Systems and methods for processing clinical trial data

Abstract

Systems and methods for determining whether combination treatment improves myeloproliferative neoplasm (MPN)-associated endpoints relative to monotherapy are provided. Data for subjects with MPN are obtained, including first baseline measurements prior to treatment and first responses after first treatment with a first composition. A subset of subjects satisfying a response threshold is identified and divided, for a second treatment, between a first and a second arm, the first arm receiving the first composition and a second composition, and the second arm receiving the first composition and a placebo. Second responses are received after the second treatment. Subjects in the subset are evaluated by comparing second responses to first baseline measurements or to optional second baseline measurements obtained after division between the first and second arms and prior to the second treatment, thus determining whether the combined treatment of the first arm improves the MPN-associated endpoints relative to the monotherapy with the first composition.

Description

SYSTEMS AND METHODS FOR PROCESSING CLINICAL TRIAL DATA TECHNICAL FIELD

[0001] The present disclosure relates generally to systems and methods for using clinical trial data to determine treatments that improve endpoints associated with clinical indications, particularly endpoints associated with a myeloproliferative neoplasm. BACKGROUND

[0002] Myelofibrosis (MF, including primary MF (PMF), post-polycythemia vera MF (post-PV-MF), or post-essential thrombocythemia MF (post-ET MF) is a clonal myeloproliferative neoplasm (MPN), characterized by progressive bone marrow fibrosis and subsequent ineffective erythropoiesis, dysplastic megakaryocyte hyperplasia, and extramedullary hematopoiesis. The typical clinical presentation includes marked splenomegaly, progressive anemia, and constitutional symptoms. Additional risk factors that worsen the prognosis include age of greater than 65 years, hemoglobin of less than 10 g / dL, white blood cell (WBC) of greater than 25 x 109 / L, and blood blasts of greater than or equal to 1%. The median survival at diagnosis in patients with high-risk disease is approximately 2 years (Cervantes 2009).

[0003] MF is a clonal stem-cell disease characterized by molecular alterations in driver genes (e.g., JAK2, MPL, CALR), and cytogenetic (e.g., 13q-, 20q-) markers (Pikman 2006; Hussein 2009). The JAK2 V617F mutation, which leads to overactive signaling from cytokine and growth factor receptors in hematopoietic progenitor cells, has been identified in over 95% of patients with PV and in approximately 50% of patients with ET and PMF.

[0004] Ruxolitinib, a Janus kinase inhibitor, is approved in the United States and the European Union for the treatment of patients with intermediate, or high-risk MF, including PMF, post-PV MF, and post-ET MF (Jakafi Prescribing Information). Treatment with ruxolitinib results in a significant reduction in spleen volume (e.g., SVR of greater than or equal to 35%) in approximately 28% to 42% of MF patients, and provides significant improvement in constitutional symptoms (e.g., total symptom score (TSS) reduction of greater than or equal to 50%) in approximately 46% of MF patients (Harrison 2012; Verstovsek 2012). However, only approximately a quarter (e.g., 20-25%) of responding patients achieve both SVR greater than or equal to 35% and TSS greater than or equal to 50%. On the other hand, a small proportion of patients do not achieve any clinicallymeaningful response after treatment with ruxolitinib (e.g., the primary refractory population). Benefit in SVR and TSS reduction from ruxolitinib treatment is reportedly achieved within 12 weeks after initiating treatment, after which ruxolitinib administration maintains but does not deepen efficacy responses (Verstovsek 2012). Ruxolitinib does not significantly affect bone marrow fibrosis, or variant allele frequency (VAF) of driver mutations (e.g., JAK2 or CALR) within the first 1-2 years of treatment, suggesting a lack of effect on the underlying disease pathology (Verstovsek 2012). Lastly, roughly 50% of patients with MF discontinue ruxolitinib treatment within 3 years (Harrison 2016; Al-Ali 2017; Verstovsek 2017) with lack of achieving significant SVR, or loss of SVR accounting for approximately 35% of all patient discontinuations (Palandri 2020). SUMMARY

[0005] Given the above background, there is an unmet need for improved therapies for patients with clinical conditions who have a suboptimal response to traditional treatments. What is needed in the art are systems and methods for improved therapies for patients with myeloproliferative neoplasm (MPN) who have a suboptimal response to front-line monotherapy, including Janus kinase (JAK) inhibitor (JAKi) monotherapy such as standard of care ruxolitinib monotherapy.

[0006] The present disclosure addresses the need in the art for systems and methods for improved treatments by providing systems and methods that include combination therapies (e.g., concurrent, sequential, and / or add-on) including a combination of a first composition and a second composition to improve one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy. Advantageously, in some embodiments, the presently disclosed systems and methods identify a subset of subjects with suboptimal responses to monotherapy (e.g., JAKi monotherapy) and utilize the subset to evaluate and determine whether a combination of a first composition and a second composition improves the one or more endpoints relative to monotherapy, for instance, to address the above-identified need in the art. As illustrated in Examples 2-8 below, preclinical study results have shown that, in some implementations, navtemadlin and ruxolitinib, when combined, synergize to increase apoptotic cell death in a TP53WTJAK2 V617F MPN cell line (UKE-1), and in CD34+ progenitor myeloid cells collected from the blood of patients with chronic phase MF.

[0007] One aspect of the present disclosure provides a method for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition (e.g., JAKi monotherapy, such as ruxolitinib monotherapy). In some embodiments, the first composition is ruxolitinib. In some embodiments, the method includes obtaining clinical data that involves a plurality of subjects that have the myeloproliferative neoplasm, where the clinical data includes and associates for each respective subject in the plurality of subjects (i) a corresponding first set of baseline measurements prior to treatment with the first composition for the myeloproliferative neoplasm and (ii) a corresponding first response set after a first treatment period with the first composition.

[0008] In some embodiments, the method further includes identifying a subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold. In some embodiments, the subset of subjects is divided between a first arm and a second arm on a randomized basis, where subjects in the first arm receive a combination of the first composition and the second composition and subjects in the second arm receive a combination of the first composition and a placebo for a second treatment period. In some embodiments, the second composition is navtemadlin.

[0009] For each respective subject in the subset of subjects, in some embodiments, the method further includes obtaining a corresponding second response set upon completion of the second treatment period. In some embodiments, each respective subject in the subset of subjects is evaluated by comparing the corresponding second response set to (a) the corresponding first set of baseline measurements for the respective subject and / or (b) an optional corresponding second set of baseline measurements obtained for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, thereby determining whether the combination of the first treatment and the second treatment of the first arm improves the one or more endpoints associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition.

[0010] In some embodiments, the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding first set of baseline measurements for the respective subject.

[0011] In some embodiments, the method further includes obtaining the corresponding second set of baseline measurements for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, and the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding second set of baseline measurements for the respective subject.

[0012] Another aspect of the present disclosure includes a method for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition, the method comprising: obtaining clinical data that involves a plurality of subjects that have the myeloproliferative neoplasm, wherein the clinical data includes and associates for each respective subject in the plurality of subjects (i) a corresponding first set of baseline measurements prior to treatment with the first composition for the myeloproliferative neoplasm and (ii) a corresponding first response set after a first treatment period with the first composition; identifying a subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold; administering a combination of the first composition and the second composition to a subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold for a second treatment period; for each respective subject in the subset of subjects, obtaining a corresponding second response set upon completion of the second treatment period; and evaluating each respective subject in the subset of subjects by comparing the corresponding second response set to: (a) the corresponding first set of baseline measurements for the respective subject and / or (b) an optional corresponding second set of baseline measurements obtained for the respective subject prior to the second treatment period, thereby determining whether the combination of the first treatment and the second treatment improves the one or more endpoints associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition.

[0013] Another aspect of the present disclosure includes a system for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition, including a display, an input device, one or more processors, and memory storing one or more programs that, when executed by the one or more processors, cause the processors to perform any of the methods disclosed above.

[0014] Another aspect of the present disclosure includes a non-transitory computer readable storage medium having stored thereon program code instructions for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition that, when executed by a processor, cause the processor to perform any of the methods disclosed above. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figures 1A, 1B, and 1C illustrates an exemplary system topology for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition, in accordance with some embodiments of the present disclosure.

[0016] Figures 2A, 2B, and 2C collectively provide a flow chart of processes and features for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition, in which optional steps are indicated by dashed lines, in accordance with some embodiments of the present disclosure.

[0017] Figure 3 illustrates an example schematic for a randomized, double-blind study evaluating safety and efficacy of navtemadlin plus ruxolitinib versus placebo plus ruxolitinib in myelofibrosis patients who have a suboptimal response to ruxolitinib, in accordance with an embodiment of the present disclosure. Each treatment cycle is 28 days.1: Stable Rux Dose is defined as ≥ 5 mg BID that does not require a treatment hold or dose adjustment in the 8 weeks prior to add-on treatment with navtemadlin.2: Ruxolitinib will continue to be administered at the Stable Rux Dose.3. The run-in period baseline assessment occurs prior to the start of ruxolitinib monotherapy dosing.4. After ≥ 18 weeks but < 25 weeks of treatment, response to ruxolitinib monotherapy will be assessed in subjects that have had a stable doseof ruxolitinib for ≥ 6 consecutive weeks (e.g., a dose ≥ 5 mg BID that did not require a treatment hold or dose adjustment). A stable dose of ruxolitinib ≥ 8 consecutive weeks is set as a baseline for randomization. Response assessment during the run-in period is allowed earlier in some implementations, after a stable dose of ≥ 6 consecutive weeks. Abbreviations: JAK, Janus kinase; MF, myelofibrosis; QD, daily; SVR, spleen volume reduction; TSS, total symptom score; EOS, end-of-study.

[0018] Figure 4 illustrates example plots showing that navtemadlin combined with ruxolitinib enhances apoptosis in MF patient-derived progenitor cells, in accordance with an embodiment of the present disclosure. Abbreviation: MFI, median fluorescent intensity; NVTM, navtemadlin; Rux, ruxolitinib. Live cells were defined as CD45+mid, SSClow, CD14-, cPARP-.

[0019] Figure 5 illustrates example plots showing that navtemadlin combined with ruxolitinib reduces pro-survival MCL-1 levels, in accordance with an embodiment of the present disclosure. Abbreviation: MFI, median fluorescent intensity; NVTM, navtemadlin; Rux, ruxolitinib.

[0020] Figures 6A, 6B, and 6C collectively illustrate that cytotoxicity of navtemadlin as monotherapy or as add-on therapy to ruxolitinib is correlated with spleen volume reduction, in accordance with an embodiment of the present disclosure. Figure 6A: Navtemadlin- Induced Reduction in CD34+Cell Count is Correlated with SVR; Figures 6B and 6C: Change in CD34+ Cell Count. Abbreviations: C1D1, Cycle 1 Day 1; SVR-35, spleen volume reduction ≥ 35%. Data from 1 patient with a cell concentration of 0 cells / μL at Week 24 is not visible in Figure 6C.

[0021] Figure 7 provides example plots illustrating that navtemadlin-induced reduction in driver gene variant allele frequency is correlated with PFS and OS, in accordance with an embodiment of the present disclosure.

[0022] Figure 8 provides example plots illustrating that navtemadlin-induced reduction in CD34+cell count is correlated with PFS and OS, in accordance with an embodiment of the present disclosure.

[0023] Figure 9 illustrates spleen volume reduction after addition of navtemadlin to a stable dose of ruxolitinib, in accordance with an embodiment of the present disclosure. Evaluable subjects with spleen volume assessments at baseline and Week 24 are shown. Six subjects discontinued treatment prior to Week 24.

[0024] Figure 10 illustrates total symptom score reduction after addition of navtemadlin to a stable dose of ruxolitinib, in accordance with an embodiment of the present disclosure.

