artificial organ system to best match the functioning of the organ the artificial organ is replacing. In this case, the efficacy profile is the circadian-mapping efficacy profile that best matches the original functioning of the organ (e.g., release at this circadian state has high efficacy because it resembles the original organ the best).

[0277] The timing system can be integrated into implantable pharmacies. The implantable pharmacy can release drugs according to administration windows set by the treatment system.

[0278] The control system can be integrated into implantable pharmacies. The implantable pharmacy can release drugs to shift a circadian trajectory so the administration windows shift to more overlap a fixed treatment time.Example Components

[0279] FIG. 14 illustrates components that might be used in a control system 1300 to change environmental cues and behavioral triggers in response a fixed treatment time and user data, according to various embodiments. FIG. 14 is a simplified figure and boxes therein might represent data structures, computational elements, sensors, and / or users. In some embodiments, elements shown that are similar to elements of FIG. 11 might operate similarly. As illustrated in FIG. 14 control system 1400 might include a patient feedback system 1402 for providing outputs to adjust a trajectory to meet some treatments schedule constraints.

[0280] A patient 1406 might have some treatment timing constraints, which might be represented a dataset 1456 that is coupled to a feedback controller 1454. Inputs from patient 1406, such as wearable sensor data and user-provided data, provided possibly via a user interface 1408, and stored in a user data storage 1412, can be provided to a treatment processing unit 1430. Sensor signal data might come from wearable sensor devices and / or environmental sensors of patient 1406. Environmental sensors might be used to detect a lighting environment, temperature environment, or other environment details the user is experiencing. Treatment processing unit 1430 might use digitized sensor data along with a circadian-mapping profile to design a series of environmental shifts that move the patient’s circadian state so the administration window beter aligns with the fixed schedule treatment time. Treatment processing unit 1430 that might derive the circadian state from a machine learning subsystem.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0281] The machine learning subsystem might comprise a processor, storage 1440 for a statistical model and storage 1442 for a biophysics model that are both trained by the processor using training data corresponding to the sensor data. Statistical models can be machine learning models that are trained on wearable time series of data streams, such as light, activity, temperature, and heart rate, to predict gold standard biomarkers of circadian rhythms, such as dim light melatonin onset time, the concentration of melatonin over time, or core body temperature. The biophysics model can be human-generated or derived from data and can be created to match the physics of the suprachiasmatic nucleus; for instance, predicting firing rates in the ventral and dorsal SCN at any point in time, which can then be mapped to outputs like timing of dim light melatonin onset.

[0282] Treatment processing unit 1430 might output a circadian timing model 1452. The statistical model, the biophysics model, and circadian-mapping profile might be accessible to treatment processing unit 1430 in a computer memory possibly structured as neural network weights or another data structure that is usable as a trained machine learning model. Feedback controller 1454 can use a circadian-mapping profile as an input, as well as being provided with dataset 1456 indicating scheduled treatment times. One operation of patient feedback system 1402 is for feedback controller 1454 to output signals and / or data corresponding to environmental outputs, behavioral reminders, and the like that are tuned to adjust the user’s circadian state to beter align with the scheduled treatment times. The signals can be output to an environmental setings controller that might control in-room lighting by sending instructions to an in-room lighting and environment controller 1458. Feedback controller 1454 might send commands to some other environmental system that can control some aspect of the patient’s environment.

[0283] For example, the control system could adjust in-room lighting to atempt to steer the user’s circadian state towards alignment with the scheduled treatment times. The control system might also cause the display or issuance of behavioral reminders 1460 to the user. For example, the control system might cause a user’s handheld device (e.g., via user interface 1408) to display a message such as ‘‘Your surgery is scheduled for 2:30 PM tomorrow. Since outcomes for that surgery are statistically improved for patients who undergo this surgery in mid-morning, you should remain active this evening later than usual and sleep in. I’ll control the lighting to help with that.” or “You have an outpatient procedure at 9:30 AM tomorrow involving taking somePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) medicine two hours before the procedure. Since beter outcomes tend to occur when your body thinks it is an hour into your waking day. you should sleep now so you can rise around 6:30 AMT In the later example, the control system might have been altering lighting during the evening to reduce an amount of blue light to assist with aligning the wall clock evening with an evening portion of the user’s circadian trajectory. In another example, a control system may prompt a patient to take melatonin in order to augment their body’s melatonin production and increase the amplitude of melatonin for a given circadian state in order to ensure the patient gets a beter night’s sleep.

[0284] FIG. 15 illustrates components that might be used for a digital twin simulation, according to various embodiments. In an example digital twin simulation, a biophysics model representing a system of differential equations provides input into a machine learning model, which in turn yields a trajectory.

[0285] In the example shown, a simulator 1500 obtains data structures corresponding to sensor ratings, activities, and / or user data. For example, a simulator might read data from a user’s wearable devices, read in demographics data from a user database, and read in patterns of caffeine intake (perhaps based on user manual input of caffeine intake, coordination with a purchasing app, coordination with a mapping app, or other information source) and then apply that data to a collection of differential equations to generate a dataset with reduced dimensionality. The simulator could then use that dataset and a trained machine learning model to generate a circadian trajectory for the digital twin and other portions of control system could use that generated circadian trajectory as a proxy for the user’s circadian trajectory.

[0286] In the detailed example shown in FIG. 15, a distiller 1506 receives wearable data 1508, demographics data 1512, and intake records 1514 and is able to distill that into data can be provided to a model generator 1510. Model generator 1510 can then generate an ML model, which can be provided to a trajectory generator 1520 to output and store a stored trajectory representation.

[0287] FIG. 16 illustrates components that might be used for a profile identification system 1600, according to various embodiments. As illustrated there, a collection of wearable data from a large population, such as 1000 people, 10,000 people, or more, might be provided to a digital twin simulator that would then generate a circadian trajectory for each member of the population. Profile identification system 1600 might also read data from a database of self-PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) reported side effects reported by members of the population. The digital twin simulation might include a statistical model, a biophysics model, or both to process the wearable data to yield trajectories. Considering both the simulated traj ectories and the reported side effects, the profile education system might be able to output data indicating which circadian states are good for reducing side effects and which circadian states are not. That output data might be represented as a toxicity profile.

[0288] FIG. 17 illustrates components that might be used for a treatment mapping module 1700, according to various embodiments. In this example, treatment mapping module 1700 includes an optimization system that can read in a data structure representing a circadian trajectory, which may have some uncertainty such as that shown in FIG. 4, another data structure representing an efficacy profile dataset, and another dataset comprising a log of prior medicine administrations. Using that data, treatment mapping module 1700 might generate a dataset or transmit data that indicates preferred administration windows. Another input into the optimization system is treatment mapping data.

[0289] FIG. 18 illustrates components that might be used for a treatment system module 1800, according to various embodiments. As illustrated there, treatment system module 1800 might provide functionality7similar to that of treatment mapping module 1700 in FIG. 17.

[0290] FIG. 19 illustrates components that might be used for a control system 1900, according to various embodiments. As illustrated there, control system 1900, as might be used as control system 1400 shown in FIG. 14, can take in a dataset representing a circadian state with uncertainty and a dataset representing treatment times and can output a dataset representing a list of controls, such as environmental light or behavioral changes, that can be output. Those outputs might be selected in order to change a user’s circadian state to align their best administration window with a fixed treatment time.

[0291] FIG. 20 illustrates components that might be used for a treatment assignment and coordination system 2000, according to various embodiments. In it, circadian state data for many people is mapped into a schedule which could assign each person to the fixed treatment time that most overlaps with their administration window; subject to the constraints of assigning each person to a treatment window and other desired parameters, such as the person's availability and timing preferences. Treatment assignment and coordination system 2000 could take in a dataset of circadian states or trajectories over a patient population (possibly with somePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) uncertainty) of patients needing a particular treatment at a clinic having limited available appointments. Treatment assignment and coordination system 2000 could take in a dataset of available appointments. From that information, treatment assignment and coordination system 2000 could generate a list of appointment assignments. The appointments might be assigned to patients to maximize or increase overlap or alignment of treatment times and circadian states patients in the population based on what is known about preferred mappings of treatments to circadian states.

[0292] FIGS. 21 A and 2 IB illustrates other examples of a trajectory uncertainty, according to various embodiments. FIG. 21 A, illustrates trajectories wherein the x axis is the time of day, and the y axis is the concentration of melatonin. Trajectory 2110 is for a person receiving 20 hours of light per day, and trajectory 2112 for a person receiving 15 hours of light per day. The offsets and amplitudes of each are impacted by the light schedule. Similarly, jet lag can result in differing offsets and amplitudes, which stabilize as one adjusts to the schedule. In the specific example, FIG. 21B, illustrates a trajectory bundle of a baseline estimate (dark line) of a circadian state at any given time with uncertainty 2104 (light shading). In this example, the circadian trajectory has a strong sinusoidal component and a large amount of uncertainty over the first four days. In this example, traveling across several time zones is assumed prior to day 0 and might be the cause of the uncertainty. However, after a number of days, such as after 7.5 days, the uncertainty is greatly reduced. Various systems described herein can take into account how uncertainty can grow during periods of significant circadian disruption, while shrinking during periods of circadian stability. In this example, uncertainty of circadian state due to jet lag becomes more certain over time as the person remains in one time zone.Hardware Components

[0293] FIG. 22 is a simplified functional block diagram of a storage device 2148 having an application that can be accessed and executed by a processor in a computer system as might be part of embodiments of a patient treatment system and / or a computer system that performs the computations needed for treatment optimization. FIG. 22 also illustrates an example of memory elements that might be used by a processor to implement elements of the embodiments described herein. In some embodiments, the data structures are used by various components and tools, some of which are described in more detail herein. The data structures and program code used to operate on the data structures may be provided and / or carried by a transitoryPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) computer readable medium, e.g., a transmission medium such as in the form of a signal transmited over a network. For example, where a functional block is referenced, it might be implemented as program code stored in memory. The application can be one or more of the applications described herein, running on servers, clients or other platforms or devices and might represent memory of one of the clients and / or servers illustrated elsewhere.

[0294] Storage device 2248 can be one or more memory device that can be accessed by a processor and storage device 2248 can have stored thereon application code 2250 that can be configured to store one or more processor readable instructions, in the form of write-only memory and / or writable memory. The application code 2250 can include application logic 2252, library functions 2254, and file I / O functions 2256 associated with the application. The memory elements of FIG. 22 might be used for a server or computer that interfaces with a user, generates data, and / or manages other aspects of a process described herein.

[0295] Storage device 2248 can also include application variables 2262 that can include one or more storage locations configured to receive input variables 2264. The application variables 2262 can include variables that are generated by the application or otherwise local to the application. The application variables 2262 can be generated, for example, from data retrieved from an external source, such as a user or an external device or application. The processor can execute the application code 2250 to generate the application variables 2262 provided to storage device 2248. Application variables 2262 might include operational details needed to perform the functions described herein.

[0296] Storage device 2248 can include storage for databases and other data described herein.One or more memory locations can be configured to store device data 2266. Device data 2266 can include data that is sourced by an external source, such as a user or an external device. Device data 2266 can include, for example, records being passed between servers prior to being transmited or after being received. Other data 2268 might also be supplied.

[0297] Storage device 2248 can also include a log file 2280 having one or more storage locations 2284 configured to store results of the application or inputs provided to the application. For example, log file 2280 can be configured to store a history of actions, alerts, error messages and the like.

[0298] According to some embodiments, the techniques described herein are implemented by one or more generalized computing systems programmed to perform the techniques pursuant toPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) program instructions in firmware, memory7, other storage, or a combination. Special-purpose computing devices may be used, such as desktop computer systems, portable computer systems, handheld devices, networking devices or any other device that incorporates hardwired and / or program logic to implement the techniques.

[0299] One embodiment might include a carrier medium carrying data that includes data having been processed by the methods described herein. The carrier medium can comprise any medium suitable for carrying the data, including a storage medium, e.g.. solid-state memory, an optical disk or a magnetic disk, or a transient medium, e.g., a signal carrying the data such as a signal transmited over a network, a digital signal, a radio frequency signal, an acoustic signal, an optical signal or an electrical signal.

[0300] FIG. 23 is a block diagram that illustrates a computer system 2300 upon which the computer systems of the systems described herein and / or data structures shown in FIG. 22 may be implemented. Computer system 2300 includes a bus 2302 or other communication mechanism for communicating information, and a processor 2304 coupled with bus 2302 for processing information. Processor 2304 may be, for example, a general-purpose microprocessor.

[0301] Computer system 2300 also includes a main memory 2306, such as a random-access memory (RAM) or other dynamic storage device, coupled to bus 2302 for storing information and instructions to be executed by processor 2304. Main memory72306 may also be used for storing temporary variables or other intermediate information during execution of instructions to be executed by processor 2304. Such instructions, when stored in non-transitory storage media accessible to processor 2304, render computer system 2300 into a special-purpose machine that is customized to perform the operations specified in the instructions.

[0302] Computer system 2300 further includes a read only memory (ROM) 2308 or other static storage device coupled to bus 2302 for storing static information and instructions for processor 2304. A storage device 2310, such as a magnetic disk or optical disk, is provided and coupled to bus 2302 for storing information and instructions.

[0303] Computer system 2300 may be coupled via bus 2302 to a display 2312, such as a computer monitor, for displaying information to a computer user. An input device 2314, including alphanumeric and other keys, is coupled to bus 2302 for communicating information and command selections to processor 2304. Another type of user input device is a cursor controlPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 2316, such as a mouse, a trackball, or cursor direction keys for communicating direction information and command selections to processor 2304 and for controlling cursor movement on display 2312. This input device typically has two degrees of freedom in two axes, a first axis (e.g., x) and a second axis (e g., y), that allows the device to specify positions in a plane.