[0025] Figure 11 illustrates reduction in driver variant allele frequency and improvement in bone marrow fibrosis after addition of navtemadlin to ruxolitinib, in accordance with an embodiment of the present disclosure. Abbreviations: BM, bone marrow; CALR, calreticulin; JAK2, Janus kinase; MF, myelofibrosis; VAF, variant allele frequency.

[0026] Figure 12 provides proposed multi-component spleen response endpoints based on spleen volume reduction, in accordance with an embodiment of the present disclosure. In Figure 12, patients who achieve an SVR35 from the pre-ruxolitinib baseline are defined as responders (despite achieving a SVR25 from pre-randomization baseline), thereby attributing within-patient clinically meaningful benefit according to established threshold. Abbreviation: SVR, spleen volume reduction, SVR35, spleen volume reduction ≥ 35%, SVR25, spleen volume reduction ≥ 25%.

[0027] Figure 13 provides proposed multi-component spleen response endpoints based on TSS, in accordance with an embodiment of the present disclosure. In Figure 13, patients who achieve an TSS50 from the pre-ruxolitinib baseline are defined as responders (despite achieving a TSS30 from pre-randomization baseline), thereby attributing within-patient clinically meaningful benefit according to established threshold. Abbreviation: TSS, total symptom score, TSS30, ≥ 30% TSS reduction, TSS50, ≥ 50% TSS reduction.

[0028] Figure 14 illustrates suboptimal spleen and symptom responders from pooled phase 3 ruxolitinib data, in accordance with an embodiment of the present disclosure. Pooled extractable data from published phase 3 JAKi-naïve MF studies for patients treated with ruxolitinib monotherapy (± placebo) SVR (N=465): COMFORT-1, SIMPLIFY-1, and TRANSFORM-1(Verstovsek 2012; Mesa 2017; Pemmaraju 2023). TSS (N=528): COMFORT-1, SIMPLIFY-1, and MANIFEST-2 (Verstovsek 2012; Mesa 2017; Rampal 2023). Week-24 data used as a proxy to Week-18 suboptimal response assessment. Abbreviations: SVR, spleen volume reduction, TSS total symptom score.

[0029] Figure 15 illustrates suboptimal spleen responders based on a SVR25 threshold, in accordance with an embodiment of the present disclosure. Utilizing the pooled dataset, it was determined that among the JAKi-naive MF patients with a suboptimal response to ruxolitinib the mean SVR was 18%. Studies Pooled: Suboptimal spleen response to ruxolitinib monotherapy (± placebo) of > 0 but ≤ 35% (N=253; COMFORT-I, SIMPLIFY-1, TRANSFORM-1).Week-24 data used as a proxy to Week-18 suboptimal response assessment. SVR, spleen volume reduction, SVR25, spleen volume reduction ≥ 25%.

[0030] Figure 16 illustrates suboptimal TSS responders based on a TSS30 response threshold, in accordance with an embodiment of the present disclosure. Utilizing the pooled dataset, it was determined among the JAKi-naive MF patients with a suboptimal response to ruxolitinib the mean TSS reduction was 28.5%. Studies Pooled: Suboptimal symptom response to ruxolitinib monotherapy (± placebo) of > 0% but < 50%. TSS, total symptom score, TSS30, ≥ 30% TSS reduction.

[0031] Figure 17 illustrates the KRT-232-109 study, showing the spleen volume reduction after add-on navtemadlin to a stable dose of ruxolitinib, in accordance with an embodiment of the present disclosure. The KRT-232-109 study is a phase 2 study of add-on navtemadlin in patients with a suboptimal response to ruxolitinib. Note: Evaluable subjects with spleen volume assessments at baseline and Week 24 are shown. Baseline spleen volume magnetic resonance imaging / computed tomography scans were taken while subjects were on a stable dose of ruxolitinib for ≥ 8 weeks (e.g., no ruxolitinib wash-out). No dose increases of ruxolitinib above the stable baseline dose occurred during the 24-week assessment period. The median duration of ruxolitinib treatment prior to the addition of navtemadlin was 21.6 months (range: 7 to 129). *Six subjects discontinued treatment prior to Week 24. Abbreviations: ITT, intention-to-treat; Rux, ruxolitinib; yrs, years.

[0032] Figure 18 illustrates a clinical trial (e.g., KRT-232-109 study), showing the total symptom score reduction after add-on navtemadlin to a stable dose of ruxolitinib, in accordance with an embodiment of the present disclosure. The KRT-232-109 study is a phase 2 study of add-on navtemadlin in patients with a suboptimal response to ruxolitinib. Note: Baseline TSS assessment was taken while subjects were on a stable dose of ruxolitinib for ≥ 8 weeks (e.g., no ruxolitinib wash-out). No dose increases of ruxolitinib above the stable baseline dose occurred during the 24-week assessment period. The median duration of ruxolitinib treatment prior to the addition of navtemadlin was 21.6 months (range: 7 to 129). *Six subjects discontinued treatment prior to Week 24. Abbreviations: MFSAF, Myelofibrosis Symptom Assessment Form; ITT, intention-to-treat; Rux, ruxolitinib; TSS, total symptom score; yrs, years.

[0033] Figure 19 illustrates expected SVR for add-on navtemadlin to ruxolitinib, in accordance with an embodiment of the present disclosure. Spleen volume reductions modeledfrom KRT-232-109 and published phase 3 myelofibrosis studies. Note: Light gray bars depict the baseline distribution of SVR based on pooled, extractable data from published phase 3 JAKi-naïve MF studies for patients with suboptimal spleen response to ruxolitinib monotherapy (± placebo); COMFORT-1, SIMPLIFY-1, and TRANSFORM-1 (Verstovsek 2012; Mesa 2017; Pemmaraju 2023). Blue bars, regardless of shade, show the expected additional benefit of treating patients with add-on navtemadlin. Darkest blue bars depict SVR25 responders from a pre-randomization baseline that also cross the SVR35 threshold from a pre-ruxolitinib baseline (e.g., proposed multi-component SVR endpoint). Abbreviations: CT, computed tomography; LOCF, last observation carried forward; MF, myelofibrosis; MRI, magnetic resonance imaging; Rux, ruxolitinib; SVR, splenic volume response; SVR25, spleen volume reduction ≥ 25%, SVR35, spleen volume reduction ≥ 35%.

[0034] Figure 20 illustrates expected SVR for add-on placebo to ruxolitinib, in accordance with an embodiment of the present disclosure. Spleen volume reductions modeled from KRT-232-109 and published phase 3 myelofibrosis studies. Note: Light gray bars depict the baseline distribution of SVR based on pooled, extractable data from published phase 3 JAKi-naïve MF studies for patients with suboptimal spleen response to ruxolitinib monotherapy (± placebo); COMFORT-1, SIMPLIFY-1, and TRANSFORM-1 (Verstovsek 2012; Mesa 2017; Pemmaraju 2023). Dark gray bars show the expected additional benefit of treating patients with add-on placebo. No (0%) of patients are modeled to achieve the proposed multi-component SVR endpoint of SVR25 from a pre-randomization baseline AND SVR35 from a pre-ruxolitinib baseline. Abbreviations: CT, computed tomography; LOCF, last observation carried forward; MF, myelofibrosis; MRI, magnetic resonance imaging; Rux, ruxolitinib; SVR, splenic volume response; SVR25, spleen volume reduction ≥ 25%, SVR35, spleen volume reduction ≥ 35%.

[0035] Figure 21 illustrates expected TSS reduction add-on navtemadlin to ruxolitinib, in accordance with an embodiment of the present disclosure. Total symptom scores modeled from KRT-232-109 and published phase 3 myelofibrosis studies. Note: Light gray bars depict the baseline distribution of TSS reductions based on pooled extractable data from published phase 3 JAKi-naïve MF studies for patients with suboptimal symptom response to ruxolitinib monotherapy (± placebo); COMFORT-1, SIMPLIFY-1, and MANIFEST-2 (Verstovsek 2012; Mesa 2017; Rampal 2023). Green bars, regardless of shade, show the expected additional symptom improvement benefit of treating patients with add-on navtemadlin. Darkest green bars depict TSS30 responders from a pre-randomization baseline that alsocross the TSS50 threshold from a pre-ruxolitinib baseline (proposed multi-component TSS endpoint). Abbreviations: CT, computed tomography; LOCF, last observation carried forward; MF, myelofibrosis; MRI, magnetic resonance imaging; Rux, ruxolitinib; TSS, total symptoms score; TSS30, total symptom score reduction ≥ 30%, TSS50, total symptom score reduction ≥ 50%.

[0036] Figure 22 illustrates expected TSS reductions for placebo add-on to ruxolitinib, in accordance with an embodiment of the present disclosure. Total symptom scores modeled from KRT-232-109 and published phase 3 myelofibrosis studies. Note: Light gray bars depict the baseline distribution of TSS reductions based on pooled extractable data from published phase 3 JAKi-naïve MF studies for patients with suboptimal symptom response to ruxolitinib monotherapy (± placebo); COMFORT-1, SIMPLIFY-1, and MANIFEST-2 (Verstovsek 2012; Mesa 2017; Rampal 2023). Darker gray bars show the expected additional benefit of treating patients with add-on placebo. Black bars depict TSS30 responders from a pre- randomization baseline that also cross the TSS50 threshold from a pre-ruxolitinib baseline (e.g., proposed multi-component TSS endpoint). Abbreviations: CT, computed tomography; LOCF, last observation carried forward; MF, myelofibrosis; MRI, magnetic resonance imaging; Rux, ruxolitinib; TSS, total symptoms score; TSS30, total symptom score reduction ≥ 30%, TSS50, total symptom score reduction ≥ 50%.

[0037] Like reference numerals refer to corresponding parts throughout the several views of the drawings. DETAILED DESCRIPTION

[0038] Given the above background, there is an unmet need for improved therapies for patients with clinical conditions who have a suboptimal response to traditional treatments. What is needed in the art are systems and methods for improved therapies for patients with myeloproliferative neoplasm (MPN) who have a suboptimal response to first-line Janus kinase (JAK) inhibitors, such as standard of care ruxolitinib monotherapy.

[0039] Advantageously, the presently disclosed subject matter addresses the above- identified need in the art by providing systems and methods for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition. In some embodiments, methods include obtaining clinical data for subjects with MPN, where the clinical data includes first baseline measurements prior totreatment and first responses after first treatment with a first composition (e.g., ruxolitinib). In some embodiments, the first baseline measurements comprises the first baseline spleen volume measurements. In some embodiments, the first baseline measurements comprises the first baseline total symptom score (TSS) measurements. In some embodiments, the first baseline measurements comprises the first baseline total symptom score (TSS) measurements, where the total symptom score is determined using a Myelofibrosis Symptom Assessment Form (MFSAF). In some embodiments, the first baseline measurements comprises the first baseline quality of life measurements, where the quality of life is determined using a the general quality of life questionnaire (EQ-5D), eHEALS, EORTC QLG Core Questionnaire (EORTC QLQ-C30), Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and / or patient activation measure (PAM-13). A subset of subjects satisfying a response threshold is identified and divided, for a second treatment, between a first and a second arm, the first arm receiving the first composition and a second composition (e.g., navtemadlin), and the second arm receiving the first composition and a placebo. Second responses are received after the second treatment. Subjects in the subset are evaluated by comparing second responses to first baseline measurements or to optional second baseline measurements obtained after division between the first and second arms and prior to the second treatment, thus determining whether the combined treatment of the first arm improves the MPN-associated endpoints relative to the monotherapy with the first composition. In some embodiments, the second baseline measurements comprises the second baseline spleen volume measurements. In some embodiments, the second baseline measurements comprises the second baseline total symptom score (TSS) measurements. In some embodiments, the second baseline measurements comprises the second baseline total symptom score (TSS) measurements, where the total symptom score is determined using a Myelofibrosis Symptom Assessment Form (MFSAF). In some embodiments, the second baseline measurements comprises the second baseline quality of life measurements, where the quality of life is determined using a the general quality of life questionnaire (EQ-5D), eHEALS, EORTC QLG Core Questionnaire (EORTC QLQ-C30), Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and / or patient activation measure (PAM-13).