[0304] Computer system 2300 may implement the techniques described herein using customized hard-wired logic, one or more ASICs or FPGAs, firmware and / or program logic which in combination with the computer system causes or programs computer system 2300 to be a special-purpose machine. According to one embodiment, the techniques herein are performed by computer system 2300 in response to processor 2304 executing one or more sequences of one or more instructions contained in main memory 2306. Such instructions may be read into main memory 2306 from another storage medium, such as storage device 2310. Execution of the sequences of instructions contained in main memory 2306 causes processor 2304 to perform the process steps described herein. In alternative embodiments, hard-wired circuitry may be used in place of or in combination with software instructions.

[0305] The term “storage media’' as used herein refers to any non-transitory media that store data and / or instructions that cause a machine to operation in a specific fashion. Such storage media may include non-volatile media and / or volatile media. Non-volatile media includes, for example, optical or magnetic disks, such as storage device 2310. Volatile media includes dynamic memory', such as main memory' 2306. Common forms of storage media include, for example, a floppy disk, a flexible disk, hard disk, solid state drive, magnetic tape, or any other magnetic data storage medium, a CD-ROM, any other optical data storage medium, any physical medium with paterns of holes, a RAM, a PROM, an EPROM, a FLASH-EPROM, NVRAM, any other memory chip or cartridge.

[0306] Storage media is distinct from but may be used in conjunction with transmission media.Transmission media participates in transferring information between storage media. For example, transmission media includes coaxial cables, copper wire, and fiber optics, including the wires that include bus 2302. Transmission media can also take the form of acoustic or light waves, such as those generated during radio-wave and infra-red data communications.

[0307] Various forms of media may be involved in carrying one or more sequences of one or more instructions to processor 2304 for execution. For example, the instructions may initially be carried on a magnetic disk or solid-state drive of a remote computer. The remote computerPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) can load the instructions into its dynamic memory and send the instructions over a network connection. A modem or network interface local to computer system 2300 can receive the data. Bus 2302 carries the data to main memory 2306, from which processor 2304 retrieves and executes the instructions. The instructions received by main memory 2306 may optionally be stored on storage device 2310 either before or after execution by processor 2304.

[0308] Computer system 2300 also includes a communication interface 2318 coupled to bus 2302.Communication interface 2318 provides a two-way data communication coupling to a network link 2320 that is connected to a local network 2322. For example, communication interface 2318 may be a network card, a modem, a cable modem, or a satellite modem to provide a data communication connection to a corresponding ty pe of telephone line or communications line. Wireless links may also be implemented. In any such implementation, communication interface 2318 sends and receives electncal, electromagnetic, or optical signals that carry digital data streams representing various types of information.

[0309] Network link 2320 typically provides data communication through one or more networks to other data devices. For example, network link 2320 may provide a connection through local network 2322 to a host computer 2324 or to data equipment operated by an Internet Sen-ice Provider (ISP) 2326. ISP 2326 in turn provides data communication services through the world-wide packet data communication network now commonly referred to as the “Internet” 2328. Local network 2322 and Internet 2328 both use electrical, electromagnetic, or optical signals that carry digital datastreams. The signals through the various networks and the signals on network link 2320 and through communication interface 2318, which carry the digital data to and from computer system 2300, are example forms of transmission media.

[0310] Computer system 2300 can send messages and receive data, including program code, through the network(s), network link 2320, and communication interface 2318. In the Internet example, a server 2330 might transmit a requested code for an application program through the Internet 2328, ISP 2326, local network 2322, and communication interface 2318. The received code may be executed by processor 2304 as it is received, and / or stored in storage device 2310, or other non-volatile storage for later execution.Operations of processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Processes described herein (or variations and / or combinations thereof) may be performed under the control of onePATENT Attorney Ref. 63036.13WO (ARC-0013-WO) or more computer systems configured with executable instructions and may be implemented as code (e.g., executable instructions, one or more computer programs or one or more applications) executing collectively on one or more processors, by hardware or combinations thereof. The code may be stored on a computer-readable storage medium, for example, in the form of a computer program comprising a plurality of instructions executable by one or more processors. The computer-readable storage medium may be non-transitory. The code may also be carried by a transitory computer readable medium e.g., a transmission medium such as in the form of a signal transmitted over a network.VEGFR Inhibitors

[0311] VEGFR inhibitors are used to prevent angiogenesis and stop the growth of blood vessels that contribute to many diseases, including cancer, cardiovascular disease, and neurodegenerative diseases. While VEGFR inhibitors are used regularly in the treatment of numerous types of cancer and solid tumors, they may have negative side effects such as vasoconstriction, elevated blood pressure, thromboembolic events, cardiac toxicity7, and proteinuria. The VEGFR inhibitors described herein may exist in various polymorphic crystalline forms.Regorafenib

[0312] Regorafenib is a small molecule compound that functions as a multi-kinase inhibitor.Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. The chemical structure of regorafenib is described in US Patent No.8,637,553, the disclosure of which is incorporated by reference herein in its entirety.

[0313] In some embodiments, regorafenib comprises a compound having the structure below or a pharmaceutically acceptable salt thereof, or an isolated stereoisomer of a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, regorafenib comprises a pharmaceutically acceptable salt of a compound above at (I).PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0315] In some embodiments, regorafenib comprises a compound which is 4{4-[3-(4-chloro-3- trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide, or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, regorafenib comprises a pharmaceutically acceptable salt of the compound above, which is a basic salt of an organic acid or inorganic acid which is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid (tosylate salt), 1- napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, or mandelic acid.

[0317] In some embodiments, regorafenib comprises a compound which is a hydrochloride, benzenesulfonate, or methanesulfonate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-2- fluoro-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea.

[0318] In some embodiments, regorafenib comprises a pharmaceutical composition comprising the compounds above and a physiologically acceptable carrier.

[0319] In some embodiments, regorafenib comprises a pharmaceutical composition which comprises a pharmaceutically acceptable salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-2- fluoro-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea and a physiologically acceptable carrier.

[0320] In some embodiments, regorafenib comprises a compound which is a metabolite of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or an isolated stereoisomer of a pharmaceutically acceptable salt thereof where the metabolism site is either one of the two urea nitrogen atoms, or the pyridine nitrogen atom, or the methylamide functionality, or any combination of the above.

[0321] In some embodiments, regorafenib comprises a compound which is a metabolite of the compound of Formula (I).

[0322] In Formula I, a) either urea nitrogen atom carries a hydroxyl group, or b) the pyridine nitrogen atom is oxidized, or c) the amide functionality is de-methyl ated, or d) the pyridine nitrogen atom is oxidized and the amide functionality is de-methylated, or e) either urea nitrogen atom carries a hydroxyl group and the pyridine nitrogen atom is oxidized, or f) either urea nitrogen atom carries a hydroxyl group and the amide functionality is de-methylated, orPATENT Attorney Ref. 63036.13WO (ARC-0013-WO) g) either urea nitrogen atom carries a hydroxyl group and the pyridine nitrogen atom is oxidized and the amide functionality’ is de-methylated.

[0323] In some embodiments, regorafenib comprises a compound which is: 4{4-[3-(4-chloro-3- trifluoromethylphenyl)-ureido] -3 -fluorophenoxy }-pyridine-2-carboxylic acid amide, 4{4-[3- (4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-l-hydroxy-pyridine-2- carboxylic acid methylamide, or 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3- fluorophenoxy}-l-hydroxy-pyridine-2-carboxylic acid amide.

[0324] In some embodiments, regorafenib comprises a compound of Formula (I).

[0325] In some embodiments, regorafenib comprises a pharmaceutical composition comprising the compound above and a physiologically acceptable carrier.Regorafenib Crystalline Polymorphic Forms

[0326] Crystalline polymorphic forms of regorafenib are known in the art and include those described in US Patent No. 9,957,232, the disclosure of which is incorporated by reference herein in its entirety.

[0327] In some embodiments, a crystalline polymorphic form of regorafenib comprises a compound of the formula (II):

[0328] In some embodiments, a crystalline polymorphic form of regorafenib comprises a compound of the formula (II) which shows in the X-ray diffractometry a peak maximum of the 2 Theta angle of 21.2.

[0329] In some embodiments, a crystalline polymorphic form of regorafenib comprises the compound above, which shows in the FIR spectrum a peak maximum of 353 cm1.Fruquintinib

[0330] Fruquintinib is a quinazoline compound that inhibits the activity of VEGF and kinase insert domain receptor. It can be used to inhibit angiogenesis and treat subjects with angiogenesis-related disorders. The structure of fruquintinib is described in U.S. Patent No.7,829,574; U.S. Patent No.8,212,033; U.S. Patent No. 10,519,142; and U.S. Patent No.11,046.674, all of which are incorporated by reference herein in their entirety.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0331] In some embodiments, fruquintinib comprises the structure of I of 6-((6,7- dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; 6-((6,7- dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide, wherein an X-ray powder diffractogram of the Form I comprises diffraction angles expressed in degrees 2-theta (20) at: 5.3, 10.7, 13.9, and 14.6, each of the diffraction angles having an error of about ±0.2 degrees (20);

[0332] In some embodiments, fruquintinib comprises the structure of a crystalline form of the compound of Formula A (below) which has an x-ray powder diffraction pattern when measured using a CuKa radiation comprising peaks expressed in degrees 2-theta (20) at 5.3±0.2, 10.7±0.2, 13.9±0.2, and 14.6±0.2; and a pharmaceutically acceptable carrier; wherein the content of other crystalline forms of the compound of Formula A in said pharmaceutical composition is less than 40% by weight.

[0333] In some embodiments, fruquintinib comprises the compound above and a physiologically acceptable carrier.

[0334] In some embodiments, fruquintinib comprises a crystalline polymorphic form of fruquintinib.Apatinib (rivoceranib)

[0335] Apatinib, also known as rivoceranib, is an amino-amide derivative used for antiangiogenic and vascular permeability reducing effects. The structure of apatinib is described in U.S. Patent No. 7,129,252; U.S. Patent No. 8,362,256; and U.S. Patent No. 11,434,202, all of which are incorporated by reference herein in their entirety.

[0336] In some embodiments, apatinib comprises a mesylate salt of N-[4-(l- cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine carboxamide.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0337] In some embodiments, apatinib comprises the compound above and a physiologically active carrier.

[0338] In some embodiments, apatinib comprises a crystalline form (designated Form RT2, characterized by data selected from one or more of the following: a) an XRPD pattern having peaks at 10.4, 11.9, 14.2, 19.8, 20.5 and 27.0 degrees 2-theta±0.2 degrees 2-theta and having absence of peaks at 18.3, 23.0 and 26.6 degrees 2-theta±0.2 degrees 2-theta; b) an XRPD pattern having peaks at 10.4, 14.2, 16.8, 17.9, 19.8, 20.5 and 23.3 degrees 2-theta±0.2 degrees 2-theta and having absence of peaks at 5.3, 19.0, 23.0, 26.6 and 28.3 degrees 2-theta±0.2 degrees 2-theta; c) an XRPD pattern having peaks at 10.4, 11.9, 14.2, 15.8, 16.8, 19.8, 20.5, 21.8, 24.1, 25.7 and 27.0 degrees 2-theta±0.2 degrees 2-theta and having absence of peaks at 18.3, 19.6, 23.0 and 26.6 degrees 2-theta±0.2 degrees 2-theta; and d) a combination of any one or more of (a), (b) and (c).PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0339] In some embodiments, apatinib comprises the compound above and a physiologically acceptable carrier.Axitinib

[0340] Axitinib is an indazole compound that modulates / inhibits protein kinase activity, including VEGFR, for treating unwanted angiogenesis and / or cellular proliferation. The structure of axitinib is described in U.S. Patent No. 6,534,524; U.S. Patent No. 8,791,140; U.S. Patent No.10,570.202; and U.S. Patent No. 10,869,924, all of which are incorporated by reference herein in their entiret .

[0341] In some embodiments, axitinib comprises N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH- indazol-6-ylsulfanyl] -benzamide or 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin- 2-yl)ethenyl]indazole.

[0342] In some embodiments, axitinib comprises the compound above and a physiologically acceptable carrier.

[0343] In some embodiments, axitinib comprises the structure below wherein R1 is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH — R3 or CH=N — R3, where R3 is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, and, or heteroaryl; Y is O, S, C=CH2, C=O, S=O, SO2, CH2, CHCH3, NH, orN— (C1-C8 alkyl); R9 is a substituted or unsubstituted alkyl, cycloalky 1, heterocycloalkyl, ary l, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl, NH — (C1-C8 alky l), NH — (aryl), NH — (heteroaryl). N=CH — alkyl), NH(C=O)R11, or NH2, where Rll is independently selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalky l, aryl, and heteroaryl; and R10 is independently selected from hydrogen, halogen, and lower-alkyl; or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)IV

[0344] In some embodiments, axitinib comprises the compound above and a physiologically acceptable carrier.

[0345] In some embodiments, axitinib comprises a crystalline polymorphic form of 6-[2- (methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyri din-2 -yl)ethenyl] indazole.

[0346] In some embodiments, axitinib comprises the compound above and a physiologically acceptable carrier.Nintedanib

[0347] Nintedanib is an indolinone that inhibits receptor tyrosine kinases such as VEGF and CDK, and which inhibits proliferation of endothelial cells, in particular tumor cells. The structure of nintedanib is described in U.S. Patent No. 6,762.180; U.S. Patent No. 9,907,756, U.S. Patent No. 10,105.323; and U.S. Patent No. 10,154,990. all of which are incorporated herein in their entirety.

[0348] In some embodiments, nintedanib comprises methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4- methylpiperazin-l-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-lEI-indole-6- carboxylate.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0349] In some embodiments, nintedanib comprises the compound above and a physiologically acceptable carrier.