[0040] Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings. In the following detailed description, numerous specific details are set forth to provide a thorough understanding of the present disclosure.However, it will be apparent to one of ordinary skill in the art that the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, circuits, and networks have not been described in detail so as not to unnecessarily obscure aspects of the embodiments.

[0041] Definitions

[0042] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0043] As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, e.g., up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, e.g., within 5-fold, or within 2-fold, of a value.

[0044] As used herein, the term “subject” refers to any animal (e.g., a mammal), including, but not limited to, humans, and non-human animals (including, but not limited to, non-human primates, dogs, cats, rodents, horses, cows, pigs, mice, rats, hamsters, rabbits, and the like (e.g., which is to be the recipient of a particular treatment, or from whom cells are harvested). In certain embodiments, the subject is a human.

[0045] As used herein, the term “treating” or “treatment” refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated and can be performed either for prophylaxis or during the course of clinical pathology. Therapeutic effects of treatment include, without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. By preventing progression of a disease or disorder, a treatment can prevent deterioration due to a disorder in an affected or diagnosed subject or a subject suspected ofhaving the disorder, but also a treatment may prevent the onset of the disorder or a symptom of the disorder in a subject at risk for the disorder or suspected of having the disorder.

[0046] As used herein, an “effective amount” or “therapeutically effective amount” is an amount sufficient to affect a beneficial or desired clinical result upon treatment. An effective amount can be administered to a subject in one or more doses. In terms of treatment, an effective amount is an amount that is sufficient to palliate, ameliorate, stabilize, reverse, or slow the progression of the disease, or otherwise reduce the pathological consequences of the disease. The effective amount is generally determined by the physician on a case-by-case basis and is within the skill of one in the art. Several factors are typically taken into account when determining an appropriate dosage to achieve an effective amount. These factors include age, sex and weight of the subject, the condition being treated, the severity of the condition and the form and effective concentration of the immunoresponsive cells administered.

[0047] As used herein, the term “diagnosis” or “diagnosed” refers to a determination as to whether a subject is likely affected by a given disease, disorder or dysfunction. The skilled artisan will appreciate that a diagnosis can be made on the basis of one or more diagnostic indicators including but not limited to, for example, biomarkers, images, and / or symptoms, the presence, absence, or amount of which is indicative of the presence or absence of the disease, disorder or dysfunction.

[0048] It will also be understood that, although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first subject could be termed a second subject, and, similarly, a second subject could be termed a first subject, without departing from the scope of the present disclosure. The first subject and the second subject are both subjects, but they are not the same subject. Furthermore, the terms “subject,” “user,” and “patient” are used interchangeably herein.

[0049] The terminology used in the present disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will also be understood that the term “and / or” as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items.It will be further understood that the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0050] As used herein, the term “if” may be construed to mean “when” or “upon” or “in response to determining” or “in response to detecting,” depending on the context. Similarly, the phrase “if it is determined” or “if [a stated condition or event] is detected” may be construed to mean “upon determining” or “in response to determining” or “upon detecting [the stated condition or event]” or “in response to detecting [the stated condition or event],” depending on the context.

[0051] Example Systems for Determining Improvement of Endpoints

[0052] One aspect of the present disclosure provides systems for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition.

[0053] A detailed description of a system 100 for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition, in accordance with the present disclosure, is described in conjunction with Figures 1A-1C. As such, Figures 1A-1C collectively illustrate the topology of the system in accordance with the present disclosure. In the topology, there is a system 100 for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition.

[0054] Referring to Figures 1A-1C, in some embodiments, the system 100 receives data directly or indirectly through radio-frequency signals. In some embodiments such signals are in accordance with an 802.11 (WiFi), Bluetooth, or ZigBee standard. In some embodiments, the system 100 receives data across one or more communications networks 16.

[0055] Examples of networks 16 include, but are not limited to, the World Wide Web (WWW), an intranet and / or a wireless network, such as a cellular telephone network, a wireless local area network (LAN) and / or a metropolitan area network (MAN), and other devices by wireless communication. The wireless communication optionally uses any of aplurality of communications standards, protocols and technologies, including but not limited to Global System for Mobile Communications (GSM), Enhanced Data GSM Environment (EDGE), high-speed downlink packet access (HSDPA), high-speed uplink packet access (HSUPA), Evolution, Data-Only (EV-DO), HSPA, HSPA+, Dual-Cell HSPA (DC-HSPDA), long term evolution (LTE), near field communication (NFC), wideband code division multiple access (W-CDMA), code division multiple access (CDMA), time division multiple access (TDMA), Bluetooth, Wireless Fidelity (Wi-Fi) (e.g., IEEE 802.11a, IEEE 802.11ac, IEEE 802.11ax, IEEE 802.11b, IEEE 802.11g and / or IEEE 802.11n), voice over Internet Protocol (VoIP), Wi-MAX, a protocol for e-mail (e.g., Internet message access protocol (IMAP) and / or post office protocol (POP)), instant messaging (e.g., extensible messaging and presence protocol (XMPP), Session Initiation Protocol for Instant Messaging and Presence Leveraging Extensions (SIMPLE), Instant Messaging and Presence Service (IMPS)), and / or Short Message Service (SMS), or any other suitable communication protocol, including communication protocols not yet developed as of the filing date of the present disclosure.

[0056] Of course, other topologies of the system 100 of Figures 1A-1C are possible. For instance, rather than relying on a communications network 16, information may be sent directly to the system 100. Further, the system 100 may constitute a portable electronic device, a server computer, or in fact constitute several computers that are linked together in a network or be a virtual machine in a cloud computing context. As such, the exemplary topology shown in Figures 1A-1C merely serves to describe the features of an embodiment of the present disclosure in a manner that will be readily understood to one of skill in the art.

[0057] Referring to Figures 1A-1C, in typical embodiments, the system 100 comprises one or more computers. For purposes of illustration in Figures 1A-1C, the system 100 is represented as a single computer that includes all of the functionality for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition. However, the disclosure is not so limited. In some embodiments, the functionality is spread across any number of networked computers and / or resides on each of several networked computers and / or is hosted on one or more virtual machines at a remote location accessible across the communications network 16. One of skill in the art will appreciate that any of a wide array of different computer topologies are used for the application and all such topologies are within the scope of the present disclosure.

[0058] Turning to Figures 1A-1C with the foregoing in mind, an exemplary system 100 for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition comprises one or more processing units (CPUs) 74, a network or other communications interface 84, a memory 192 (e.g., random access memory), one or more magnetic disk storage and / or persistent devices 90 optionally accessed by one or more controllers 288, one or more communication busses 13 for interconnecting the aforementioned components, a user interface 78, the user interface 78 including a display 82 and input 80 (e.g., keyboard, keypad, touch screen), and a power supply 76 for powering the aforementioned components. In some embodiments, the input 80 is a touch-sensitive display, such as a touch-sensitive surface. In some embodiments, the user interface 78 includes one or more soft keyboard embodiments. The soft keyboard embodiments may include standard (QWERTY) and / or non-standard configurations of symbols on the displayed icons. In some embodiments, data in memory 92 is seamlessly shared with non-volatile memory 90 using known computing techniques such as caching. In some embodiments, memory 92 and / or memory 90 includes mass storage that is remotely located with respect to the central processing unit(s) 74. In other words, some data stored in memory 92 and / or memory 90 may in fact be hosted on computers that are external to the system 100 but that can be electronically accessed by the system 100 over an Internet, intranet, or other form of network or electronic cable (e.g., illustrated as element 16) using network interface 84.

[0059] In some embodiments, the memory 92 of the system 100 for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition includes: • an optional operating system 102 that includes procedures for handling various basic system services; • a clinical data store for obtaining clinical data that involves a plurality of subjects 122 (e.g., 122-1,…122-J) that have the myeloproliferative neoplasm, where the clinical data optionally includes and associates for each respective subject 122 in the plurality of subjects (i) a corresponding first set of baseline measurements 124 (e.g., 124-1- 1,…124-1-K) prior to treatment with the first composition for the myeloproliferative neoplasm and (ii) a corresponding first response set 126 (e.g., 126-1-1,…126-1-L)after a first treatment period with the first composition; • a subsetting construct 130, optionally including: o a suboptimal response threshold 132 for identifying a subset of subjects 122 (e.g., 122-1,…122-M, 122-N,…122-P) in the plurality of subjects that each satisfies the suboptimal response threshold 132; o a first arm 134-1 from a division of the subset of subjects 122 (e.g., 122- 1,…122-M), where subjects in the first arm receive a combination of the first composition and the second composition for a second treatment period; o a second arm 134-2 from a division of the subset of subjects 122 (e.g., 122- N,…122-P), where subjects in the second arm receive a combination of the first composition and a placebo for the second treatment period; o for each respective subject 122 in the subset of subjects, a corresponding second response set 138 (e.g., 138-1-1,…138-1-R, 138-N-1,…138-N-T) upon completion of the second treatment period; and o for each respective subject 122 in the subset of subjects, an optional corresponding second set of baseline measurements 136 (e.g., 136-1-1,…136- 1-Q, 136-N-1,…136-N-S); • an endpoint data store 140, optionally including one or more endpoints 142 (e.g., 142- 1,…142-V) associated with a myeloproliferative neoplasm; and • an evaluation construct 150, that optionally evaluates each respective subject 122 in the subset of subjects by comparing the corresponding second response set 138 to (a) the corresponding first set of baseline measurements 124 for the respective subject and / or (b) an optional corresponding second set of baseline measurements 136 obtained for the respective subject 122 after division of the subset of subjects between the first arm 134-1 and the second arm 134-2 and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, thereby determining whether the combination of the first treatment and the second treatment of the first arm 134-1 improves the one or more endpoints 142 associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition 134-2.

[0060] In some implementations, one or more of the above identified data elements or modules of the system 100 are stored in one or more of the previously described memory devices, and correspond to a set of instructions for performing a function described above.The above-identified data, modules, or programs (e.g., sets of instructions) need not be implemented as separate software programs, procedures or modules, and thus various subsets of these modules may be combined or otherwise re-arranged in various implementations. In some implementations, the memory 92 and / or 90 optionally stores a subset of the modules and data structures identified above. Furthermore, in some embodiments the memory 92 and / or 90 stores additional modules and data structures not described above. Further still, in some embodiments, the system 100 stores data for two or more subjects, five or more subjects, one hundred or more subjects, or 1000 or more subjects.

[0061] In some embodiments, the system 100 comprises a smart phone (e.g., an iPhone), laptop, tablet computer, desktop computer, or other form of electronic device (e.g., a gaming console). In some embodiments, the system 100 is not mobile. In some embodiments, the system 100 is mobile.

[0062] It should be appreciated that the system 100 illustrated in Figures 1A-1C is only one example of a device that may be used for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition, and that the system 100 optionally has more or fewer components than shown, optionally combines two or more components, or optionally has a different configuration or arrangement of the components. The various components shown in Figures 1A-1C are implemented in hardware, software, firmware, or a combination thereof, including one or more signal processing and / or application specific integrated circuits.

[0063] In some embodiments, the system 100 has any or all of the circuitry, hardware components, and software components found in the system 100 depicted in Figures 1A-1C. In the interest of brevity and clarity, only a few of the possible components of the system 100 are shown in order to better emphasize the additional software modules that are installed on the system 100.