[0350] In some embodiments, nintedanib comprises a formulation of the active substance 3-Z-[ 1 - (4-(N-((4-methyl-piperazin- 1 -yl)-methylcarbonyl)-N-methyl-amino)-anilino)- 1 -phenyl- methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate which comprises a lipid suspension of the active substance in 1 to 90 wt. % of medium chain triglycerides. 1 to 30 wt. % of hard fat and 0.1 to 10 wt. % of lecithin, or A lipid suspension consisting essentially of 3- Z-[l-(4-(N-((4-methyl-piperazin-l-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-l -phenyl- methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate, medium chain triglycerides, hard fat and lecithin, wherein the medium chain triglycerides, hard fat and lecithin are present in the lipid suspension in the following amounts: 1 to 90 wt. % of medium chain triglycerides, 1 to 30 wt. % of hard fat, and 0.1 to 10 wt. % of lecithin.

[0351] In some embodiments, nintedanib comprises a pharmaceutical dosage form which is a viscous lipid suspension formulation comprising: 10 to 50 wt. % of the active substance 3-Z- [ 1 -(4-(N-((4-methyl-piperazin- 1 -y l)-methylcarbonyl)-N-methyl-amino)-anilino)- 1 -phenyl- methylenel]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate, 10 to 70 wt. % of medium chain triglycerides; 10 to 30 wt. % of hard fat; and 0.25 to 2.5 wt. % of lecithin, which delivers an immediate release profde in which not less than 70% (Q65%) of the active substance is dissolved in 60 minutes in vitro under the following in vitro dissolution conditions according to European Pharmacopeia 6.2: Apparatus 2 (paddle), dissolution medium with 0.1 M HC1 (pH 1) and stirring speed of 50 to 150 rpm, at a temperature of 37° C.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0352] In some embodiments, nintedanib comprises a therapeutically effective amount of 3-Z-[ 1 - (4-(N-((4-methy 1-piperazin- 1 -yl)-methylcarbonyl)-N-methyl-amino)-anilino)- 1 -phenyl- methylene]-6-methoxycarbonyl-2-indolinone, or a salt or crystalline polymorphic form thereof.Pexidartinib

[0353] Pexidartinib is a kinase inhibitor of c-Kit, c-fms, and VEGF. The structure of pexidartinib is provided in U.S. Patent No. 7,893.75; U.S. Patent No. 8,404,700; U.S. Patent No. 8,461,169; U.S. Patent No. 8,722,702; U.S. Patent No. 9,169,250; U.S. Patent No. 9,358,235; U.S. Patent No. 9,802,932; U.S. Patent No. 10,189,833; U.S. Patent No. 10,435,404; U.S. Patent No.10,730,876; U.S. Patent No. 10,941,142; and U.S. Patent No. 10,961,240, all of which are incorporated by reference herein in their entirety.

[0354] In some embodiments, pexidartinib comprises the chemical structure 5-[(5-Chloro-lH- pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)-3-pyridinyl]methyl}-2- pyridinamine.

[0355] In some embodiments, pexidartinib comprises a crystalline form of the compound above characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.1, 22.9 and 27.6 °20 as determined on a diffractometer using Cu — Kot radiation.

[0356] In some embodiments, pexidartinib comprises a therapeutically effective amount of a polymorphic cry stalline form of pexidartinib.

[0357] In some embodiments, pexidartinib comprises a composition 40% to 60% WAV of Compound I, having the structure above wherein Compound I is a crystalline HC1 salt characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.3, 23.3 andPATENT Attorney Ref. 63036.13WO (ARC-0013-WO) 28.2° 20 as determined on a diffractometer using Cu-Ka radiation; 20% to 35% WAV of a poloxamer; 10% to 22% WAV of an excipient; 1% to 5% WAV of a disintegrant; and 0.5% to 3% WAV of a lubricant.Ponatinib

[0358] Ponatinib is a protein kinase inhibitor. The structure of ponatinib is described in U.S.Patent No. 8.114,874; U.S. Patent No 9,029,533; U.S. Patent No 9,493,470; U.S. Patent No.11,192.895; U.S. Patent No 11,192,897; and U.S. Patent No. 11,384,086, all of which are incorporated by reference herein in their entirety.

[0359] In some embodiments, ponatinib comprises 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methylpiperazin-l-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide.

[0360] In some embodiments, ponatinib comprises Crystalline Form A of ponatinib hydrochloride characterized by an x-ray powder diffraction pattern comprising at least five 20 values (±0.3) chosen from 5.9, 7.1, 10.0, 12.5, 16.4, 19.3, 21.8, 23.8, and 26.1.

[0361] In some embodiments, ponatinib comprises Crystalline Form A ponatinib hydrochloride characterized by an x-ray powder diffraction pattern comprising at least five 20 values (±0.3) chosen from 5.9, 7.1, 10.0. 12.5, 13.6, 14.1, 15.0, 16.4, 17.7, 18.6, 19.3, 20.4.21.8, 22.3, 23.8, 24.9. 26.1, 27.0, 28.4, 30.3, 31.7, and 35.1.

[0362] In some embodiments, ponatinib comprises at least one crystalline form of ponatinib hydrochloride characterized by: a) an x-ray powder diffraction pattern comprising at least three 20 values (±0.3) chosen from 5.9, 7.1, 10.0, 12.5, 13.6, 14.1, 15.0, 16.4, 17.7. 18.6, 19.3, 20.4, 21.8, 22.3, 23.8, 24.9, 26.1, 27.0. 28.4. 30.3. 31.7. and 35.1; b) an x-ray powder diffraction pattern comprising at least three 20 values (±0.3) chosen from 3.1, 6.5, 12.4, 13.8, 15.4, 16.2, 17.4, 18.0, 20.4, 23.2, 24.4, 26.1, and 26.9; c) an x-ray powder diffraction pattern comprising at least three 20 values (±0.3) chosen from 3.1, 6.5, 12.4, 13.8, 17.4, 18.0, 20.6, 22.0, 23.0,PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 25.5, 26.5, 27.4, 28.4, and 29.0; d) an x-ray powder diffraction pattern comprising at least three 29 values (±0.3) chosen from 8.2, 10.1, 10.9. 14.9, 16.0, 16.3, 16.8, 17.7, 18.7, 20.2.22.9, 24.0, 25.6, 26.7, and 28.5; e) an x-ray powder diffraction patern s labelled HC11+HC14 (GRPl.l); 1 an x-ray powder diffraction pattern comprising at least three 20 values (±0.3) chosen from 7.9, 8.7, 9.7, 11.4, 15.6, 16.5, and 25.8; g) an x-ray powder diffraction patern substantially as shown in FIG. 41 labelled HC15b (VDS28.2); h) an x-ray powder diffraction patern comprising at least three 20 values (±0.3) chosen from 8.0. 10.2. 10.9. 11.8. 14.1. 15.4, 16.3, 19.9, 22.3, 23.7, 25.0, and 28.2; i) an x-ray powder diffraction patern comprising at least three 20 values (±0.3) chosen from 6.1, 7.0, 13.3, 16.4, 20.7, 22.2, 23.9, 25.5, and 29.1; or j) an x- ray powder diffraction patern comprising at least three 20 values (±0.3) chosen from 6.1, 7.4, 13.5, 17.4, 18.5, 20.7, 23.9, and 28.3.

[0363] In some embodiments, ponatinib comprises a crystalline form of ponatinib hydrochloride characterized by an x-ray powder diffraction patern comprising at least three 20 values (±0.3) chosen from 5.9, 7.1, 10.0, 12.5, 13.6, 14.1, 15.0, 16.4, 17.7, 18.6, 19.3, 20.4, 21.8, 22.3, 23.8, 24.9, 26.1, 27.0, 28.4, 30.3, 31.7, and 35.1.

[0364] In some embodiments, ponatinib comprises crystalline anhydrous ponatinib hydrochloride, characterized by an X-ray diffraction patern comprising 20 values (±0.3) at 5.9, 7.1, 12.5, 19.3, 23.8, and 26.1.

[0365] In some embodiments, ponatinib comprises a pharmaceutical composition comprising crystalline anhydrous ponatinib hydrochloride characterized by an X-ray diffraction patern comprising 20 values (±0.3) at 5.9, 7.1, 12.5, 19.3, 23.8, and 26.1 and a pharmaceutically acceptable carrier.

[0366] In some embodiments, ponatinib comprises a therapeutically effective amount of the compounds described in this section, or a salt or crystalline polymorphic form thereof.Surufatinib

[0367] Surufatinib is a VEGFR-2 and FGF inhibitor. The structure of surufatinib is described in W.O. 2011 / 060746, the content of which is incorporated by reference herein in its entirety.

[0368] In some embodiments, surufatinib comprises A / -(2-(dimethylamino) ethyl)-l -(3-((4-((2- methyl-1 H-indol-5- yl)oxy)pyrimi din-2- l)amino)phenyl)methanesulfonamide and / or a pharmaceutically acceptable salt thereof, and / or a polymorphic crystalline form of surufatinib.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0369] In some embodiments, surufatinib comprises a pharmaceutical composition, comprising at least one pharmaceutically acceptable carrier and A / -(2-(dimethylamino) ethyl)- 1 -(3-((4- ((2-methyl-l H-indol- 5-yl)oxy)p rimidin-2-yl)amino)phenyl)methanesulfonamide, or a polymorphic crystalline form of surufatinib.

[0370] In some embodiments, surufatinib comprises the compound described in this section and a physiologically acceptable carrier.Brivanib

[0371] Brivanib is a selective inhibitor of VEGF and FGF. The structure of brivanib is described in U.S. Patent Publication No. 2015 / 0297603, the content of which is incorporated by reference herein in its entirety.

[0372] In some embodiments, brivanib comprises a wet granulated tablet formulation of Compound la, which comprises Compound la as the active pharmaceutical ingredient and one or more fillers, binders, disintegrants, and / or lubricants.

[0373] In some embodiments, brivanib comprises a crystalline polymorphic form of brivanib. In some embodiments, brivanib comprises the structure above and a physiologically acceptablePATENT Attorney Ref. 63036.13WO (ARC-0013-WO) carrier. In some embodiments, brivanib comprises a cry stalline polymorphic form of brivanib and a physiologically acceptable carrier.Cediranib

[0374] Cediranib is an inhibitor of VEGF. The structure of cediranib is described in the content of U.S. Patent Application No. 2007 / 0129387 and U.S. Patent No. 8,859,570, all of which are incorporated by reference herein in their entirety.

[0375] In some embodiments, cediranib comprises 4-[(4-fluoro-2-methyl-lH-indol-5-yl)oxy]-6- methoxy-7-[3-(pyrrolidin-l-yl)propoxy]quinazoline.

[0376] In some embodiments, cediranib comprises a maleate salt of 4-((4-fluoro-2-methyl-lH- indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-l-yl)propoxy)quinazoline in a Form A crystalline form, wherein the salt has at least three XRPD peaks selected from 21.5, 16.4, and 24.4 degrees theta.

[0377] In some embodiments, cediranib comprises maleate salt of 4-((4-fluoro-2-methyl-lH- indol-5-yl)oxy)-6 -methoxy-7-(3-(pyrrolidin-l-yl)propoxy)quinazoline in a Form B crystalline form, wherein the salt has at least three XRPD peaks selected from 24.2, 22.7 and 15.7 degrees theta.

[0378] In some embodiments, cediranib comprises a polymorphic crystalline form of cediranib.

[0379] In some embodiments, cediranib comprises the compound described in this section a physiologically acceptable carrier. In some embodiments, cediranib comprises a polymorphic crystalline form of cediranib and a physiologically acceptable carrier.Chiauranib

[0380] Chiauranib is a small molecule antitumor targeted drug targeting multiple protein kinases.The structure of chiauranib is described in CN Patent Application 2009 / 10223861 and CNPATENT Attorney Ref. 63036.13WO (ARC-0013-WO) Patent Application 2009 / 1022386, all of which are incorporated by reference herein in their entirety.

[0381] In some embodiments, chiauranib comprises N-(2-aminophenyl)-6-(7-methoxyquinolin- 4-yl)oxynaphthalene- 1 -carboxamide.

[0382] In some embodiments, chiauranib comprises a napthamide derivative with both the protein kinase inhibition activity and histone deacetylase inhibition activity, and may be used for treating diseases associated with abnormal protein kinase activity or abnormal histone deacetylase activity.

[0383] In some embodiments, chiauranib comprises a pharmaceutical composition of nonsolvated chiauranib crystals A, B, and C.

[0384] In some embodiments, chiauranib comprises the compound above with a physiologically acceptable carrier.

[0385] In some embodiments, chiauranib comprises a polymorphic crystalline form of chiauranib.In some embodiments, chiauranib comprises a polymorphic crystalline form of chiauranib and a physiologically acceptable carrier.Dovitinib

[0386] Dovitinib (also known as TKI258) is a small-molecule inhibitor of VEGF, TNF alpha, PDGFR, and c-KIT. The method for use of dovitinib is described in WO Patent Application 2022 / 026851, which is incorporated by reference herein in its entirety.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0387] In some embodiments, dovitinib comprises the structure 4-amino-5-fluoro-3-[6-(4- methylpiperazin-l-yl)-lH-benzimidazol-2-yl]-lH-quinolin-2-one.

[0388] In some embodiments, a method for the use of dovitinib comprises targeting an RNA entity comprising contacting the RNA entity with a binding composition wherein the RNA entity is pre-miR-21, an oncogenic cell line containing pre-miR-21, the cell line being TNBC breast cancer cell line, MDA-MD-231 breast cancer cell line, prostate cancer cell line, nonsmall-cell lung carcinoma cell line, an animal host having an oncogenic cell line associated with pre-miR-21, a human having an oncogenic malignancy associated with pre-miR-21; or an animal host having Alport Syndrome kidney disease, or a human having Alport Syndrome kidney disease; or any disease in which pre-miR-21 is causative or contributive; and, the binding composition comprises at least a Ribotac-Dovitinib having a formula of Compound 2 or a Protac-Dovitinib having a formula of Compound 3.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)Compound 3

[0389] In some embodiments, dovitinib comprises the compound 2 or compound 3 above with a physiologically acceptable carrier.

[0390] In some embodiments, dovitinib comprises a polymorphic crystalline form of dovitinib.In some embodiments, dovitinib comprises a polymorphic crystalline form of dovitinib and a physiologically acceptable carrier.Enzastaurin

[0391] Enzastaurin is a VEGF and PKC beta inhibitor. The structure of enzastaurin is described in U.S. Patent No. 11,938,135, which is incorporated by reference herein in its entirety.

[0392] In some embodiments, enzastaurin comprises 3-(l-methyl-3-indolyl)-4-[l-[l-(2- pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2, 5-dione.

[0393] In some embodiments, the structure of enzastaurin is as below:PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0394] In some embodiments, enzastaurin comprises the compound described above and a physiologically acceptable carrier.

[0395] In some embodiments, enzastaurin comprises the compound described above or an acceptable salt thereof, or a polymorphic crystalline form of enzastaurin.

[0396] In some embodiments, enzastaurin comprises a polymorphic crystalline form of enzastaurin and a physiologically acceptable carrier.Famitinib

[0397] Famitinib is a VEGF and EGFR inhibitor. The structure of famitinib is further disclosed in U.S. Patent No. 10,973,807; and [Hu] which are incorporated by reference herein in their entiretv.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0398] In some embodiments, famitinib comprises a pharmaceutical composition, comprising 5- (2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-l,2-dihydro-indol-3-ylidene-methyl)-3-methyl-l, 5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one or a pharmacologically acceptable salt thereof as an active ingredient and mannitol as a water-soluble filler, wherein d(0.9) of the active ingredient, determined by a Malvern Laser Particle Size Analyzer Mastersizer2000, is less than 100 pm.

[0399] In some embodiments, famitinib comprises an acceptable salt thereof. In some embodiments, famitinib comprises a polymorphic crystalline form.

[0400] In some embodiments, famitinib comprises the compound described above and a physiologically acceptable carrier.Foretinib

[0401] Foretinib is an inhibitor of kinases, including Ret, c-Met, and VEGFR2. The structure of foretinib is described in WO2014145693, which is incorporated by reference herein in its entirety7.

[0402] In some embodiments, foretinib comprises N-[3-fluoro-4-({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide.

[0403] In some embodiments, foretinib comprises an isolated metabolite of foretinib. In some embodiments, foretinib comprises a polymorphic form of foretinib.

[0404] In some embodiments, foretinib comprises the compound described above in combination with a physiologically acceptable carrier.Linifanib

[0405] Linifanib acts strongly and selectively on Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF), inhibiting the growth of tumor cells by inhibitingPATENT Attorney Ref. 63036.13WO (ARC-0013-WO) tumor angiogenesis. The structure of linifanib is described in EP Patent No. 1638941, which is incorporated by reference herein in its entirety.In some embodiments, linifanib comprises N- [4- (3-amino-lH-indazol-4-yl) phenyl ] -N' - (2- fluoro-5 -methylphenyl) urea, as in the compound depicted below.

[0406] In some embodiments, linifanib comprises a polymorphic crystalline form of linifanib.

[0407] In some embodiments, linifanib comprises the compound above in combination with a physiologically acceptable carrier. In some embodiments, linifanib comprises a polymorphic cry stalline form of lucitanib and a physiologically acceptable carrier.Lucitanib

[0408] Lucitanib is an angiogenesis inhibitor and a potent inhibitor of the fibroblast growth factor receptors 1-3 (FGFR1-3), vascular endothelial growth factor receptors 1-3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFRa / b). The structure of lucitanib is described in WO 2021 / 142237, which is incorporated by reference herein in its entirety.

[0409] In some embodiments, lucitanib comprises 6-((7-((l-aminocyclopropyl)methoxy)-6- methoxyquinolin-4- yl)oxy)-N-methyl-l-naphthamide.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0410] In some embodiments, lucitanib comprises a polymorphic crystalline form of lucitanib.

[0411] In some embodiments, lucitanib comprises the compound above and a physiologically acceptable carrier. In some embodiments, lucitanib comprises a polymorphic crystalline form of lucitanib and a physiologically acceptable carrier.Motesanib

[0412] Motesanib is a VEGFR and c-Met inhibitor. The structure of motesanib is further described in U.S. Patent Publication No. 2014 / 0243339, which is incorporated by reference herein in its entirety.

[0413] In some embodiments, motesanib comprises 4-(4-{3-[4-chloro-3- (trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide.

[0414] In further embodiments, motesanib further comprises pharmaceutically acceptable derivatives, such as fluorinated derivatives and pharmaceutically active diphenyl urea compounds.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0415] In some embodiments, motesanib comprises a polymorphic crystalline form of motesanib.

[0416] In further embodiments, motesanib comprises the compounds described in this section and a physiologically acceptable earner.Orantinib

[0417] Orantinib is a multi-kinase inhibitor. The structure of orantinib is further described in [Menendez] , and WO 2017 / 120601, which are incorporated by reference herein in their entirety.

[0418] In some embodiments, orantinib comprises 3-(2,4-dimethyl-5-((2-oxo-l,2-dihydro-3H- indol-3-ylidene)methyl)-lH-pyrrol-3-yl)propionic acid.

[0419] In some embodiments, orantinib further comprises a polymorphic crystalline form of orantinib.

[0420] In some embodiments, orantinib comprises the structure above or a polymorphic crystalline form of orantinib and a physiologically acceptable carrier.Semaxanib

[0421] Semaxanib is a receptor tyrosine kinase inhibitor. The structure of semaxanib is provided in U.S. Patent Publication No. 2014 / 0011855, which is incorporated by reference herein in its entirety7.

[0422] In some embodiments, semaxanib comprises (3Z)-3-[(3,5-dimethyl-lH-pyrrol-2- yl)methylidene]-lH-indol-2-one or a polymorphic crystalline form thereof.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0423] In some embodiments, semaxanib comprises a composition comprising a compound comprising (i) a semaxanib moiety residue covalently attached via a linkage to a water-soluble, non-peptidic oligomer, and (ii) optionally, a pharmaceutically acceptable excipient.

[0424] In some embodiments, semaxanib comprises a polymorphic crystalline form of semaxanib.

[0425] In some embodiments, semaxanib comprises the compound described above and a physiologically acceptable carrier.Sitravatinib

[0426] Sitravatinib is a small molecule inhibitor of tyrosine kinases.

[0427] The structure of sitravatinib is described in [Yang], which is incorporated by reference herein in its entirety.

[0428] In some embodiments, sitravatinib further comprises the compound above and a physiologically acceptable carrier. In some embodiments, sitravatinib comprises a polymorphic crystalline form of sitravatinib. In some embodiments, sitravatinib comprises a polymorphic crystalline form of sitravatinib in a physiologically acceptable carrier.TelatinibPATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0429] Telatinib is an inhibitor of VEGFR-2 (vascular endothelial grow th factor receptor 2) and PDGFR (human platelet-derived growth factor receptor) kinase activity, The structure of telatinib is described in Patent Application WO 2018 / 188495 and EP Patent No. 4367120, which are incorporated by reference herein in their entirety.

[0430] In some embodiments, telatinib comprises the crystalline compound of Formula 1, such that when X-ray diffraction CuKa analysis is used, X-ray appears in the X-ray diffraction patern at 4.01. 7.85. 9.94. 13.4. 19.8. 19.46, 20.10, 21.82, 22.49, 23.76. 24.26, 27.17, 28.52, 30.48 of a Ray powder diffraction peak.

[0431] In some embodiments, telatinib comprises a crystalline form of Telatinib mono mesylate, designated as Form TM2, which is characterized by an XRPD patern having peaks at 16.0, 16.5, 18.0, 22.6 and 24.9 degrees 2-theta± 0.2 degrees 2-theta.

[0432] In some embodiments, telatinib comprises telatinib and a physiologically acceptable carrier.

[0433] In some embodiments, telatinib comprises a polymorphic cry stalline form of telatinib. In some embodiments, telatinib comprises a polymorphic cry stalline form of telatinib in a physiologically acceptable carrier.Vadimezan

[0434] Vadimezan (also known as ASA404 or DMXAA) is a tumor vascular disrupting agent.The structure of vadimezan is described in U.S. Patent No. 7,585,893, which is incorporated by reference herein in its entirety’.

[0435] In some embodiments, vadimezan comprises 5,6-dimethylxanthenone-4-acetic acid (DMXAA) or a pharmaceutically acceptable salt or ester thereof, as in Formula I.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO)

[0436] In some embodiments, vadimezan comprises vadimezan and a physiologically acceptable carrier.

[0437] In some embodiments, vadimezan comprises a polymorphic crystalline form of vadimezan. In some embodiments, vadimezan comprises a polymorphic crystalline form of vadimezan in a physiologically acceptable carrier.Vatalanib

[0438] Vatalanib is a small molecule protein kinase inhibitor that inhibits VEGF family members and blocks angiogenesis. The structure of vatalanib is described U.S. Patent No. 6,710,147, which is incorporated by reference herein in its entirety.

[0439] In some embodiments, vatalanib comprises the structure N-(4-chlorophenyl)-4-(pyridin- 4-y lmethyl)phthalazin- 1 -amine.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0440] In some embodiments, vatalanib further comprises a therapeutically effective amount of the compound above or a pharmaceutically acceptable salt thereof. In some embodiments, vatalanib comprises a polymorphic crystalline form of vatalanib.

[0441] In some embodiments, vorolanib comprises the structure above or a polymorphic crystalline form thereof, and a physiologically acceptable carrier.Vorolanib

[0442] Vorolanib is a small molecule VEGFR and PDGFR inhibitor. The structure of vorolanib is described in U.S. Patent Publication No. 2022 / 0168142, which is incorporated by reference herein in its entirety.

[0443] In some embodiments, vorolanib (also known as X-82) comprises the chemical designation S,Z) — N-(l-(Dimethylcarbamoyl)pyrrolidin-3-yl)-5-((5-fluoro-2-oxoindolin-3- ylidene)methyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide. In some embodiments, vorolanib has the structure below:

[0444] In some embodiments, vorolanib comprises amorphous and crystalline forms, polymorphic crystalline forms, hydrates and solvates of vorolanib or its pharmaceutically acceptable salts.

[0445] In some embodiments, vorolanib comprises the structure above or a polymorphic crystalline form thereof, and a physiologically acceptable carrier.Pharmaceutical Compositions. Uses and Methods of Treatment

[0446] It is another aspect of the present invention to provide pharmaceutical compositions comprising regorafemb or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0447] It is another aspect of the present invention to provide pharmaceutical compositions comprising apatinib (rivoceranib) or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0448] It is another aspect of the present invention to provide pharmaceutical compositions comprising axitinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0449] It is another aspect of the present invention to provide pharmaceutical compositions comprising brivanib or a cry stal I i ne polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0450] It is another aspect of the present invention to provide pharmaceutical compositions comprising cediranib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0451] It is another aspect of the present invention to provide pharmaceutical compositions comprising chiauranib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0452] It is another aspect of the present invention to provide pharmaceutical compositions comprising dovitinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0453] It is another aspect of the present invention to provide pharmaceutical compositions comprising enzastaurin or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0454] It is another aspect of the present invention to provide pharmaceutical compositions comprising famitinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0455] It is another aspect of the present invention to provide pharmaceutical compositions comprising fruquintinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0456] It is another aspect of the present invention to provide pharmaceutical compositions comprising foretinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0457] It is another aspect of the present invention to provide pharmaceutical compositions comprising linifanib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0458] It is another aspect of the present invention to provide pharmaceutical compositions comprising lucitanib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0459] It is another aspect of the present invention to provide pharmaceutical compositions comprising motesanib or a cry stalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0460] It is another aspect of the present invention to provide pharmaceutical compositions comprising nintedanib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0461] It is another aspect of the present invention to provide pharmaceutical compositions comprising orantinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0462] It is another aspect of the present invention to provide pharmaceutical compositions comprising pexidartinib or a cry stalline polymorphic form thereof in admixture wi th a suitable pharmaceutically acceptable carrier.

[0463] It is another aspect of the present invention to provide pharmaceutical compositions comprising ponatinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0464] It is another aspect of the present invention to provide pharmaceutical compositions comprising regorafenib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0465] It is another aspect of the present invention to provide pharmaceutical compositions comprising semaxanib or a cry stalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0466] It is another aspect of the present invention to provide pharmaceutical compositions comprising sitravatinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0467] It is another aspect of the present invention to provide pharmaceutical compositions comprising surufatinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0468] It is another aspect of the present invention to provide pharmaceutical compositions comprising telatinib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0469] It is another aspect of the present invention to provide pharmaceutical compositions comprising vadimezan or a cr stal line polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0470] It is another aspect of the present invention to provide pharmaceutical compositions comprising vatalanib or a crystalline polymorphic form thereof in admixture with a suitable pharmaceutically acceptable carrier.

[0471] Pharmaceutical compositions in accordance with embodiments of the invention include a compound of the present invention and pharmaceutically acceptable salts thereof. These compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. The term '‘pharmaceutically acceptable carrier” is meant as any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed-release preparations, orally, parenterally, topically, nasally, opthalmically, sublingually, rectally, vaginally, and the like.

[0472] For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and com starch.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0473] In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, com starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, com starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify7the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both.

[0474] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or weting agent, a suspending agent and one or more preservatives. Suitable dispersing or weting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.

[0475] The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soybean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[0476] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil suchPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

[0477] Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.