[0064] While the system 100 disclosed in Figures 1A-1C can work standalone, in some embodiments it can also be linked with electronic medical records to exchange information in any way.

[0065] Example Embodiments for Determining Improvement of Endpoints

[0066] Now that details of a system 100 for determining whether treatment with a combination of a first composition and a second composition improves one or moreendpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition have been disclosed, details regarding a flow chart of processes and features, that optionally use the system 100, in accordance with an embodiment of the present disclosure, are disclosed with reference to Figures 2A-2C. In some embodiments, such processes and features are conducted by the system 100 illustrated in Figures 1A-1C. In some embodiments, the processes and features referenced in Figures 2A-2C are conducted without the use of the system illustrates I Figures 1A-1C.

[0067] Figures 2A-2C collectively illustrate a method 200 for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints 142 associated with a myeloproliferative neoplasm relative to monotherapy with the first composition.

[0068] Patients with suboptimal response to ruxolitinib.

[0069] As described above, there is an unmet need for subjects with a suboptimal response to ruxolitinib. While ruxolitinib treatment results in significant SVR (e.g., > 35%) and symptom control (e.g., TSS reduction of > 50%) in a subset of patients, many patients have a suboptimal response (e.g., SVR < 35% and TSS reduction < 50%) (Harrison 2012; Verstovsek 2012; Mesa 2017). While this group of patients has, in some embodiments, modest benefit from ongoing ruxolitinib use, spleen volume remains enlarged, and symptom burden remains clinically relevant. Thus, maximizing SVR is important to optimize patient outcomes because magnitude of SVR is correlated with, among other endpoints, improvements in quality of life, as assessed by TSS, and overall survival (OS). Without being limited to any one theory of operation, the smaller the spleen becomes, the greater the improvement in quality of life, and the longer an MF patient lives (Mesa 2013; Vannuchi 2015).

[0070] Traditional treatment options to improve outcomes for suboptimal ruxolitinib responders are limited. There are currently no drugs approved that may be added to ruxolitinib to optimize patient care. Unfortunately, as noted above, suboptimal response may also contribute to patient treatment discontinuation and patient outcomes after discontinuing ruxolitinib are dismal. In patients who discontinue ruxolitinib, median OS was just 13.2 months (95% confidence interval [CI], 8.0-22.7 months) (Newberry 2017). Together, these data clearly show the unmet medical need for improved treatment options in MF patients with suboptimal response to ruxolitinib.

[0071] Navtemadlin.

[0072] Navtemadlin is a potent and selective, small molecule mouse double minute 2 (MDM2) inhibitor that binds human MDM2 to neutralize its interaction with p53. This restores p53-mediated activity and induces apoptosis in TP53 wild-type (WT) malignancies (Sun 2014). The primary determinant of sensitivity to MDM2 inhibition is TP53 mutation status. Specifically, if tumors have TP53 mutations that impair the transcriptional activity of p53, then MDM2 inhibition may not modulate the tumor suppressor functions of p53. Therefore, the safety and efficacy of navtemadlin treatment should only be evaluated in patients with TP53WTtumors. To this point, strategies to maximize efficacy of MDM2i may be most apparent in tumor cells that have evaded normal p53 tumor suppressor function through upregulating MDM2 levels (e.g., MDM2 gene amplification, MDM2 overexpression, or MDM2 nuclear protein upregulation).

[0073] Nonclinical pharmacology studies have shown that navtemadlin drives a dose- dependent reduction in tumor growth in xenograft models representing various genetic backgrounds, and tumor types harboring TP53WT. Activation of the p53 pathway was observed with navtemadlin treatment as measured by increases in cyclin-dependent kinase inhibitor protein (p21) mRNA, a direct transcriptional target of p53, and induction of pro- apoptosis proteins leading to tumor cell death. Preclinical studies conducted with navtemadlin have yielded promising results in in vitro, ex vivo, and in vivo experiments, representing solid tumors and hematologic malignancies, including MF and acute myeloid leukemia secondary to an MPN.

[0074] Repeat-dose toxicity studies of up to 13 weeks duration in rats and monkeys, along with in vitro and in vivo safety pharmacology studies, have been completed for navtemadlin. In a standard panel of assays, navtemadlin was not mutagenic or genotoxic, and had negligible potential for phototoxicity. Nonclinical embryofetal toxicity and fertility studies have not been conducted for navtemadlin due to the well documented requirement for p53 / MDM2 control during embryonic and fetal development. Based on its mechanism of action, navtemadlin alters cell proliferation and is expected to result in adverse effects on embryofetal viability and development.

[0075] Improved treatment considerations.

[0076] Janus kinase (JAK) inhibitors, including the JAK 1 / 2 inhibitor ruxolitinib, have become the standard of care and backbone therapy for the treatment of patients with MF.However, many MF patients have a suboptimal response to ruxolitinib (e.g., SVR < 35% and TSS reduction < 50%). In this group, spleen volume remains enlarged, and symptom burden remains clinically relevant. There is an unmet need for improved therapies, with complementary mechanisms, which can be safely combined with a JAKi backbone to treat patients with MF who have a suboptimal response to JAKi treatment. Effective novel therapies would enable more patients to achieve clinically meaningful reductions in splenomegaly and symptom burden and the potential for disease modification, with the goal of survival benefit.

[0077] MF is characterized by elevated circulating CD34+progenitors that overexpress MDM2, due to upstream somatic gain-of-function mutations (e.g., JAK2 V617F) (Nakatake 2012; Orvain 2016). MDM2 is the key negative regulator of tumor suppressor protein 53 (p53). MDM2 overexpression by malignant progenitors is a mechanism by which these malignant CD34+cells can evade normal p53 tumor suppressor detection and apoptosis.

[0078] Almost all patients with MF are TP53WT; just 2-4% of patients with chronic-phase MF carry a TP53 mutation (Harutyunyan 2011; Raza 2012), suggesting that overexpression of MDM2 is sufficient for MF progenitors to suppress normal p53 function, resulting in unchecked cancer cell proliferation. Therapeutic inhibition of MDM2 offers the potential to restore normal p53 function, leading to apoptosis of malignant MDM2-overexpressing MF progenitors, thereby complementing the immunomodulatory, anti-proliferative effects of backbone JAKi (e.g., ruxolitinib) therapy.

[0079] The apoptotic threshold of CD34+MF progenitors can be influenced by factors including upstream pro-proliferative signaling (e.g., constitutive JAK-STAT activation), p21 induction of cell cycle arrest, and extrinsic pro-survival receptor signaling present within the supportive tumor microenvironment. Navtemadlin has potential for synergy with agents that lower the apoptotic threshold to enhance tumor cell death (Vousden 2007). Preclinical data have demonstrated that navtemadlin combined with ruxolitinib enhances apoptosis of MF patient-derived progenitors by lowering the apoptotic threshold (see, e.g., Example 3, below). The combination leverages complementary mechanisms converging on apoptotic cell death by inhibiting transient p21-mediated cell-cycle arrest and expression of pro-survival Bcl-2 family proteins (Clevenger 2023).

[0080] Ex vivo experiments demonstrated the synergistic cytotoxicity of navtemadlin and ruxolitinib (see, for instance, Examples 2-8, below) is clinically relevant and associated withimproved clinical outcomes. Navtemadlin, both as a single agent in study KRT-232-101A, and as add-on therapy to ruxolitinib in study KRT-232-109, decreased circulating CD34+ cells (see, e.g., Figure 6A and Figures 6B-C, respectively). In both studies, reduction in CD34+ cells correlated with SVR – patients with the largest decreases in peripheral CD34+ cell count had the largest reductions in spleen volume. As discussed above, reduction in spleen volume is associated with both increased OS, and improved symptom severity (Mesa 2013; Vannucchi 2015). These results establish the relevance of a cytotoxic mechanism for disease modification for navtemadlin as add-on therapy to ruxolitinib that improves MF patient outcomes. Furthermore, this mechanism of action is distinct from and complementary to the mechanism through which ruxolitinib monotherapy acts (e.g., inhibition of the JAK- STAT signaling pathway).

[0081] Additionally, and without being limited to any particular theory, in some instances, there are beneficial effects of MDM2 inhibition toward the addictive feedback loop between stromal / microenvironment cells and the malignant clone. Because p53 activation reduces NF-κB-mediated signaling, it may synergize with ruxolitinib (Lussana 2017; Greenfield 2018). In combination with JAK inhibition, p53 activation by navtemadlin may deprive the malignant clone of its proliferative “niche” within the bone marrow, and sites of extramedullary hematopoiesis. Synergistic anticancer effects suggest that add-on therapy of navtemadlin to ruxolitinib may be of particular benefit in patients with MF who have had a suboptimal response to ruxolitinib. As noted in Examples 2-8, interim results from the ongoing KRT-232-109 study demonstrated preliminary evidence of efficacy of navtemadlin as add-on therapy to ruxolitinib, providing clinical support for potential synergy in the therapeutic effects summarized above.

[0082] Clinical data.

[0083] Referring to Block 202, in some embodiments, the method further includes obtaining clinical data that involves a plurality of subjects 122 that have the myeloproliferative neoplasm, where the clinical data includes and associates for each respective subject 122 in the plurality of subjects (i) a corresponding first set of baseline measurements 124 prior to treatment with the first composition for the myeloproliferative neoplasm and (ii) a corresponding first response set 126 after a first treatment period with the first composition. In some embodiments, the run-in period is the first treatment period when the first composition is administered to the myeloproliferative neoplasm patient.

[0084] In some embodiments, the method is performed for a plurality of subjects that have an indication (e.g., a clinical indication). In some embodiments, the first composition and / or the second composition is for the indication (e.g., selected and / or used for treatment of the indication). In some embodiments, the method is performed to determine whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with the indication relative to monotherapy with the first composition.

[0085] In some embodiments, the indication is myeloproliferative neoplasm. In some embodiments, the myeloproliferative neoplasm is myelofibrosis.

[0086] In some embodiments, the indication is a disease, such as cancer. In some embodiments, the cancer comprises breast cancer, lung cancer, prostate cancer, colorectal cancer, skin cancer, bladder cancer, blood cancer, leukemia, lymphoma, ovarian cancer, pancreatic cancer, kidney cancer, brain cancer, thyroid cancer, stomach (gastric) cancer, liver cancer, cervical cancer, esophageal cancer, bone cancer, a sarcoma, and / or testicular cancer.

[0087] In some embodiments, the indication is for a stage of cancer, such as stage I, II, III, or IV of the tumor, nodes, and metastasis (TNM) system.

[0088] In some embodiments, the corresponding first set of baseline measurements comprises a plurality of baseline measurements. In some embodiments, the corresponding first set of baseline measurements comprises at least 1, at least 2, at least 5, at least 10, at least 20, at least 50, at least 100, or at least 200 baseline measurements. In some embodiments, the corresponding first set of baseline measurements comprises no more than 500, no more than 200, no more than 100, no more than 50, no more than 10, or no more than 5 baseline measurements. In some embodiments, the corresponding first set of baseline measurements consists of from 1 to 10, from 2 to 20, from 20 to 100, or from 100 to 500 baseline measurements. In some embodiments, the corresponding first set of baseline measurements falls within another range starting no lower than 1 baseline measurement and ending no higher than 500 baseline measurements.

[0089] In some embodiments, the first set of baseline measurements comprises one or more baseline measurements for each respective endpoint in the one or more endpoints.

[0090] In some embodiments, the one or more endpoints comprises at least 1, at least 2, at least 5, at least 10, at least 20, at least 50, at least 100, or at least 200 endpoints. In some embodiments, the one or more endpoints comprises no more than 500, no more than 200, nomore than 100, no more than 50, no more than 10, or no more than 5 endpoints. In some embodiments, the one or more endpoints consists of from 1 to 10, from 2 to 20, from 20 to 100, or from 100 to 500 endpoints. In some embodiments, the one or more endpoints falls within another range starting no lower than 1 endpoint and ending no higher than 500 endpoints.