[0478] The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally. as injectable dosages of the compound in a physiologically acceptable diluent w ith a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-l,l-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, an oil. a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

[0479] Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cotonseed oil, com oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylenePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta- aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

[0480] The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

[0481] Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

[0482] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or weting agents and suspending agents such as. for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alky lene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatly acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

[0483] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed includingPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0484] A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such material is, for example, cocoa buter and polyethylene glycol.

[0485] Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art.

[0486] The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: [Powell], [Strickley], and [Nema],

[0487] Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-CCIF2 and CCIF3); air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyd alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehydePATENT Attorney Ref. 63036.13WO (ARC-0013-WO) sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carry ing agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, com oil, mineral oil, peanut oil, sesame oil. bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (examples include but are not limited to edetate disodium and edetic acid); colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate); flavorants (examples include but are not limited to anise oil. cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxyhc acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas); plasticizers (examples include but are not limited to diethyl phthalate and glycerol); solvents (examples include but are not limited to ethanol, com oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository basesPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) (examples include but are not limited to cocoa buter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, com starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet / capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnauba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, sodium alginate and tragacanth); and weting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0488] Pharmaceutical compositions according to the present invention can be illustrated as follows:

[0489] Sterile IV Solution: a 5 mg / mL solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1-2 mg / mL with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.

[0490] Lyophilized powder for IV administration: A sterile preparation can be prepared with (i) 100-1000 mg of the desired compound of this invention as a lyphilized powder, (ii) 32-327 mg / mL sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg / mL, which is further diluted with saline or dextrose 5% to 0.2-0.4 mg / mL, and is administered either IV bolus or by IV infusion over 15-60 minutes.

[0491] Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:• 50 mg / mL of the desired, water-insoluble compound of this invention• 5 mg / mL sodium carboxymethylcellulose• 4 mg / mL Tween 80• 9 mg / mL sodium chloride• 9 mg / mL benz l alcohol

[0492] Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two- piece hard galantine capsules each with 100 mg of pow dered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

[0493] Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cotonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.

[0494] Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg ofPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

[0495] Immediate Release Tablets / Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.

[0496] Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of any of the diseases described herein, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[0497] The total amount of the active ingredient to be administered can range from about 0.001 mg / kg to about 200 mg / kg, and preferably from about 0.1 mg / kg to about 50 mg / kg body weight per day. A unit dosage may preferably contain from about 5 mg to about 4000 mg of active ingredient, and can be administered one or more times per day. The daily dosage for oral administration will preferably be from 0.1 to 50 mg / kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.1 to 10 mg / kg of total body weight. The daily rectal dosage regimen will preferably be from 0.1 to 50 mg / kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.1 to 50 mg / kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 10 mg / kg administered between one to four times daily. The transdermal concentration will preferablyPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) be that required to maintain a daily dose of from 0.1 to 10 mg / kg. The daily inhalation dosage regimen will preferably be from 0.1 to 10 mg / kg of total body weight. Other dosages and amounts can be selected routinely.

[0498] The specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the atending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

[0499] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of a VEGFR-inhibitor to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with a VEGFR-inhibitor. In some embodiments, the VEGFR inhibitor is selected from the group consisting of: apatinib (rivoceranib), axitinib, brivanib, cediranib, chiauranib, dovitinib, enzastaurin, famitinib, foretinib, fruquintinib, linifanib, lucitanib, motesanib, nintedanib, orantinib, pexidartinib, ponatinib, regorafenib, semaxanib, sitravatinib, surufatinib, telatinib, vadimezan, vatalanib, and vorolanib, or a cry stalline polymorphic form thereof. In some embodiments, the method further comprises determining a second circadian administration window, and administering an anti-cancer therapy to the patient during the second circadian administration window. In some embodiments, the anti-cancer therapy comprises a chemotherapeutic agent, a radiotherapy, an immunotherapy, or any combination thereof.

[0500] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of regorafenib (or a cry stalline polymorphic form of regorafenib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulatingPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) protocol prior to treatment with regorafenib. In some embodiments, the VEGFR-mediated disease is cancer, retinopathy or preeclampsia.

[0501] Methods for the treatment of cancers using regorafenib or crystalline polymorphic forms of regorafenib are described in US Patent No. 8,680,124, the disclosure of which is incorporated by reference herein. In some embodiments, the cancer has acquired resistance to a KIT tyrosine kinase inhibitor.

[0502] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of apatinib / rivoceranib (or a crystalline polymorphic form of apatinib / rivoceranib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with apatinib / rivoceranib. As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of axitinib(or a crystalline polymorphic form of axitinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with axitinib. In some embodiments, the VEGFR-mediated disease is advanced renal cell carcinoma.

[0503] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of brivanib (or a crystalline polymorphic form of brivanib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with brivanib.

[0504] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of chiauranib (or a cry stalline polymorphic formPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) of chiauranib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with regorafenib. As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of chiauranib (or a crystalline polymorphic form of chiauranib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with chiauranib.

[0505] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of dovitinib (or a crystalline polymorphic form of dovitinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with dovitinib.

[0506] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of enzastaurin (or a cry stalline polymorphic form of enzastaurin) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory w ith a circadian rhythm modulating protocol prior to treatment with enzastaurin.

[0507] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of famitinib (or a crystalline polymorphic form of famitinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with famitinib.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0508] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of foretinib (or a crystalline polymorphic form of foretinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with foretinib. As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian- mapping profiles to determine a circadian administration window for a dose of fruquintinib (or a crystalline polymorphic form of fruquintinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with fruquintinib. In some embodiments, the VEGFR-mediated disease is metastatic colorectal cancer.

[0509] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of linifanib (or a crystalline polymorphic form of linifanib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory’ with a circadian rhythm modulating protocol prior to treatment with linifanib.

[0510] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of lucitanib (or a crystalline polymorphic form of lucitanib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory' with a circadian rhythm modulating protocol prior to treatment with lucitanib. As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian- mapping profiles to determine a circadian administration window for a dose of motesanib (or a crystalline polymorphic form of motesanib) to be administered to the patient, andIll of 149PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient's circadian trajectory with a circadian rhythm modulating protocol prior to treatment with motesanib.

[0511] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of orantinib (or a crystalline polymorphic form of orantinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with orantinib. As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian- mapping profiles to determine a circadian administration window for a dose of nintedanib (or a crystalline polymorphic form of nintedanib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient's circadian trajectory with a circadian rhythm modulating protocol prior to treatment with nintedanib.

[0512] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of pexidartinib (or a crystalline polymorphic form of pexidartinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with pexidartinib. In some embodiments, the VEGFR-mediated disease is a tenosynovial giant cell tumor.

[0513] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of ponatinib (or a crystalline polymorphic form of ponatinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulatingPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) protocol prior to treatment with ponatinib. In some embodiments, the VEGFR-mediated disease is acute lymphoblastic leukemia.

[0514] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of semaxanib (or a crystalline polymorphic form of semaxanib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with semaxanib. As described herein, aspects of the invention include performing a circadian trajectory7assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of sitravatinib (or a crystalline polymorphic form of sitravatimb) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with sitravatinib. As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining a circadian administration window for the VEGFR-mediated disease based on the circadian trajectory assessment and a dose of sitravatinib to be administered to the patient, and administering the dose to the patient during the circadian administration window;

[0515] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window7for a dose of surufatinib (or a crystalline polymorphic form of surufatinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory' with a circadian rhythm modulating protocol prior to treatment with surufatinib. In some embodiments, the VEGFR-mediated disease is extrapancreatic NET, or advanced pancreatic NET.

[0516] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of telatinib (or a crystalline polymorphic form ofPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) telatinib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory with a circadian rhythm modulating protocol prior to treatment with telatinib.

[0517] As described herein, aspects of the invention include performing a circadian trajectory7assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of vadimezan (or a crystalline polymorphic form of vadimezan) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory7with a circadian rhythm modulating protocol prior to treatment with vadimezan.

[0518] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of vatalanib (or a cry stalline polymorphic form of vatalanib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient’s circadian trajectory7with a circadian rhythm modulating protocol prior to treatment with vatalanib.

[0519] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining one or more circadian-mapping profiles to determine a circadian administration window for a dose of vorolanib (or a crystalline polymorphic form of vorolanib) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, aspects of the invention further comprise modifying a patient's circadian trajectory7with a circadian rhythm modulating protocol prior to treatment with vorolanib. In some embodiments, the VEGFR-mediated disease is renal cell carcinoma.

[0520] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining a circadian administration window for the VEGFR- mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor has a mean half-life thatPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) ranges from 24 to 30 hours, such as 24 hours, 24.5 hours, 25 hours, 25.5 hours, 26 hours, 26.5 hours, 27 hours, 27.5 hours, 28 hours. 28.5 hours, 29 hours, 29.5 hours, or 30 hours. In some embodiments, the VEGFR inhibitor is selected from the group consisting of regorafenib, ponatinib, chiauranib, and pexidartinib.

[0521] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining a circadian administration window for the VEGFR- mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor has a mean half-life that ranges from 19 to 24 hours, such as 19 hours, 19.5 hours, 20 hours, 20.5 hours, 21 hours, 21.5 hours, 22 hours, 22.5 hours, 23 hours, 23.5 hours, or 24 hours. In some embodiments, the VEGFR inhibitor is selected from the group consisting of nintedanib and cediranib.

[0522] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining a circadian administration window for the VEGFR- mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor has a mean half-life that ranges from 15 to 19 hours, such as 15 hours, 15.5 hours, 16 hours, 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, or 19 hours. In some embodiments, the VEGFR inhibitor is selected from the group consisting of surufatinib and linifanib.

[0523] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining a circadian administration window for the VEGFR- mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor has a mean half-life that ranges from 10 to 15 hours, such as 10 hours, 10.5 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, or 15 hours. In some embodiments, the VEGFR inhibitor is selected from the group consisting of axitinib, brivanib, and enzastaurin.

[0524] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining a circadian administration window for the VEGFR- mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitorPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor has a mean half-life that ranges from 5 to 10 hours, such as 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, or 10 hours. In some embodiments, the VEGFR inhibitor is selected from the group consisting of telatinib, vorolanib, apatinib (rivoceranib), vadimezan, and motesanib.

[0525] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining a circadian administration window for the VEGFR- mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor has a mean half-life that ranges from 0.5 to 5 hours, such as 0.5 hours, 1 hours, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours. In some embodiments, the VEGFR inhibitor is selected from the group consisting of semaxanib, orantinib, and vatalanib.

[0526] As described herein, aspects of the invention include performing a circadian trajectory assessment on the patient, determining a circadian administration window for the VEGFR- mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient, and administering the dose to the patient during the circadian administration window. In some embodiments, the VEGFR inhibitor has a mean half-life that is greater than 30 hours, such as 30.5 hours, 31 hours. 31.5 hours, 32 hours, 32.5 hours. 33 hours, 33.5 hours, 34 hours, 34.5 hours, 35 hours, 35.5 hours, 36 hours, 36.5 hours, 37 hours, 37.5 hours, 38 hours, 38.5 hours, 39 hours, 39.5 hours, 40 hours, 40.5 hours, 41 hours, 41.5 hours, 42 hours, 42.5 hours, 43 hours, 43.5 hours, 44 hours, 44.5 hours, or greater than 45 hours. In some embodiments, the VEGFR inhibitor is selected from the group consisting of famitinib, dovitinib, lucitanib, foretinib, and sitravatinib.

[0527] In some embodiments, aspects of the invention include methods of treating a VEGFR- mediated disease in a patient in need thereof, the method comprising: estimating a circadian trajectory of the patient using, at least in part, a set of patient inputs; determining one or more circadian-mapping profiles; determining, from the circadian trajectory and the one or more circadian-mapping profiles, a preferred circadian administration window for the patient; and based on the circadian trajectory and a dose of a VEGFR inhibitor to be administered to thePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) patient, administering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

[0528] In some embodiments, the circadian trajectory is represented by data that includes a circadian state, a circadian amplitude, a circadian period, and a Midline Estimating Statistic of Rhythm (MESOR). In some embodiments, modifying the circadian trajectory of the patient comprises administering a circadian rhythm modulating protocol prior to administering the treatment. In some embodiments, the circadian rhythm modulating protocol comprises one or more of a behavioral therapy, light therapy, pharmacological protocol, sleep schedule modification, or a dietary modification. In some embodiments, the circadian trajectory is modified by increasing the circadian amplitude. In some embodiments, the circadian trajectory is modified by decreasing the circadian amplitude. In some embodiments, the circadian trajectory is modified by increasing the circadian period. In some embodiments, the circadian trajectory is modified by decreasing the circadian period. In some embodiments, the circadian trajectory is modified by increasing the MESOR. In some embodiments, the circadian trajectory is modified by decreasing the MESOR. In some embodiments, the duration of the circadian administration window varies according to an uncertainty measure of the circadian trajectory, with the length being longer when the uncertainty measure is higher and the length being shorter when the uncertainty measure is lower. In some embodiments, the circadian trajectory is derived by a scheduler using at least one biophysics model of a human circadian clock and at least one statistical model of the human circadian clock. In some embodiments, the circadian traj ectory is derived by a scheduler using at least one biophysics model of a human circadian clock and at least one statistical model of the human circadian clock. In some embodiments, the circadian administration window is optimized based on associating a circadian time with a time for taking a drug for generating a raw model output. In some embodiments, the circadian trajectory is tissue-specific, organ-specific or whole-body.

[0529] In some embodiments, the methods comprise a set of patient inputs. In some embodiments, the set of patient inputs comprises data derived from signals received from a wearable data system worn by the patient. In some embodiments, patient treatment outputs are provided in a human-interpretable form.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0530] In some embodiments, the methods comprise adapting a model output to environmental controls to adjust an environment such that circadian-relevant behaviors are adjusted towards a target-constrained time.EXAMPLES

[0531] As referenced herein, aspects of the invention include methods for estimating one or more circadian trajectories of the patient using, at least in part, a set of patient inputs; determining one or more circadian-mapping profiles; based on the circadian trajectories and the one or more circadian-mapping profiles, determining a preferred circadian administration window for the patient; and administering a treatment for a VEGFR-mediated disease to the patient during the circadian administration window. A circadian trajectory7may be whole body, organ-specific, or tissue-specific, such as a particular type of tumor or cancer. In some embodiments, a circadian trajectory7of the patient may be modified before the treatment is administered. Example 1: Circadian Optimized Treatment of Glioblastoma

[0532] Using a glioblastoma model, treatment was administered with circadian administration of a VEGFR inhibitor, as provided herein. A circadian trajectory assessment was performed to determine a circadian-mapping profile, wherein a circadian state is a biological state corresponding to where the patient is in a circadian cycle. As explained herein, a given patient might have multiple circadian cycles, not all of which need be aligned, such as a central circadian cycle and peripheral circadian cycles, or organ-specific or tissue-specific circadian cycles. In this example, BMAL1. VEGF-A, and VEGFR mRNA levels from LN-229 glioblastoma cells were determined every three hours of a 48-hour period, with GAPDH expression used as a control. This data was further analyzed with precomputed machinelearning models and stored data to determine periodicity of gene expression, resulting in an estimated circadian trajectory and circadian-mapping profile, wherein the circadian trajectory is represented by circadian states, circadian amplitudes, circadian periods, and a MESOR. The 48-hour period shown in FIGS. 24A-24C depicts time in hours, starting from T4 and ranging up to T52. FIG. 24A shows the circadian expression profile for BMAL1 mRNA, FIG. 24B shows a circadian expression profile for VEGF-A mRNA, and FIG. 24C shows a circadian expression profile for VEGFR mRNA. FIGS. 24A and 24B show that peak VEGF-A mRNA levels for LN-229 glioblastoma cells occur ~8 hours before the peak of BMAL1 mRNA levels and begin to rise -12-16 hours before peak BMAL1 mRNA levels.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0533] The circadian trajectory is derived by a scheduler using a biophysics model of a circadian clock and a statistical model of the circadian clock. The circadian administration window is then optimized based on associating a circadian time with a time for taking a drug for generating a raw model output. From these models, dosing as VEGF-A rnRNA begins to rise is calculated as the preferred circadian administration time for a VEGFR inhibitor in LN-229 glioblastoma, in accordance with the methods described herein. Dosing time can be coordinated in a tissue-specific manner, such that TO corresponds to the time at which VEGF- A begins to rise (preferred circadian administration time), and T12 is 12 hours after VEGF-A begins to rise. As shown in FIGS. 24A and 24B, the preferred circadian administration time TO is 16 hours before the peak of BMAL1 levels. In the graphs shown in FIGS. 24A-C, the time corresponding to TO is hour 0, which is not shown, and the 48-hour period depicted spans from hour 4 to hour 52.

[0534] FIG. 25 demonstrates that dosing VEGFR inhibitor PTK-787 (vatalanib) at TO (preferred circadian administration) in mice implanted with LN-229 glioblastoma cells largely hinders tumor grow th when compared to dosing at T12. Mice were separated into a TO dosing group, a T12 dosing group, and Vehicle dosing groups for each cohort. The Vehicle dosing cohorts were ultimately combined for analysis, as there was no significant difference between the two groups. All mice were dosed for 3 days before the mice were sacrificed. Tumor volumes were log-transformed prior to analysis to reflect multiplicative growth dynamics, stabilize variance, and allow for the post-treatment changes to be interpreted as fold change. FIG. 25A shows tumor volume for each cohort pre and post treatment. FIG. 25 B show's the change in tumor volume during treatment, wherein the T12 and Vehicle groups increased in tumor volume, but the TO group did not increase. FIG. 25C shows fold change during treatment. Fold change was around 1 for the group dosed at TO but was greater than 1 for the T12 and Vehicle groups, indicating reduced growth in the TO group. By accounting for circadian trajectories via levels of BMALE VEGF-A, and VEGFR rnRNA, according to the methods described herein, administering vatalanib at the preferred circadian administration time demonstrates reduced tumor growth.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0535] Using a non-small cell lung cancer (NSCLC) model, treatment was administered with circadian administration of a VEGFR inhibitor, as provided herein. A circadian trajectory assessment was performed to determine circadian state, wherein circadian state is a biological state corresponding to where a subject is in a circadian cycle. As explained herein, a given patient might have multiple circadian cycles, not all of which need be aligned, such as a central circadian cycle and peripheral circadian cycles, or organ-specific or tissue-specific circadian cycles. From BMAL1 gene expression, VEGF gene expression, and VEGFR gene expression, the circadian trajectories and circadian-mapping profiles of FI358 NSCLC cells were determined according to the methods described herein. Thus, the preferred circadian time, or the time at which VEGF-A mRNA levels begin to rise (TO) in H358 NSCLC was determined to occur four hours before peak BMAL1 levels.

[0536] FIG. 26 demonstrates that dosing the VEGFR inhibitor motesanib at TO (preferred circadian administration) in mice implanted with H358 NSCLC hinders tumor growth, prolongs viability, and reduces side effects when compared to mice dosed at the suboptimal time T12. Mice were separated into a TO and a T12 dosing group, and dosed for 14 days. Tumors were allowed to grow for 50 days or until death. As shown in FIG. 26A, tumors grew more in mice dosed at the suboptimal time (T12) compared to mice dosed in the preferred circadian administration time (TO). The median tumor volume growth of the mice in the suboptimal time group was 193mm3compared to 110mm3in the TO preferred circadian administration time group. As shown in FIG. 26B, after 50 days, 67 percent of the mice in the suboptimal time group died, compared to 17 percent of the mice in the preferred circadian administration group. Further, the mice in the preferred circadian administration time group exhibited fewer side effects, demonstrated by higher body weight at day 50. By accounting for the circadian trajectories of BMAL11, VEGF-A, and VEGFR, according to the methods described herein, administering motesanib at the preferred circadian administration time demonstrates reduced tumor growth and reduced mortality.

[0537] The invention now' being fully described, it will be apparent to one of ordinary skill in the art that various changes and modifications can be made without departing from the spirit or scope of the invention.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO)

[0538] Conjunctive language, such as phrases of the form “at least one of A, B, and C,” or “at least one of A, B and C,” unless specifically stated otherwise or otherwise clearly contradicted by context, is otherwise understood with the context as used in general to present that an item, term, etc., may be either A or B or C, or any nonempty subset of the set of A and B and C. For instance, in the illustrative example of a set having three members, the conjunctive phrases “at least one of A, B, and C” and “at least one of A, B and C” refer to any of the following sets: {A}, {B}, {C}, {A, B}, {A, C}, {B, C}, {A. B, C}. Thus, such conjunctive language is not generally intended to imply that certain embodiments require at least one of A, at least one of B and at least one of C each to be present.

[0539] The use of examples, or exemplary language (e g., “such as”) provided herein, is intended merely to beter illuminate embodiments of the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0540] In the foregoing specification, embodiments of the invention have been described with reference to numerous specific details that may vary from implementation to implementation. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. The sole and exclusive indicator of the scope of the invention, and what is intended by the applicants to be the scope of the invention, is the literal and equivalent scope of the set of claims that issue from this application, in the specific form in which such claims issue, including any subsequent correction.

[0541] Further embodiments can be envisioned to one of ordinary skill in the art after reading this disclosure. In other embodiments, combinations or sub-combinations of the above-disclosed invention can be advantageously made. The example arrangements of components are shown for purposes of illustration and combinations, additions, re-arrangements, and the like are contemplated in alternative embodiments of the present invention. Thus, while the invention has been described with respect to exemplary embodiments, one skilled in the art will recognize that numerous modifications are possible.

[0542] For example, the processes described herein may be implemented using hardware components, software components, and / or any combination thereof. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. It will, however, be evident that various modifications and changes may be made thereuntoPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) without departing from the broader spirit and scope of the invention as set forth in the claims and that the invention is intended to cover all modifications and equivalents within the scope of the following claims.

[0543] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0544] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) WHAT IS CLAIMED IS:

1. A method of treating a vascular endothelial growth factor receptor (VEGFR)-mediated disease in a patient in need thereof, the method comprising:a) estimating a circadian trajectory of the patient using, at least in part, a set of patient inputs;b) determining one or more circadian-mapping profiles;c) determining, from the circadian trajectory and the one or more circadian-mapping profiles, a preferred circadian administration window for the patient; and d) based on the circadian trajectory and a dose of a VEGFR inhibitor to be administered to the patient, administering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

2. The method of claim 1, wherein the circadian trajectory is represented by¬ data that includes a circadian state, a circadian amplitude, a circadian period, and a Midline Estimating Statistic of Rhythm (MESOR).

3. The method of claim 1, further comprising modifying the circadian trajectory of the patient by administering a circadian rhythm modulating protocol prior to administering the treatment.

4. The method of claim 3, wherein the circadian rhythm modulating protocol comprises a behavioral therapy.

5. The method of claim 3, wherein the circadian rhythm modulating protocol comprises a light therapy.

6. The method of claim 3, wherein the circadian rhythm modulating protocol comprises a pharmacological protocol.

7. The method of claim 3, wherein the circadian rhythm modulating protocol comprises sleep schedule modification.

8. The method of claim 3, wherein the circadian rhythm modulating protocol comprises a dietary- modification.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 9. The method of any one of claims 1 to 8, wherein the circadian trajectory7is modified by increasing the circadian amplitude.

10. The computer-implemented method of any one of claims 1 to 8, wherein the circadian trajectory7is modified by decreasing the circadian amplitude.

11. The method of any one of claims 1 to 8, wherein the circadian trajectory7is modified by increasing the circadian period.

12. The method of any one of claims 1 to 7, wherein the circadian trajectory7is modified by decreasing the circadian period.

13. The method of any one of claims 1 to 8, wherein the circadian trajectory7is modified by increasing the MESOR.

14. The method of any one of claims 1 to 8, wherein the circadian trajectory7is modified by decreasing the MESOR.

15. The method of any one of claims 1 to 14, wherein a duration of the circadian administration window varies according to an uncertainty7measure of the circadian trajectory7, with the length being longer when the uncertainty7measure is higher and the length being shorter when the uncertainty measure is low er.

16. The method of any one of claims 1 to 15, wherein the set of patient inputs comprises data derived from signals received from a w earable data system worn by the patient.

17. The method of any one of claims 1 to 16, wherein the circadian trajectory is derived by a scheduler using at least one biophysics model of a human circadian clock and at least one statistical model of the human circadian clock.

18. The method of any one of claims 1 to 17, wherein the circadian administration w indow7is optimized based on associating a circadian time with a time for taking a drug for generating a raw model output.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 19. The method of any one of claims 1 to 18, wherein the circadian trajectory is tissue-specific.

20. The method of any one of claims 1 to 18, wherein the circadian trajectory is organ-specific.

21. The method of any one of claims 1 to 18, wherein the circadian trajectory is whole-body.

22. The method of any one of claims 1 to 21, further comprising presenting patient treatment outputs in a human-interpretable form.

23. The method of any one of claims 1 to 22, further comprising: connecting a model output to environmental controls to adjust an environment such that circadian-relevant behaviors are adjusted towards a target-constrained time.

24. The method of claim 1, wherein the VEGFR-mediated disease is cancer, retinopathy, pulmonary- fibrosis, systemic sclerosis-associated interstitial lung disease, Vascular Ehlers-Danlos syndrome, or preeclampsia.

25. The method of claim 24, wherein the cancer is one or more of: acute myeloid leukemia, advanced colorectal cancer, benign gastrointestinal stromal tumor (GIST), breast cancer, chronic myelogenous leukemia (CML). germ cell tumors, hepatocellular carcinoma, lymphoma, malignant gastrointestinal stromal tumor (GIST), a mast cell tumor, a mesenchymal tumor of the intestinal tract, metastatic colorectal cancer (MCC), metastatic renal cell carcinoma, neuroblastoma, non-small-cell lung cancer (NSCLC), small cell lung cancer (SCLC), or tumors of the central nervous system.

26. A method of treating a vascular endothelial growth factor receptor (VEGFR)-mediated disease in a patient in need thereof, the method comprising:a) estimating a circadian trajectory of the patient using, at least in part, a set of patient inputs;b) determining one or more circadian-mapping profiles;PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) c) determining, from the circadian trajectory and the one or more circadian-mapping profiles, a preferred circadian administration window for the patient;d) based on the circadian trajectory and a dose of a VEGFR inhibitor to be administered to the patient, administering the dose of the VEGFR inhibitor to the patient during the circadian administration window; ande) administering an additional anti-cancer therapy to the patient.

27. The method of claim 26, wherein the VEGFR inhibitor and the anti-cancer therapy are both administered to the patient during the circadian administration window.

28. The method of claim 26, further comprising determining a second circadian administration window for the VEGFR-mediated disease based on the circadian trajectory assessment and a dose of the anti-cancer therapy to be administered to the patient, and administering the anti-cancer therapy to the patient during the second circadian administration window.

29. The method of any one of claims 26-28, wherein the anti-cancer therapy comprises a chemotherapeutic agent, a radiotherapy, an immunotherapy, or any combination thereof.