[0091] In some embodiments, the first treatment period is greater than 5 weeks and less than 40 weeks. In some embodiments, the first treatment period is equal to or greater than 12 weeks and less than 36 weeks. In some embodiments, the first treatment period includes at least 5 weeks of daily administration of the first composition free of a treatment hold or a dose adjustment. In some embodiments, the first treatment period includes at least 8 weeks of daily administration of the first composition free of a treatment hold or a dose adjustment. In some embodiments, an active ingredient of the first treatment composition is ruxolitinib. Suitable embodiments for the first treatment period is described in further detail elsewhere herein (see, for instance, the section entitled “First treatment and second treatment,” below).

[0092] In some embodiments, the corresponding first response set comprises a plurality of first responses. In some embodiments, the corresponding first response set comprises at least 1, at least 2, at least 5, at least 10, at least 20, at least 50, at least 100, or at least 200 first responses. In some embodiments, the corresponding first response set comprises no more than 500, no more than 200, no more than 100, no more than 50, no more than 10, or no more than 5 first responses. In some embodiments, the corresponding first response set consists of from 1 to 10, from 2 to 20, from 20 to 100, or from 100 to 500 first responses. In some embodiments, the corresponding first response set falls within another range starting no lower than 1 first response and ending no higher than 500 first responses.

[0093] In some embodiments, the first response set comprises one or more first responses for each respective endpoint in the one or more endpoints.

[0094] In some embodiments, one or more first baseline measurements, first responses, and / or endpoints are selected from any of the endpoints, inclusion criteria, and / or exclusion criteria disclosed herein (see, e.g., the section entitled “Subjects,” above and / or the section entitled “Endpoints,” below).

[0095] Subjects.

[0096] In some embodiments, the plurality of subjects comprises 200 subjects. In some embodiments, the plurality of subjects comprises 500 subjects.

[0097] In some embodiments, the plurality of subjects comprises at least 10, at least 20, at least 50, at least 100, at least 200, at least 500, at least 1000, at least 2000, at least 5000, or at least 10,000 subjects. In some embodiments, the plurality of subjects comprises no more than 100,000, no more than 10,000, no more than 5000, no more than 2000, no more than 1000, no more than 500, no more than 100, or no more than 50 subjects. In some embodiments, the plurality of subjects consists of from 10 to 100, from 80 to 500, from 200 to 1000, from 1000 to 10,000, or from 10,000 to 100,000 subjects. In some embodiments, the plurality of subjects falls within another range starting no lower than 10 subjects and ending no higher than 100,000 subjects.

[0098] Referring to Block 204, in some embodiments, the plurality of subjects is JAK- inhibitor treatment naïve.

[0099] In some embodiments, each subject in the plurality of subjects comprises one or more inclusion criteria in a plurality of inclusion criteria (e.g., in the corresponding first set of baseline measurements). In some embodiments, the one or more inclusion criteria are selected from any of the inclusion criteria listed in Table 1. In some embodiments, each respective subject in the plurality of subjects comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 of the inclusion criteria listed in Table 1. In some embodiments, each respective subject in the plurality of subjects comprises all of the inclusion criteria listed in Table 1. In some embodiments, each respective subject in the plurality of subjects comprises no more than 14, no more than 10, no more than 8, no more than 5, or no more than 3 of the inclusion criteria listed in Table 1.

[0100] In some embodiments, each subject in the plurality of subjects is free of one or more exclusion criteria in a plurality of exclusion criteria. In some embodiments, the one or more exclusion criteria are selected from any of the exclusion criteria listed in Table 2. In some embodiments, each respective subject in the plurality of subjects comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, or at least 30 of the exclusion criteria listed in Table 2. In some embodiments, each respective subject in the plurality of subjects comprises all of the exclusion criteria listed in Table 2. In some embodiments, each respective subject in the plurality of subjects comprises no more than 41, no more than 30, no more than 20, no more than 10, no more than 8, no more than 5, or no more than 3 of the exclusion criteria listed in Table 2.

[0101] In some embodiments, each subject in the plurality of subjects has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 in the corresponding first set of baseline measurements. In some embodiments, each subject in the plurality of subjects has an ECOG performance status of 0, 1, 2, 3, or 4 in the corresponding first set of baseline measurements.

[0102] In some embodiments, each subject in the plurality of subjects has a spleen measuring greater than or equal to 450 cm3as determined by magnetic resonance imaging or computed tomography in the corresponding first set of baseline measurements.

[0103] In some embodiments, each subject in the plurality of subjects has a spleen measuring at least 50, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 550, at least 600, or at least 650 cm3as determined by magnetic resonance imaging or computed tomography in the corresponding first set of baseline measurements. In some embodiments, each subject in the plurality of subjects has a spleen measuring no more than 700, no more than 600, no more than 500, no more than 400, no more than 300, no more than 200, or no more than 100 cm3as determined by magnetic resonance imaging or computed tomography in the corresponding first set of baseline measurements. In some embodiments, each subject in the plurality of subjects has a spleen measuring from 50 to 200, from 100 to 300, from 200 to 500, or from 400 to 700 cm3as determined by magnetic resonance imaging or computed tomography in the corresponding first set of baseline measurements. In some embodiments, each subject in the plurality of subjects has a spleen measurement that falls within another range starting no lower than 50 cm3and ending no higher than 700 cm3as determined by magnetic resonance imaging or computed tomography in the corresponding first set of baseline measurements.

[0104] In some embodiments, each subject in the plurality of subjects has a platelet count of 100 x 109 / L or greater in the corresponding first set of baseline measurements.

[0105] In some embodiments, each subject in the plurality of subjects has a platelet count of at least 50 x 109 / L, at least 100 x 109 / L, at least 200 x 109 / L, at least 300 x 109 / L, at least 500 x 109 / L, at least 600 x 109 / L, or at least 800 x 109 / L in the corresponding first set of baseline measurements. In some embodiments, each subject in the plurality of subjects has a platelet count of no more than 1 x 1010 / L, no more than 800 x 109 / L, no more than 500 x 109 / L, no more than 300 x 109 / L, no more than 200 x 109 / L, or no more than 100 x 109 / L in the corresponding first set of baseline measurements. In some embodiments, each subject inthe plurality of subjects has a platelet count of from 50 x 109 / L to 200 x 109 / L, from 100 x 109 / L to 500 x 109 / L, from 300 x 109 / L to 800 x 109 / L, or from 500 x 109 / L to 1 x 1010 / L in the corresponding first set of baseline measurements. In some embodiments, each subject in the plurality of subjects has a platelet count that falls within another range starting no lower than 50 x 109 / L and ending no higher than 1 x 1010 / L in the corresponding first set of baseline measurements.

[0106] Table 1: Example Inclusion Criteria Example Inclusion Criteria for Run-In Period Adults ≥ 18 years of age able to provide informed consent. Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF, as assessed by treating physician according to the World Health Organization (WHO) criteria. Spleen measuring ≥ 450 cm3by MRI or CT scan (central review) MF symptoms as defined by a baseline TSS of ≥ 10. Baseline TSS will be assessed by the 7-day average per MFSAF v4.0. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of ruxolitinib monotherapy): a. Hematologic: i. Absolute neutrophil count (ANC) ≥ 1.5 × 109 / L in the absence of myeloid growth factors during the prior 28 days. ii. Platelet count ≥ 100 × 109 / L b. Hepatic: iii. Total serum bilirubin within normal limits. If total bilirubin is > upper limit of normal (ULN), subjects are eligible if direct bilirubin ≤ 2.0 ULN, unless documented Gilbert’s Syndrome. iv. Aspartate transaminase / serum glutamic oxaloacetic transaminase (AST / SGOT) and alanine transaminase / serum glutamic pyruvic transaminase (ALT / SGPT) ≤ 2.5 ULN. c. Renal: estimated creatinine clearance ≥ 30 mL / min by the Cockcroft Gault equation. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for 1 months and 1 week and males subjects must continue to use a highly effective method of contraception for 3 months and 1 week. A woman is considered of childbearing potential (e.g., fertile) following menarche and until becoming post-menopausal unless permanently sterile. Example Inclusion Criteria for Randomized Period PMF, post–PV-MF, or post–ET-MF that is TP53WTas assessed by central testing. IPSS risk category of Intermediate 1, Intermediate 2, or High.ECOG performance status of 0 to 2. Treatment with ruxolitinib for ≥ 18 weeks and < 25 weeks, and on a stable dose of ruxolitinib in the 8 consecutive weeks prior to study treatment. a. A stable dose is defined as a ruxolitinib dose that has not required a treatment hold or dose adjustment. b. Subjects must be taking a stable dose of ruxolitinib of ≥ 5 mg BID. Suboptimal response to ruxolitinib monotherapy, defined as one or both of > 0% but < 35% reduction in spleen volume and > 0% but < 50% reduction in TSS, will be assessed from the start of the run-in period baseline to the end of the run-in period while on a stable dose of ruxolitinib in the 8 consecutive weeks prior to the end of the run-in period. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of study treatment): a. Hematologic: i. ANC ≥ 1.5 × 109 / L in the absence of myeloid growth factors during the prior 28 days. ii. Platelet count ≥ 100 × 109 / L b. Hepatic: iii. Total serum bilirubin within normal limits. If total bilirubin is > ULN, subjects are eligible if direct bilirubin ≤ 2.0 ULN, unless documented Gilbert’s Syndrome. iv. AST / SGOT and ALT / SGPT ≤ 2.5 ULN c. Renal: estimated creatinine clearance ≥ 30 mL / min by the Cockcroft Gault equation Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for 1 months and 1 week and males subjects must continue to use a highly effective method of contraception for 3 months and 1 week. A woman is considered of childbearing potential (e.g., fertile) following menarche and until becoming post-menopausal unless permanently sterile.

[0107] Table 2: Example Exclusion Criteria Example Exclusion Criteria for Run-In Period Participation in another interventional clinical trial within 4 weeks prior to the first dose of ruxolitinib monotherapy (participation in observational studies is permitted). Prior therapy with any JAKi. Prior therapy with BCL-XL, BET, MDM2, PI3K, PIM, or XPO1 inhibitors; prior p53- directed therapy. Subjects must have discontinued all drugs used to treat underlying MF disease ≥ 28 days prior to first dose of ruxolitinib monotherapy. Erythroid growth factors, danazol (or equivalent androgen), or prednisone (or equivalent corticosteroid) are permitted if the subject is on a stable dose for 2 months prior to starting ruxolitinib. Prior splenectomy. Splenic irradiation within 3 months prior to the first dose of ruxolitinib monotherapy.Non-spleen-directed radiation therapy for MF or major surgery or planned major surgery within 28 days prior to the first dose of ruxolitinib monotherapy. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation. Subjects who are eligible for stem cell transplant but refuse transplant are not excluded. Peripheral blood or bone marrow blast count ≥ 10% at any time within 28 days prior to the first dose of ruxolitinib monotherapy. Women who are pregnant or breastfeeding. History of solid organ transplant. Known infection with human immunodeficiency virus (HIV). Known active hepatitis B or C infection. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before screening / randomization. Subjects with acute infections requiring systemic antibiotic use should delay screening / randomization until the course of antibiotic therapy has been completed. Subjects with uncontrolled intercurrent illness including, but not limited to; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or subjects with psychiatric illness / social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority. Active or chronic bleeding within 28 days prior to the first dose of ruxolitinib monotherapy. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of ruxolitinib monotherapy. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial / non-invasive transitional cell bladder carcinoma. Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version 5.0). History of difficulty swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease conditions that may hamper compliance and / or absorption of the study treatment. History of severe hypersensitivity reaction to any component of navtemadlin, any of its excipients, or to required prophylaxis. History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to first dose of ruxolitinib monotherapy. Subjects with indwelling surgical drains (e.g., peritoneal, CNS, or pleural). Subjects with symptomatic ascites or requiring paracentesis. White blood cell count that exceeds 50 × 109 / L at screening in the run-in period. Example Exclusion Criteria for Randomized PeriodWhite blood cell count that meets both of the following criteria: a. Increases by 2-fold (e.g., doubles) or more during therapy with ruxolitinib monotherapy (comparing Cycle 1 Day 1 in the run-in period vs screening in the randomized period) and b. Exceeds 50 × 109 / L at screening in the randomized period. Active treatment with BCL-XL, BET, MDM2, PI3K, PIM, or XPO1 inhibitors, or p53- directed therapy other than ruxolitinib. Splenic irradiation within 3 months prior to the first dose of study treatment. Non-spleen-directed radiation therapy for MF or major surgery or planned major surgery within 28 days prior to the first dose of study treatment. Eligible for allogeneic stem cell transplantation. Subjects who are eligible for stem cell transplant but refuse transplant are not excluded. Peripheral blood or bone marrow blast count ≥ 10% at any time within 28 days prior to the first dose of study treatment. Women who are pregnant or breastfeeding. History of solid organ transplant. Known infection with HIV. Known active hepatitis B or C infection. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before screening / randomization. Subjects with acute infections requiring systemic antibiotic use should delay screening / randomization until the course of antibiotic therapy has been completed. Subjects with uncontrolled intercurrent illness including, but not limited to; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or subjects with psychiatric illness / social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority. Active or chronic bleeding within 28 days prior to the first dose of study treatment. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment. Subjects with indwelling surgical drains (e.g., peritoneal, CNS, or pleural). Subjects with symptomatic ascites or requiring paracentesis. Any concurrent disease or condition that would make the subject unsuitable for participation in the study.

[0108] Suboptimal response.

[0109] Referring to Block 206, in some embodiments, the method further includes identifying a subset of subjects 122 in the plurality of subjects that each satisfies a suboptimalresponse threshold 132. In some embodiments, less than eighty percent of the plurality of subjects satisfies the suboptimal response threshold (e.g., the subset of subjects is at least 20% of the plurality of subjects). In some embodiments, less than forty percent of the plurality of subjects satisfies the suboptimal response threshold (e.g., the subset of subjects is at least 60% of the plurality of subjects).

[0110] In some embodiments, the subset of subjects comprises at least 10, at least 20, at least 50, at least 100, at least 200, at least 500, at least 1000, at least 2000, at least 5000, or at least 10,000 subjects. In some embodiments, the subset of subjects comprises no more than 100,000, no more than 10,000, no more than 5000, no more than 2000, no more than 1000, no more than 500, no more than 100, or no more than 50 subjects. In some embodiments, the subset of subjects consists of from 10 to 100, from 80 to 500, from 200 to 1000, from 1000 to 10,000, or from 10,000 to 100,000 subjects. In some embodiments, the subset of subjects falls within another range starting no lower than 10 subjects and ending no higher than 100,000 subjects.

[0111] In some embodiments, the subset of subjects comprises at least 10%, at least 20%, at least 30%, at least 50%, at least 60%, or at least 70% of the plurality of subjects. In some embodiments, the subset of subjects comprises no more than 80%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, or no more than 20% of the plurality of subjects. In some embodiments, the subset of subjects consists of from 10% to 40%, from 20% to 60%, from 30% to 70%, or from 50% to 80% of the plurality of subjects. In some embodiments, the subset of subjects falls within another range starting no lower than 10% and ending no higher than 80% of the plurality of subjects.

[0112] In some embodiments, satisfaction of the suboptimal response threshold is based on one or more metrics for each subject in the plurality of subjects. In some embodiments, the one or more metrics includes a reduction in spleen size. In some embodiments, the reduction in spleen size is a spleen volume reduction (SVR). In some embodiments, the one or more metrics includes a total symptom score (TSS). In some embodiments, the one or more metrics includes any of the endpoints, inclusion criteria, and / or exclusion criteria disclosed elsewhere herein (see, e.g., the section entitled “Subjects,” above and / or the section entitled “Endpoints,” below).

[0113] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) less than 35 percentreduction in spleen size (e.g., < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) a fifty percent reduction in total symptom score (e.g., < 50% TSS reduction) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied). When the SVR is negative (for example, -10%), it indicates that the spleen volume has increased by 10%. When TSS reduction is negative (for example, -10%), it indicates that the TSS has increased by 10%.

[0114] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) less than 35 percent reduction in spleen size (e.g., < 35% SVR) between the baseline measurement and after the first treatment period, and (ii) a fifty percent reduction in total symptom score (e.g., < 50% TSS reduction) between the baseline measurement and after the first treatment period.

[0115] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than - 25 percent and a 35 percent reduction in spleen size (e.g., > -25% but < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than -35 percent and a fifty percent reduction in total symptom score (e.g., > -35% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0116] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than - 20 percent and a 35 percent reduction in spleen size (e.g., > -20% but < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than -30 percent and a 50 percent reduction in total symptom score (e.g., > -30% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0117] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than - 15 percent and a 35 percent reduction in spleen size (e.g., > -15% but < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than -25 percent and a 50 percent reduction in total symptom score (e.g., > -25% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0118] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than - 10 percent and a 35 percent reduction in spleen size (e.g., > -10% but < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than -20 percent and a 50 percent reduction in total symptom score (e.g., > -20% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0119] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than -5 percent and a 35 percent reduction in spleen size (e.g., > -5% but < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than - 15 percent and a 50 percent reduction in total symptom score (e.g., > -15% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0120] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a 35 percent reduction in spleen size (e.g., > 0 % but < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than - 5 percent and a 50 percent reduction in total symptom score (e.g., > -5% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0121] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a 35 percent reduction in spleen size (e.g., > 0 % but < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than 0 percent and a 50 percent reduction in total symptom score (e.g., > 0% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0122] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a 20 percent reduction in spleen size (e.g., > 0 % but < 20% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than 0percent and a 30 percent reduction in total symptom score (e.g., > 0% but < 30% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0123] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between an equal or greater than 20 percent and a 35 percent reduction in spleen size (e.g., ≥ 20 % but < 35% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between an equal or greater than 30 percent and a 50 percent reduction in total symptom score (e.g., ≥ 30% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0124] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a 50 percent reduction in spleen size (e.g., > 0% but < 50% SVR) between the baseline measurement and after the first treatment period, and / or (ii) between a greater than 0 percent and a seventy percent reduction in total symptom score (e.g., > 0% but < 70% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0125] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a forty percent reduction in spleen size (e.g., > 0% but < 40% SVR) between the baseline measurement and after the first treatment period and / or (ii) between a greater than 0 percent and a sixty percent reduction in total symptom score (e.g., > 0% but < 60% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0126] Referring to Block 208, in some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a thirty-five percent reduction in spleen size (e.g., > 0% but < 35% SVR) between the baseline measurement and after the first treatment period and / or (ii) between a greater than 0 percent and a fifty percent reduction in total symptom score (e.g., > 0% but < 50% TSS) between the baseline measurement and after the first treatment period (e.g., one or both of the conditions are satisfied).

[0127] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold based on, for each respective first response in one or more first responses of the first response set, a comparison between the respective first response and a corresponding baseline measurement in the first set of baseline measurements. In some embodiments, the one or more first responses used for determining satisfaction of the suboptimal response threshold is selected from any of the endpoints, inclusion criteria, and / or exclusion criteria disclosed herein (see, e.g., the section entitled “Subjects,” above and / or the section entitled “Endpoints,” below).

[0128] In some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold based on a comparison between a respective first response and a corresponding baseline measurement for a spleen size, where the comparison determines a reduction in spleen size between the baseline measurement and after the first treatment period.

[0129] In some embodiments, the reduction in spleen size (e.g., SVR) is at least 1%, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 60%, or at least 70% reduction. In some embodiments, the reduction in spleen size is no more than 80%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, or no more than 3% reduction. In some embodiments, the reduction in spleen size is from 1% to 20%, from 10% to 40%, from 25% to 60%, or from 50% to 80%. In some embodiments, the reduction in spleen size falls within another range starting no lower than 1% and ending no higher than 80% reduction. In some embodiments, the reduction in spleen size is greater than 0%. In some embodiments, the reduction in spleen size falls within another range that is greater than 0% and no higher than 80%.

[0130] Alternatively or additionally, in some embodiments, the corresponding first response set of the respective subject satisfies the suboptimal response threshold based on a comparison between a respective first response and a corresponding baseline measurement for total symptom score (TSS), where the total symptom score is determined using a Myelofibrosis Symptom Assessment Form (MFSAF) and where the comparison determines a reduction in total symptom score between the first baseline TSS measurement and the TSS after the first treatment period or between the second baseline TSS measurement and the TSS after the second treatment period. In some embodiments, the first treatment period refers to the monotherapy period. In some embodiments, the first treatment period refers toRuxolitinib monotherapy period. In some embodiments, the second treatment period refers to the combination therapy period, when the first composition and the second composition are concurrently administered to the patients. In some embodiments, the second treatment period refers to the combination therapy period, when the first composition and the second composition are concurrently administered to the patients, wherein the first composition comprises Ruxolitinib; the second composition comprises navtemadlin. See, e.g., Mesa et al. The Myelofibrosis Symptom Assessment Form (MFSAF): An Evidence-based Brief Inventory to Measure Quality of Life and Symptomatic Response to Treatment in Myelofibrosis. Leuk Res.2009 September ; 33(9): 1199–1203. doi:10.1016 / j.leukres.2009.01.035, which is hereby incorporated herein by reference in its entirety.

[0131] In some embodiments, the reduction in TSS is at least 1%, at least 2%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 50%, at least 60%, or at least 70% reduction. In some embodiments, the reduction in TSS is no more than 80%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, or no more than 3% reduction. In some embodiments, the reduction in TSS is from 1% to 20%, from 10% to 40%, from 25% to 60%, or from 50% to 80%. In some embodiments, the reduction in TSS falls within another range starting no lower than 1% and ending no higher than 80% reduction. In some embodiments, the reduction in TSS is greater than 0%. In some embodiments, the reduction in TSS falls within another range that is greater than 0% and no higher than 80%. In some embodiments, the reduction in TSS is about 30% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition. In some embodiments, the reduction in TSS is about 35% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition. In some embodiments, the reduction in TSS is about 40% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition. In some embodiments, the reduction in TSS is about 45% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior totreatment with the combination of the first composition and the second composition. In some embodiments, the reduction in TSS is about 50% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition. In some embodiments, the reduction in TSS is about 55% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition. In some embodiments, the reduction in TSS is about 60% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition.

[0132] In some embodiments, the reduction in TSS is about 30% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition. In some embodiments, the reduction in TSS is about 35% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition. In some embodiments, the reduction in TSS is about 40% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition. In some embodiments, the reduction in TSS is about 45% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition. In some embodiments, the reduction in TSS is about 50% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition. In some embodiments, the reduction in TSS is about 55% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition. In some embodiments, the reduction in TSS is about 60% comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition.

[0133] Division of subjects and study arms.

[0134] Referring to Block 209, in some embodiments, the method further includes dividing the subset of subjects 122 between a first arm 134-1 and a second arm 134-2 on a randomized basis, where subjects 122 in the first arm 134-1 receive a combination of the first composition and the second composition and subjects 122 in the second arm 134-2 receive a combination of the first composition and a placebo for a second treatment period. In some embodiments, the subjects are not divided, and the subjects are administered the combination of the first composition and the second composition.