30. The method of any one of claims 1-29 wherein the disease is cancer, and the cancer that is treated is: Accelerated Phase Chronic Myelogenous Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Lymphocytic Leukemia; Acute Monoblastic and Acute; Monocytic Leukemia; Acute Myelogenous Leukemia; Acute Myeloid Leukemia; Adenocarcinoma of the Prostate; Adenoid Cystic Carcinoma of the Head and Neck; Advanced Gastrointestinal Stromal Tumor; Advanced Pancreatic Neuroendocrine Tumors (NET); Agnogenic Myeloid; Metaplasia; Anaplastic Oligodendroglioma; Astrocytoma; B-Cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Bone Metastases; Brain Tumor; Breast Cancer; Cancer; Central Nervous System Cancer; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Central Nervous System Germ Cell Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Soft Tissue Sarcoma; Chordoma; Chronic Eosinophilic Leukemia (CEL); Chronic IdiopathicPATENT Attorney Ref. 63036.13WO (ARC-0013-WO) Myelofibrosis; Chronic Myelogenous Leukemia; Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Colon Cancer; Colorectal Cancer; Dermatofibrosarcoma; Dermatofibrosarcoma Protuberans (DFSP);Desmoid Tumor; Eosinophilia; Epidemic Kaposi's Sarcoma; Essential Thrombocythemia; Ewing's Family of Tumors; Extensive Stage Small Cell Lung Cancer; Extrapancreatic Neuroendocrine Tumors (NET); Fallopian Tube Cancer; Familiar Hypereosinophilia;Fibrosarcoma; Gastric Adenocarcinoma; Gastrointestinal Neoplasm; Gastrointestinal Stromal Tumor; Glioblastoma; Glioma; Gliosarcoma; Grade I Meningioma; Grade II Meningioma; Grade III Meningioma; Hematopoietic and Lymphoid Cancer; High-Grade Childhood Cerebral Astrocytoma; Hypereosinophilic Syndrome; Idiopathic Pulmonary' Fibrosis; LI Adult Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; Leukemia, Lymphocytic, Acute L2; Leukemia, Myeloid, Chronic; Leukemia, Myeloid, Chronic Phase; Liver Dysfunction and Neoplasm; Lung Disease; Lymphoid Blastic Phase of Chronic Myeloid Leukemia; Male Breast Cancer; Malignant Fibrous Histiocytoma; Mastocytosis; Meningeal Hemangiopericytoma; Meningioma; Meningioma; Meningioma; Metastatic Cancer; Metastatic Solid Tumors; Myelofibrosis; Myeloid Leukemia, Chronic; Myeloid Leukemia, Chronic Accelerated-Phase; Myeloid Leukemia, Chronic, Chronic-Phase; Myeloid Metaplasia; Myeloproliferative Disorder (MPD) with Eosinophilia; Neuroblastoma; Non-T, Non-B Childhood Acute Lymphoblastic Leukemia; Oligodendroglioma; Osteosarcoma; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Ovarian Neoplasms; Pancreatic Cancer; Pelvic Neoplasms; Peritoneal Cavity Cancer; Peritoneal Neoplasms; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Philadelphia Positive Acute Ly mphoblastic Leukemia; Philadelphia Positive Chronic My eloid Leukemia in Myeloid Blast Crisis; Polycythemia Vera; Pulmonary Fibrosis; Recurrent Adult Brain Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Glioblastoma Multiforme (GBM); Recurrent Kaposi's Sarcoma; Recurrent Melanoma; Recurrent Merkel Cell Carcinoma; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Tumors of the Ewing's Family; Recurrent Uterine Sarcoma; Relapsing Chronic Myelogenous Leukemia; Rheumatoid Arthritis; Salivary Gland AdenoidPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) Cystic Carcinoma; Sarcoma; Small Cell Lung Cancer; Stage II Melanoma; Stage II Merkel Cell Carcinoma; Stage III Adult Soft Tissue Sarcoma; Stage III Esophageal Cancer; Stage III Merkel Cell Carcinoma; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Salivary Gland Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage W Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Melanoma; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer; Systemic Mastocytosis; T-Cell Childhood Acute Lymphoblastic Leukemia; Testicular Cancer; Thyroid Cancer; Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumor (GIST);Unspecified Adult Solid Tumor; Untreated Childhood Brain Stem Glioma; Uterine Carcinosarcoma, and Uterine Sarcoma.

31. The method of any one of claims 1-30, wherein the VEGFR inhibitor is selected from the group consisting of; apatinib (rivoceranib), axitinib, brivanib, cediranib, chiauranib, dovitinib, enzastaurin, famitinib, foretinib, fruquintinib. linifanib, lucitanib, motesanib, nintedanib, orantinib, pexidartinib, ponatinib, regorafenib, semaxanib, sitravatinib, surufatinib, telatinib, vadimezan, vatalanib, and vorolanib.

32. The method of any one of claims 1-31. wherein the VEGFR inhibitor has a mean half-life of less than 30 hours.

33. The method of any one of claims 1-31, wherein the VEGFR inhibitor has a mean half-life of less than 24 hours.

34. The method of any one of claims 1-31, wherein the VEGFR inhibitor has a mean half-life of less than 19 hours.

35. The method of any one of claims 1-31, wherein the VEGFR inhibitor has a mean half-life of less than 15 hours.

36. The method of claim 32, wherein the VEGFR inhibitor has a mean halflife that ranges from 24 to 30 hours.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO) 37. The method of claim 32, wherein the VEGFR inhibitor has a mean halflife that ranges from 19 to 24 hours.

38. The method of claim 32, wherein the VEGFR inhibitor has a mean halflife that ranges from 15 to 19 hours.

39. The method of claim 32, wherein the VEGFR inhibitor has a mean halflife that ranges from 10 to 15 hours.

40. The method of claim 32, wherein the VEGFR inhibitor has a mean halflife that ranges from 5 to 10 hours.

41. The method of claim 32, wherein the VEGFR inhibitor has a mean halflife that ranges from 0.5 hours to 5 hours.

42. The method of claim 36, wherein the VEGFR inhibitor is selected from the group consisting of: regorafenib, ponatinib, chiauranib, and pexidartinib.

43. The method of claim 37, wherein the VEGFR inhibitor is selected from the group consisting of: nintedanib and cediranib.

44. The method of claim 38, wherein the VEGFR inhibitor is selected from the group consisting of: surufatinib and limfamb.

45. The method of claim 39, wherein the VEGFR inhibitor is selected from the group consisting of: axitinib, brivanib. and enzastaurin.

46. The method of claim 40, wherein the VEGFR inhibitor is selected from the group consisting of: telatinib, vorolanib, apatinib (rivoceranib), vadimezan, and motesanib.

47. The method of claim 41, wherein the VEGFR inhibitor is selected from the group consisting of: semaxanib, orantinib, and vatalanib.

48. The method of any one of claims 1-31, wherein the VEGFR inhibitor has a mean half-life that is greater than 30 hours.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 49. The method of claim 48, wherein the VEGFR inhibitor is selected from the group consisting of: famitinib, dovitinib, lucitanib, foretinib, and sitravatinib.

50. A computer-implemented method for treating metastatic colorectal cancer in a patient who has been treated with fluoropyrimidine-, oxaliplatin-, irinotecan-based chemotherapy, and anti-VEGF therapy, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory7assessment on the patient;determining a circadian administration window for the metastatic colorectal cancer based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; andadministering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

51. The method of claim 50, wherein the metastatic colorectal cancer is RAS wild-type.

52. A computer-implemented method for treating RAS-wild type metastatic colorectal cancer in a patient who has been treated with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the RAS-wild ty pe metastatic colorectal cancer based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; andadministering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

53. The method of any one of claims 50-52, wherein the VEGFR inhibitor is fruquintinib.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 54. The method of any one of claims 50-52 wherein the VEGFR inhibitor is a polymorphic crystalline form of fruquintinib.

55. The method of any one of claims 50-52 wherein the anti-VEGF therapy is bevacizumab, aflibercept, or ramucirumab.

56. The method of claim 52, wherein the anti-EGFR therapy is cetuximab or panitumumab.

57. A computer-implemented method for treating systemic sclerosis-associated interstitial lung disease in a patient, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the systemic sclerosis-associated interstitial lung disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; andadministering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

58. The method of claim 57, wherein treating comprises slowing the rate of decline in pulmonary function.

59. The method of claim 57 or 58, wherein the VEGFR inhibitor is nintedanib.

60. The method of claim 57 or 58, wherein the VEGFR inhibitor is a polymorphic crystalline form of nintedanib.

61. A computer-implemented method for treating a VEGFR-mediated disease in a patient in need thereof, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) determining a circadian administration window for the VEGFR-mediated disease based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; andadministering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

62. The method of claim 61, further comprising administering camrelizumab to the patient.

63. The method of claim 61 or 62, wherein the VEGFR-mediated disease is unresectable hepatocellular carcinoma.

64. The method of claim 61, further comprising administering paclitaxel to the patient.

65. The method of claim 61 or 64, wherein the VEGFR-mediated disease is gastric cancer.

66. The method of claim 61, further comprising administering fluzoparib to the patient.

67. The method of claim 61 or 66, wherein the VEGFR-mediated disease is ovarian cancer.

68. The method of claims 61-67, wherein the VEGFR inhibitor is rivoceranib or apatinib.

69. A computer-implemented method for treating well-differentiated extra-pancreatic neuroendocrine tumors in a patient, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the well -differentiated extra- pancreatic neuroendocrine tumors based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; andPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) administering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

70. A computer-implemented method for treating advanced pancreatic neuroendocrine tumors in a patient, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the advanced pancreatic neuroendocrine tumors based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; andadministering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

71. The method of claim 69 or 70, wherein the VEGFR inhibitor is surufatinib.

72. A computer-implemented method for treating advanced renal cell carcinoma in a patient who has failed one prior systemic therapy, the method comprising: under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the advanced renal cell carcinoma based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; andadministering the dose of the VEGFR inhibitor to the patient during the circadian administration window.

73. The method of claim 72, wherein the VEGFR inhibitor is axitinib.

74. The method of claim 72, further comprising administering pembrolizumab to the patient.

75. A computer-implemented method for treating Philadelphia chromosomepositive acute lymphoblastic leukemia in a patient in need thereof, the method comprising:PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the Philadelphia chromosomepositive acute lymphoblastic leukemia based on the circadian trajectory assessment and a dose of a VEGFR inhibitor to be administered to the patient; administering the dose of the VEGFR inhibitor to the patient during the circadian administration window; andadministering a chemotherapeutic agent to the patient.

76. The method of claim 75, further comprising administering the chemotherapeutic agent to the patient during the circadian administration window.

77. The method of claim 75, further comprising determining a second circadian administration window for the Philadelphia chromosome-positive acute lymphoblastic leukemia based on the circadian trajectory assessment and a dose of the chemotherapeutic agent to be administered to the patient, and administering the chemotherapeutic agent to the patient during the second circadian administration window.

78. The method of any one of claims 75-77, wherein the VEGFR inhibitor is ponatinib.

79. A computer-implemented method for administering treatment for a vascular endothelial growth factor receptor (VEGFRj-mediated disease in a patient in need thereof, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the VEGFR-mediated disease based on the circadian traj ectory assessment and a dose of regorafenib to be administered to the patient; andadministering the dose of regorafenib to the patient during the circadian administration window.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 80. A computer-implemented method for treating a vascular endothelial growth factor receptor (VEGFR)-mediated disease in a patient in need thereof, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the VEGFR-mediated disease based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

81. The method of claim 79 or 80, wherein the VEGFR-mediated disease is cancer, retinopathy, or preeclampsia.

82. The method of claim 81, wherein the disease is cancer, and wherein the cancer was initially sensitive to a KIT tyrosine kinase inhibitor and acquired resistance to the KIT ty rosine kinase inhibitor.

83. The method of claim 82, wherein the cancer has acquired resistance to one of the following KIT inhibitors: imatinib mesylate, salts of imatinib mesylate; PPl(4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine); MLN518 (CT53518); PD180970; SUI 12481 SU5416; SU5414; SU6597; SU6663 or SU6561.

84. The method of claim 82, wherein the cancer is one or more of a malignant gastrointestinal stromal tumor (GIST), a benign gastrointestinal stromal tumor (GIST), a mesenchymal tumor of the intestinal tract, chronic myelogenous leukemia (CML), a mast cell tumor, SCLC, a germ cell tumors, breast cancer, and / or neuroblastoma.

85. The method of claim 82, wherein the cancer has acquired resistance to imatinib mesylate.

86. The method of claim 82, wherein the acquired resistance of the cancer is associated with a secondary mutation in a KIT gene mutated in a primary' tumor.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO) 87. The method of claim 86, wherein the secondary7mutation is in a kinase catalytic domain of the KIT gene.

88. The method of claim 87, wherein the secondary mutation is in Exon 13, 14, and / or 17.

89. The method of claim 87, wherein the secondary mutation is at residues 654, 670, 716, 816, 820, 822, and 823.

90. The method of claim 87, wherein the secondary mutation is at residues 650-654.

91. The method of claim 87, wherein the secondary7mutation is at residues 670-674.

92. The method of claim 87, wherein the secondary mutation is at residues 816-824.

93. The method of claim 87, wherein the secondary mutation is one or more of V654A (Exon 13), T670I (Exon 14), T670E, D716N, S709F (Exon 14), D816G, D816E (Exon 17), D820E, D820Y, D820GN822K, Y823D (Exon 17), or deletions and other amino acid substitutions at such positions or adjacent positions.

94. The method of claim 87, wherein the secondary mutation is one or more of:i) deletion of amino acid residues 557-558;ii) deletion of amino acid residues 551-555;iii) deletion of amino acid residues 550-558;iv) deletion of amino acid residues 559-560;v) deletion of amino acid residues 557-561;vi) deletion of amino acid residues 554-558;vii) deletion of amino acid residues 552-557;viii) mutations at residue 559, including V559D, V559A, or V559G;ix) mutations at residue 560, including V560D, V560E, or V560G;PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) x) W557S, alone, or in combination w ith a deletion of amino acids 552-556;xi) mutations at amino acid residue 557, including W557R; andxii) mutations at amino acid residue 576, including L576P.

95. The method of claim 87, wherein the secondary mutation is deletion of residues 557-558 and at least one of the following mutations: V654A, T670I. D820Y, N822K, orY823D.