[0135] In some embodiments, the combination of the first composition and the second composition (alternately described herein as a “combined treatment”) comprises receiving the first composition and the second composition concurrently. In some embodiments, the combination of the first composition and the second composition comprises receiving the first composition and the second composition sequentially. In some such embodiments, the first composition is received prior to the second composition. In some embodiments, the second composition is received prior to the first composition. In some embodiments, the first composition and the second composition are received sequentially with no breaks in treatment (e.g., where the subsequent treatment is received immediately after cessation of the prior treatment). In some embodiments, the subsequent treatment is not received immediately after cessation of the prior treatment, but after a period of time following cessation of the prior treatment (e.g., 1 day or more, 2 days or more, 1 week or more, between 1 day and 1 week, etc.). In some embodiments, the combination of the first composition and the second composition are received as an “add-on” treatment, where one of the first composition and the second composition is supplemented with the other of the first composition and the second composition after an initial treatment period. In some implementations, the “add-on” treatment comprises, after a first treatment period with the first composition, supplementing the first composition with the second composition for a second treatment period. In some implementations, the “add-on” treatment comprises, after a first treatment period with the second composition, supplementing the second composition with the first composition for a second treatment period. Any suitable method for combining treatments (e.g., as concurrent, sequential, and / or add-on) are contemplated for use in the present disclosure, as will be apparent to one skilled in the art.

[0136] In some embodiments, the dividing the subset of subjects into two or more arms is performed using a stratification across one or more blocks. In some embodiments, each blockin the one or more blocks represents a stratification factor, score, and / or criterion, such as an inclusion criteria or an endpoint measurement. In some embodiments, a respective block in the one or more blocks is selected from any of the endpoints, inclusion criteria, and / or exclusion criteria disclosed herein (see, e.g., the section entitled “Subjects,” above and / or the section entitled “Endpoints,” below).

[0137] In some embodiments, the dividing the subset of subjects between a first arm and a second arm on the randomized basis is in accordance with a stratified, permuted-block randomization scheme that balances representation in the first arm and the second arm for each block in a plurality of blocks, where a first block in the plurality of blocks is scoring intermediate-1 on the International Prognostic Scoring System, and a second block in the plurality of blocks is scoring Intermediate-2 or High on the International Prognostic Scoring System.

[0138] In some embodiments, the one or more blocks includes a stratification factor that is a score on the International Prognostic Scoring System (IPSS) (e.g., Intermediate-1, Intermediate-2, and / or High).

[0139] In some embodiments, the one or more blocks includes a stratification factor that is a total daily dose of the first treatment by the first composition (e.g., < 20 mg versus ≥ 20 mg).

[0140] In some embodiments, a third block in the plurality of blocks is total daily dose of the first treatment regimen at the end of the first treatment regimen below a threshold dosage, and a fourth block in the plurality of blocks is total daily dose of the first treatment regimen at the end of the first treatment regimen equal to or above the threshold dosage.

[0141] In some embodiments, a third block in the plurality of blocks is total daily dose of the first treatment regimen at the end of the first treatment regimen at or below a threshold dosage, and a fourth block in the plurality of blocks is total daily dose of the first treatment regimen at the end of the first treatment regimen above the threshold dosage.

[0142] In some embodiments, the threshold dosage is at least 5, at least 10, at least 20, at least 30, or at least 40 mg. In some embodiments, the threshold dosage is no more than 50, no more than 40, no more than 30, no more than 20, or no more than 10 mg. In some embodiments, the threshold dosage is from 5 to 20, from 10 to 40, or from 30 to 50 mg. In some embodiments, the threshold dosage falls within another range starting no lower than 5mg and ending no higher than 50 mg. In some embodiments, the threshold dosage is about 20 mg.

[0143] Alternatively or additionally, in some embodiments, dividing the subset of subjects between a first arm and a second arm on the randomized basis is in accordance with a stratified, randomization scheme that balances representation in the first arm and the second arm for each block in a plurality of blocks, where each respective block in the plurality of blocks corresponds to a respective response category. In some embodiments, a first block in the plurality of blocks is a first range of responses for a first response category (e.g., an endpoint), and a second block in the plurality of blocks is a second range of responses for the first response category (e.g., the endpoint). In some embodiments, the first response category is SVR. In some embodiments, the first response category is TSS reduction.

[0144] In some embodiments, a first block in the plurality of blocks is a first range of responses for a first response category (e.g., a first endpoint), a second block in the plurality of blocks is a second range of responses for the first response category (e.g., the first endpoint), a third block in the plurality of blocks is a first range of responses for a second response category (e.g., a second endpoint), and a fourth block in the plurality of blocks is a second range of responses for the second response category (e.g., the second endpoint). In some embodiments, the first response category is SVR and the second response category is TSS reduction.

[0145] Referring to Block 210, in some embodiments, dividing the subset of subjects between a first arm and a second arm on the randomized basis is in accordance with a stratified, permuted-block randomization scheme that balances representation in the first arm and the second arm for each block in a plurality of blocks, where a first block in the plurality of blocks is SVR > 0% but < 20%, and a second block in the plurality of blocks is SVR ≥ 20% but < 35%. Referring to Block 212, in some embodiments, a third block in the plurality of blocks is TSS reduction > 0% but < 30%, and a fourth block in the plurality of blocks is TSS reduction ≥ 30% but < 50%.

[0146] Any number of response categories (e.g., SVR, TSS, etc.) and any number of ranges or strata within each response category (e.g., low, mid, high, and / or any numeric value ranges thereof) are contemplated for use in stratification and / or randomization of study arms in the present disclosure, as will be apparent to one skilled in the art. Moreover, response categories can be further subdivided into a higher or lower number of blocks (e.g., strata) toincrease balanced representation at greater or lower resolution, as desired, as will be apparent to one skilled in the art.

[0147] Advantageously, and without being limited to any one theory of operation, in some embodiments, this approach mitigates the risk of treatment bias (e.g., where treatment response to add-on navtemadlin is driven by a heavier weighting of subjects in the upper strata of SVR ≥ 30% but < 35% after randomization).

[0148] In some embodiments, the plurality of blocks comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or at least 15 blocks. In some embodiments, the plurality of blocks comprises no more than 20, no more than 15, no more than 10, no more than 5, or no more than 3 blocks. In some embodiments, the plurality of blocks consists of from 2 to 5, from 3 to 8, from 5 to 12, or from 12 to 20 blocks. In some embodiments, the plurality of blocks falls within another range starting no lower than 2 blocks and ending no higher than 20 blocks.

[0149] In some embodiments, the plurality of blocks corresponds to at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or at least 15 response categories (e.g., SVR, TSS). In some embodiments, the plurality of blocks corresponds to no more than 20, no more than 15, no more than 10, no more than 5, or no more than 3 response categories. In some embodiments, the plurality of blocks corresponds to from 1 to 3, from 2 to 5, from 3 to 8, from 5 to 12, or from 12 to 20 response categories. In some embodiments, the plurality of blocks corresponds to a set of response categories that falls within another range starting no lower than 1 response category and ending no higher than 20 response categories.

[0150] In some embodiments, the plurality of blocks includes, for each respective response category in a set of response categories used for stratification, a corresponding subset of blocks. In some embodiments, a respective subset of blocks for a respective response category comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 blocks. In some embodiments, the subset of blocks comprises no more than 10, no more than 8, no more than 5, or no more than 3 blocks. In some embodiments, the subset of blocks consists of from 1 to 3, from 2 to 5, from 3 to 8, or from 5 to 10 blocks. In some embodiments, the subset of blocks falls within another range starting no lower than 1 blocks and ending no higher than 10 blocks.

[0151] In some embodiments, a first response category is stratified into the same or a different number of blocks as a second response category (e.g., SVR is stratified into 3 blocks, while TSS is stratified into 2 blocks). In some embodiments, a respective response category is stratified based on value range (e.g., percent reduction, etc.), response type (e.g., presence or degree of suboptimal response), subject distribution (e.g., percent of subject population falling with a range or response type), and / or any other approach to stratification as will be apparent to one skilled in the art.

[0152] In some embodiments, the first arm comprises at least 10, at least 20, at least 50, at least 100, at least 200, at least 500, at least 1000, at least 2000, at least 5000, or at least 10,000 subjects. In some embodiments, the first arm comprises no more than 50,000, no more than 10,000, no more than 5000, no more than 2000, no more than 1000, no more than 500, no more than 100, or no more than 50 subjects. In some embodiments, the first arm consists of from 10 to 100, from 80 to 500, from 200 to 1000, from 1000 to 10,000, or from 10,000 to 50,000 subjects. In some embodiments, the first arm falls within another range starting no lower than 10 subjects and ending no higher than 50,000 subjects.

[0153] In some embodiments, the second arm comprises at least 10, at least 20, at least 50, at least 100, at least 200, at least 500, at least 1000, at least 2000, at least 5000, or at least 10,000 subjects. In some embodiments, the second arm comprises no more than 50,000, no more than 10,000, no more than 5000, no more than 2000, no more than 1000, no more than 500, no more than 100, or no more than 50 subjects. In some embodiments, the second arm consists of from 10 to 100, from 80 to 500, from 200 to 1000, from 1000 to 10,000, or from 10,000 to 50,000 subjects. In some embodiments, the second arm falls within another range starting no lower than 10 subjects and ending no higher than 50,000 subjects.

[0154] In some embodiments, the first arm comprises the same number of subjects in the second arm. In some embodiments, the first arm comprises a greater number of subjects than the second arm. In some embodiments, the first arm comprises fewer subjects than the second arm. In some embodiments, the first arm comprises twice as many or about twice as many subjects than the second arm. In some embodiments, the first arm comprises half or about half as many subjects as the second arm.

[0155] In some embodiments, the method further includes, after identifying the subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold and before dividing the subset of subjects between the first arm and the second arm: for a firstblock in a plurality of blocks (e.g., for a respective response category), limiting the subset of subjects such that the first block represents a proportion of subjects in the subset of subjects that is no greater than an enrollment threshold. In some embodiments, the first block is a spleen size reduction of between 30% and 35%, and the enrollment threshold is 15%. In some embodiments, the first block is any of the response categories, endpoints, or criteria disclosed herein. In some embodiments, the enrollment threshold is at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, or at least 30%. In some embodiments, the enrollment threshold is no more than 50%, no more than 30%, no more than 20%, no more than 15%, no more than 10%, or no more than 5%. In some embodiments, the enrollment threshold is from 2% to 5%, from 5% to 12%, from 10% to 25%, from 20% to 40%, or from 25% to 50%. In some embodiments, the enrollment threshold falls within another range starting no lower than 2% and ending no higher than 50%. In some illustrative embodiments, the first block is a range of SVR ≥ 30% but < 35% for suboptimal response subjects, and the limiting comprises capping the subset of subjects such that the proportion of subjects with SVR ≥ 30% but < 35% constitute no more than 15% of all enrolled suboptimal subjects.

[0156] Advantageously, and without being limited to any one theory of operation, in some embodiments, capping enrollment for one or more strata allows for clinically meaningful effect of study design by aligning subject enrollment with the natural incidence and distribution of suboptimal responders. This further allows for improved balancing of subject representation between and within different arms of the study.

[0157] First treatment period and second treatment period.

[0158] In some embodiments, the first treatment period is greater than 5 weeks and less than 40 weeks. In some embodiments, the first treatment period is equal to or greater than 12 weeks and less than 36 weeks.

[0159] In some embodiments, the first treatment period is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 4 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, or at least 5 years. In some embodiments, the first treatment period is no more than 10 years, no more than 5 years, no more than 2 years, no more than 1 year, no more than 6 months, no more than 4 months, no more than 2 months, no more than 4 weeks, or no more than 2 weeks. In some embodiments, the first treatment period is from 1 week to 2 months, from 1 month to 6 months, from 6 months to 1 year, from 1 year to 5 years, or from 5 years to 10 years. In some embodiments,the first treatment period falls within another range starting no lower than 1 week and ending no higher than 10 years.