96. A computer-implemented method for treating a VEGFR-mediated cancer in a patient in need thereof, the cancer having a primary and / or secondary' KIT gene mutation in the primary tumor, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; andadministering the dose of regorafenib to the patient during the circadian administration window.

97. A computer-implemented method for treating a VEGFR-mediated cancer in a patient in need thereof, the cancer having a primary' and / or secondary' KIT gene mutation in the primary tumor, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory' assessment on the patient;determining a circadian administration window- for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration w indow.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO) 98. The method of claim 96 or 97, wherein the primary' and / or secondary7KIT gene mutation in the primary7tumor is associated with acquired resistance of the cancer to KIT tyrosine kinase inhibitors.

99. The method of any one of claims 96-98, wherein the secondary7mutation is in a kinase catalytic domain of a KIT gene.

100. The method of claim 99, wherein the secondary7mutation is in Exon 13, 14, and / or 17.

101. The method of claim 99, wherein the secondary7mutation is at residues 654, 670, 716, 816, 820, 822, and 823.

102. The method of claim 99, wherein the secondary mutation is at residues 650-654.

103. The method of claim 99, wherein the secondary7mutation is at residues 670-674.

104. The method of claim 99, wherein the secondary7mutation is at residues 816-824.

105. The method of claim 99, wherein the secondary mutation is one or more of V654A (Exon 13), T670I (Exon 14), T670E, D716N, S709F (Exon 14), D816G, D816E (Exon 17), D820E, D820Y, D820GN822K, Y823D (Exon 17), or deletions and other amino acid substitutions at such positions or adjacent positions.

106. The method of claim 99, wherein the secondary mutation is one or more of:i) deletion of amino acid residues 557-558;ii) deletion of amino acid residues 551-555;iii) deletion of amino acid residues 550-558;iv) deletion of amino acid residues 559-560;v) deletion of amino acid residues 557-561;vi) deletion of amino acid residues 554-558;PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) vii) deletion of amino acid residues 552-557;viii) mutations at residue 559. including V559D, V559A. or V559G;ix) mutations at residue 560, including V560D, V560E, or V560G;x) W557S, alone, or in combination with a deletion of amino acids 552-556;xi) mutations at amino acid residue 557, including W557R; andxii) mutations at amino acid residue 576, including L576P.

107. The method of claim 99, wherein the secondary mutation is deletion of residues 557-558 and at least one of the following mutations: V654A, T670I, D820Y, N822K, orY823D.

108. A computer-implemented method for treating a VEGFR-mediated cancer in a patient in need thereof, the cancer having a primary and / or secondary KIT gene mutation associated with resistance or acquired resistance to imatinib mesylate or salts of imatinib mesylate, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; andadministering the dose of regorafenib to the patient during the circadian administration window.

109. A computer-implemented method for treating a VEGFR-mediated cancer in a patient in need thereof, the cancer having a primary and / or secondary' KIT gene mutation associated with resistance or acquired resistance to imatinib mesylate or salts of imatinib mesylate, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

110. A computer-implemented method for treating a VEGFR-mediated cancer in a human patient with imatinib mesylate or salts of imatinib mesylate, which additionally comprises:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the VEGFR-mediated cancer based on the circadian traj ectory assessment and a dose of regorafenib to be administered to the patient; andadministering the dose of regorafenib to the patient dunng the circadian administration window.

111. A computer-implemented method for treating a VEGFR-mediated cancer in a human patient with imatinib mesylate or salts of imatinib mesylate, which additionally comprises:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib; andadministering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

112. The method of any one of claims 81-111, wherein the cancer that is treated is: Accelerated Phase Chronic Myelogenous Leukemia; Acute Erythroid Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia in Remission; AcutePATENT Atorney Ref. 63036.13WO (ARC-0013-WO)Lymphocytic Leukemia; Acute Monoblastic and Acute; Monocytic Leukemia; Acute Myelogenous Leukemia: Acute Myeloid Leukemia: Adenocarcinoma of the Prostate;Adenoid Cystic Carcinoma of the Head and Neck; Advanced Gastrointestinal Stromal Tumor; Agnogenic Myeloid; Metaplasia; Anaplastic Oligodendroglioma; Astrocytoma; B-Cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Bone Metastases; Brain Tumor; Breast Cancer; Cancer; Central Nervous System Cancer; Childhood Acute Lymphoblastic Leukemia: Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Central Nervous System Germ Cell Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Soft Tissue Sarcoma: Chordoma; Chronic Eosinophilic Leukemia (CEL); Chronic Idiopathic Myelofibrosis; Chronic Myelogenous Leukemia;Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Colon Cancer; Colorectal Cancer; Dermatofibrosarcoma;Dermatofibrosarcoma Protuberans (DFSP); Desmoid Tumor; Eosinophilia; Epidemic Kaposi's Sarcoma; Essential Thrombocythemia; Ewing's Family of Tumors; Extensive Stage Small Cell Lung Cancer; Fallopian Tube Cancer; Familiar Hypereosinophilia; Fibrosarcoma; Gastric Adenocarcinoma; Gastrointestinal Neoplasm; Gastrointestinal Stromal Tumor;Glioblastoma; Glioma; Gliosarcoma; Grade I Meningioma; Grade II Meningioma; Grade III Meningioma; Hematopoietic and Lymphoid Cancer; High-Grade Childhood Cerebral Astrocytoma; Hypereosinophilic Syndrome; Idiopathic Pulmonary Fibrosis; LI Adult Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; Leukemia.Lymphocytic, Acute L2; Leukemia, Myeloid, Chronic; Leukemia, Myeloid, Chronic Phase; Liver Dysfunction and Neoplasm; Lung Disease; Lymphoid Blastic Phase of Chronic Myeloid Leukemia; Male Breast Cancer; Malignant Fibrous Histiocytoma; Mastocytosis; Meningeal Hemangiopericytoma; Meningioma; Meningioma; Meningioma; Metastatic Cancer; Metastatic Solid Tumors; Myelofibrosis; Myeloid Leukemia, Chronic: Myeloid Leukemia, Chronic Accelerated-Phase; Myeloid Leukemia, Chronic, Chronic-Phase; Myeloid Metaplasia; Myeloproliferative Disorder (MPD) with Eosinophilia; Neuroblastoma; Non-T, Non-B Childhood Acute Lymphoblastic Leukemia; Oligodendroglioma; Osteosarcoma; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Ovarian Neoplasms: Pancreatic Cancer; Pelvic Neoplasms; Peritoneal Cavity Cancer; Peritoneal Neoplasms; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Philadelphia PositivePATENT Atorney Ref. 63036.13WO (ARC-0013-WO) Acute Lymphoblastic Leukemia; Philadelphia Positive Chronic Myeloid Leukemia in Myeloid Blast Crisis; Polycythemia Vera; Pulmonary Fibrosis; Recurrent Adult Brain Tumor; Recurrent Adult Soft Tissue Sarcoma; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Glioblastoma Multiforme (GBM); Recurrent Kaposi's Sarcoma; Recurrent Melanoma; Recurrent Merkel Cell Carcinoma; Recurrent Ovarian Epithelial Cancer; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer: Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Tumors of the Ewing's Family; Recurrent Uterine Sarcoma; Relapsing Chronic Myelogenous Leukemia; Rheumatoid Arthritis; Salivary Gland Adenoid Cystic Carcinoma; Sarcoma; Small Cell Lung Cancer; Stage II Melanoma; Stage II Merkel Cell Carcinoma; Stage III Adult Soft Tissue Sarcoma; Stage III Esophageal Cancer; Stage III Merkel Cell Carcinoma; Stage III Ovarian Epithelial Cancer; Stage III Pancreatic Cancer; Stage III Salivary Gland Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage W Breast Cancer; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Melanoma; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Rectal Cancer: Stage IV Salivary Gland Cancer; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer; Systemic Mastocytosis; T-Cell Childhood Acute Lymphoblastic Leukemia; Testicular Cancer; Thyroid Cancer; Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumor (GIST);Unspecified Adult Solid Tumor; Untreated Childhood Brain Stem Glioma; Uterine Carcinosarcoma, and Uterine Sarcoma.

113. A computer-implemented method for treating a VEGFR-mediated cancer in a patient who has acquired resistance to imatinib. the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory' assessment on the patient;determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of regorafenib to be delivered to the patient; andadministering the dose of regorafenib to the patient during the circadian administration window.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 114. A computer-implemented method for treating a VEGFR-mediated cancer in a patient who has acquired resistance to imatinib. the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory7assessment on the patient;determining a circadian administration window for the VEGFR-mediated cancer based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

115. A computer-implemented method for treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST) in a patient who has been treated with imatinib, salts of imatinib mesylate, PPl(4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine); MLN518 (CT53518); PD180970; SU112481; SU5416; SU5414; SU6597; SU6663 or SU6561, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the malignant or benign GIST based on the circadian traj ectory assessment and a dose of regorafenib to be administered to the patient; andadministering the dose of regorafenib to the patient during the circadian administration window.

116. A computer-implemented method for treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST) in a patient who has been treated with imatinib. salts of imatinib mesylate, PPl(4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine); MLN518 (CT53518); PD180970; SU1I248I; SU5416; SU5414; SU6597; SU6663 or SU6561, the method comprising:under the control of one or more computer systems configured with executableinstructions:PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) performing a circadian trajectory assessment on the patient;determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

117. A computer-implemented method for treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST) in a patient who has been treated with imatinib. the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; andadministering the dose of regorafenib to the patient during the circadian administration window.

118. A computer-implemented method for treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST) in a patient who has been treated with imatinib, the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administenng the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 119. A computer-implemented method for treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST), the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory assessment on the patient;determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of regorafenib to be administered to the patient; andadministering the dose of regorafenib to the patient during the circadian administration window.

120. A computer-implemented method for treating a malignant gastrointestinal stromal tumor (GIST) or a benign gastrointestinal stromal tumor (GIST), the method comprising:under the control of one or more computer systems configured with executable instructions:performing a circadian trajectory7assessment on the patient;determining a circadian administration window for the malignant or benign GIST based on the circadian trajectory assessment and a dose of a crystalline polymorphic form of regorafenib to be administered to the patient; and administering the dose of the crystalline polymorphic form of regorafenib to the patient during the circadian administration window.

121. The method of claim 119 or 120, wherein the patient has not been treated with imatinib.

122. The method of claim 119 or 120, wherein the patient has not acquired resistance to a c-Kit inhibitor.

123. The method of any one of claims 79-122, wherein performing the circadian trajectory7assessment on the patient and determining the circadian administrationPATENT Atorney Ref. 63036.13WO (ARC-0013-WO) window comprises performing a computer-implemented method under the control of one or more computer systems configured with executable instructions for:estimating a circadian trajectory of the patient using, at least in part, a set of patient inputs;determining one or more circadian-mapping profiles;determining, from the circadian trajectory and the one or more circadian-mapping profiles, and the dose of regorafenib or the crystalline polymorphic form of regorafenib to be administered to the patient, the circadian administration window; andalerting the patient that the circadian administration window is occurring or is to occur.

124. The method of any one of claims 79-123, wherein a duration of the circadian administration window is modified according to an uncertainty measure of the circadian trajectory'.

125. The method of any one of claims 79-123, wherein the circadian administration window has a duration that ranges from 30 minutes to 12 hours.

126. The method of claim 79-124, wherein the circadian administration window has a duration that ranges from 4-8 hours.

127. The method of any one of claims 123-126, wherein the set of patient inputs comprises data derived from signals received from a patient wearing a wearable data system.

128. The method of any one of claims 79-127, wherein the circadian trajectory' is derived by a scheduler using at least one biophysics model of a human circadian clock and at least one a statistical model of the human circadian clock.

129. The method of any one of claims 79-128, wherein the circadian administration window is optimized based on associating a circadian time with a time for taking regorafenib or a crystalline polymorphic form of regorafenib for generating a raw model output.PATENT Attorney Ref. 63036.13WO (ARC-0013-WO) 130. A non- transitory computer-readable storage medium storing instructions, which when executed by at least one processor of a computer system, causes the computer system to carry out the method of claim 123.

131. A computer system comprising:one or more processors; anda storage medium storing instructions, which when executed by the at least one processor, cause the system to implement the method of claim 123.

132. The method of any one of claims 1-78 wherein performing the circadian trajectory assessment on the patient and determining the circadian administration window comprises:estimating a circadian trajectory of the patient using, at least in part, a set of patient inputs;determining one or more circadian-mapping profiles;determining, from the circadian trajectory and the one or more circadian-mapping profiles, and the dose of the VEGFR inhibitor to be administered to the patient, the circadian administration window; andalerting the patient that the circadian administration window is occurring or is to occur.

133. The method of claim 132, wherein a duration of the circadian administration window varies according to an uncertainty' measure of the circadian trajectory', with the duration being longer when the uncertainty measure is higher and the duration being shorter when the uncertainty measure is lower.

134. The method of any one of claims 132, wherein the circadian administration window has a duration that ranges from 30 minutes to 12 hours.

135. The method of claim 132, wherein the circadian administration window has a duration that ranges from 4-8 hours.

136. The method of any one of claims 132-135, wherein the set of patient inputs comprises data derived from signals received from a patient wearing a wearable data system.PATENT Atorney Ref. 63036.13WO (ARC-0013-WO) 137. The method of any one of claims 132-136, wherein the circadian trajectory is derived by a scheduler using at least one biophysics model of a human circadian clock and at least one statistical model of the human circadian clock.

138. The method of any one of claims 132-137, wherein the circadian administration window is optimized based on associating a circadian time with a time for taking a VEGFR inhibitor for generating a raw model output.

139. A non- transitory' computer-readable storage medium storing instructions, which when executed by at least one processor of a computer system, causes the computer system to carry out the method of any one of claims 132-138.

140. A computer system comprising:one or more processors; anda storage medium storing instructions, which when executed by the at least one processor, cause the system to implement the method of any one of claims 110-117.

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