[0160] In some embodiments, the first treatment period includes at least 5 weeks of daily administration of the first composition free of a treatment hold or a dose adjustment. In some embodiments, the first treatment period includes at least 8 weeks of daily administration of the first composition free of a treatment hold or a dose adjustment. In some embodiments, the first treatment period includes an administration period of the first composition free of a treatment hold or a dose adjustment of at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 4 months, at least 6 months, at least 1 year, or at least 2 years. In some embodiments, the administration period is no more than 3 years, no more than 2 years, no more than 1 year, no more than 6 months, no more than 4 months, no more than 2 months, no more than 4 weeks, or no more than 2 weeks. In some embodiments, the administration period is from 2 weeks to 2 months, from 1 month to 6 months, from 6 months to 1 year, or from 1 year to 3 years. In some embodiments, the administration period falls within another range starting no lower than 2 weeks and ending no higher than 3 years.

[0161] In some embodiments, the second treatment period is between 5 weeks and 100 weeks. In some embodiments, the second treatment period is between 12 weeks and 200 weeks.

[0162] In some embodiments, the second treatment period is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 4 months, at least 6 months, at least 1 year, at least 2 years, at least 5 years, or at least 10 years. In some embodiments, the second treatment period is no more than 20 years, no more than 10 years, no more than 5 years, no more than 1 year, no more than 6 months, no more than 4 months, no more than 2 months, no more than 4 weeks, or no more than 2 weeks. In some embodiments, the second treatment period is from 1 week to 2 months, from 1 month to 12 months, from 1 year to 5 years, from 5 years to 10 years, or from 10 years to 20 years. In some embodiments, the second treatment period falls within another range starting no lower than 1 week and ending no higher than 20 years.

[0163] Referring to Block 214, in some embodiments, an active ingredient of the first treatment composition is Ruxolitinib.

[0164] In some embodiments, the Ruxolitinib is administered at a total dose of ≥ 3 mg per day during the first treatment period and the second treatment period to the plurality ofsubjects. In some embodiments, the Ruxolitinib is administered at a total dose of ≥ 5 mg per day during the first treatment period and the second treatment period to the plurality of subjects. In some embodiments, the Ruxolitinib is administered at a total dose of ≥ 8 mg per day during the first treatment period and the second treatment period to the plurality of subjects. In some embodiments, the Ruxolitinib is administered at a total dose of between 2 mg and 10 mg per day during the first treatment period and the second treatment period to the plurality of subjects.

[0165] In some embodiments, the Ruxolitinib is administered at a total dose of at least 1, at least 2, at least 5, at least 10, at least 20, or at least 30 mg. In some embodiments, the Ruxolitinib is administered at a total dose of no more than 50, no more than 30, no more than 20, no more than 10, or no more than 5 mg. In some embodiments, the Ruxolitinib is administered at a total dose of from 1 mg to 10 mg, from 5 mg to 20 mg, or from 20 mg to 50 mg. In some embodiments, the Ruxolitinib is administered at a total dose falling within another range starting no lower than 1 mg and ending no higher than 50 mg.

[0166] In some embodiments, the Ruxolitinib is administered twice a day. In some embodiments, the Ruxolitinib is administered once a day.

[0167] In some embodiments, the Ruxolitinib is administered at least once a week, at least 2 times a week, at least 3 times a week, at least 5 times a week, at least once a day, at least twice a day, or at least 3 times a day. In some embodiments, the Ruxolitinib is administered no more than 4 times a day, no more than twice a day, no more than once a day, no more than 3 times a week, or no more than 2 times a week. In some embodiments, the Ruxolitinib is administered at a frequency of from once a week to 3 times a week, from 3 times a week to once a day, or from once a day to 4 times a day. In some embodiments, the Ruxolitinib is administered at a frequency that falls within another range starting no lower than once a week and ending no higher than 4 times a day.

[0168] Referring to Block 216, in some embodiments, an active ingredient of the second treatment composition is Navtemadlin.

[0169] In some embodiments, the Navtemadlin is administered at a total dose of ≥ 100 mg per day during the second treatment period to each subject in the first arm. In some embodiments, the Navtemadlin is administered at a total dose of ≥ 200 mg per day during the second treatment period to each subject in the first arm. In some embodiments, the Navtemadlin is administered at a total dose of between 150 mg and 300 mg per day duringthe second treatment period to each subject in the first arm. In some embodiments, the Navtemadlin is administered at a total dose of 240 mg per day during the second treatment period to each subject in the first arm.

[0170] In some embodiments, the Navtemadlin is administered at a total dose of at least 20, at least 50, at least 100, at least 200, at least 300, or at least 400 mg. In some embodiments, the Navtemadlin is administered at a total dose of no more than 500, no more than 300, no more than 200, no more than 100, or no more than 50 mg. In some embodiments, the Navtemadlin is administered at a total dose of from 20 mg to 100 mg, from 50 mg to 200 mg, or from 200 mg to 500 mg. In some embodiments, the Navtemadlin is administered at a total dose falling within another range starting no lower than 20 mg and ending no higher than 500 mg.

[0171] In some embodiments, the Navtemadlin is administered twice a day during the second treatment period to each subject in the first arm. In some embodiments, the Navtemadlin is administered once a day during the second treatment period to each subject in the first arm.

[0172] In some embodiments, the Navtemadlin is administered at least once a week, at least 2 times a week, at least 3 times a week, at least 5 times a week, at least once a day, at least twice a day, or at least 3 times a day. In some embodiments, the Navtemadlin is administered no more than 4 times a day, no more than twice a day, no more than once a day, no more than 3 times a week, or no more than 2 times a week. In some embodiments, the Navtemadlin is administered at a frequency of from once a week to 3 times a week, from 3 times a week to once a day, or from once a day to 4 times a day. In some embodiments, the Navtemadlin is administered at a frequency that falls within another range starting no lower than once a week and ending no higher than 4 times a day.

[0173] Second response set and second baseline measurements.

[0174] Referring to Block 218, in some embodiments, the method further includes, for each respective subject 122 in the subset of subjects, obtaining a corresponding second response set 138 upon completion of the second treatment period.

[0175] In some embodiments, the corresponding second response set comprises a plurality of second responses. In some embodiments, the corresponding second response set comprises at least 1, at least 2, at least 5, at least 10, at least 20, at least 50, at least 100, or at least 200 second responses. In some embodiments, the corresponding second response setcomprises no more than 500, no more than 200, no more than 100, no more than 50, no more than 10, or no more than 5 second responses. In some embodiments, the corresponding second response set consists of from 1 to 10, from 2 to 20, from 20 to 100, or from 100 to 500 second responses. In some embodiments, the corresponding second response set falls within another range starting no lower than 1 second response and ending no higher than 500 second responses.

[0176] In some embodiments, the second response set comprises one or more second responses for each respective endpoint in the one or more endpoints.

[0177] In some embodiments, the method further includes obtaining a corresponding second set of baseline measurements for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo.

[0178] In some embodiments, the corresponding second set of baseline measurements comprises a plurality of baseline measurements. In some embodiments, the corresponding second set of baseline measurements comprises at least 1, at least 2, at least 5, at least 10, at least 20, at least 50, at least 100, or at least 200 baseline measurements. In some embodiments, the corresponding second set of baseline measurements comprises no more than 500, no more than 200, no more than 100, no more than 50, no more than 10, or no more than 5 baseline measurements. In some embodiments, the corresponding second set of baseline measurements consists of from 1 to 10, from 2 to 20, from 20 to 100, or from 100 to 500 baseline measurements. In some embodiments, the corresponding second set of baseline measurements falls within another range starting no lower than 1 baseline measurement and ending no higher than 500 baseline measurements.

[0179] In some embodiments, the second set of baseline measurements comprises one or more baseline measurements for each respective endpoint in the one or more endpoints.

[0180] In some embodiments, one or more second baseline measurements, second responses, and / or endpoints are selected from any of the endpoints, inclusion criteria, and / or exclusion criteria disclosed herein (see, e.g., the section entitled “Subjects,” above and / or the section entitled “Endpoints,” below).

[0181] Evaluation.

[0182] Referring to Block 219, in some embodiments, the method further includes evaluating each respective subject 122 in the subset of subjects by comparing the corresponding second response set 138 to (a) the corresponding first set of baseline measurements 124 for the respective subject 122 and / or (b) an optional corresponding second set of baseline measurements 136 obtained for the respective subject 122 after division of the subset of subjects between the first arm 134-1 and the second arm 134-2 and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, thereby determining whether the combination of the first treatment and the second treatment of the first arm 134-1 improves the one or more endpoints 142 associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition 134-2.

[0183] Referring to Block 220, in some embodiments, the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding first set of baseline measurements for the respective subject.

[0184] Referring to Block 222, in some embodiments, the method further includes obtaining the corresponding second set of baseline measurements for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, and the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding second set of baseline measurements for the respective subject.

[0185] Endpoints.

[0186] In some embodiments, an endpoint in the one or more endpoints is a coprimary endpoint, a secondary endpoint, or an exploratory endpoint. In some embodiments, the one or more endpoints comprises coprimary endpoints, secondary endpoints, and / or exploratory endpoints.

[0187] In some embodiments, an endpoint in the one or more endpoints is selected from any of the endpoints listed in Table 3. In some embodiments, the one or more endpoints comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 of the endpoints listed in Table 3. In some embodiments, the one ormore endpoints comprises all of the endpoints listed in Table 3. In some embodiments, the one or more endpoints comprises no more than 13, no more than 10, no more than 8, no more than 5, or no more than 3 of the endpoints listed in Table 3.

[0188] In some embodiments, an endpoint in the one or more endpoints is selected from any of the endpoints listed in Table 4. In some embodiments, the one or more endpoints comprises at least 1, at least 2, at least 3, at least 4, or at least 5 of the endpoints listed in Table 4. In some embodiments, the one or more endpoints comprises all of the endpoints listed in Table 4. In some embodiments, the one or more endpoints comprises no more than 5, no more than 4, no more than 3, or no more than 2 of the endpoints listed in Table 4.

[0189] In some embodiments, the one or more endpoints comprises a reduction in spleen size. In some embodiments, the one or more endpoints comprises a reduction in spleen size as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan (e.g., a coprimary endpoint).

[0190] In some embodiments, an endpoint in the one or more endpoints is a comparison of: a proportion of subjects in the first arm that exhibit an amount of reduction in spleen size as measured by magnetic resonance imaging or computed tomography, between the run-in period and a set time in the second treatment period, that is greater than a threshold amount of spleen size reduction, and a proportion of subjects in the second arm that exhibit an amount of reduction in spleen size as measured by magnetic resonance imaging or computed tomography, between the run-in period and a set time in the second treatment period, that is greater than the threshold amount of spleen size reduction.

[0191] In some embodiments, the first treatment period is between 12 weeks and 36 weeks, and the set time in the second treatment period is between 12 weeks and 36 weeks after initiation of the second treatment period. In some embodiments, the first treatment period is between 12 weeks and 36 weeks, and the set time in the second treatment period is 24 weeks after initiation of the second treatment period.

[0192] In some embodiments, the set time in the second treatment period is at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 4 months, at least 6 months, at least 1 year, or at least 2 years after initiation of the second treatment period. In some embodiments, the set time in the second treatment period is no more than 3 years, no more than 2 years, no more than 1 year, no more than 6 months, no more than 4 months, no more than 2 months, no more than 4 weeks, or no more than 2 weeks after initiation of thesecond treatment period. In some embodiments, the set time in the second treatment period is from 2 weeks to 2 months, from 1 month to 6 months, from 6 months to 1 year, or from 1 year to 3 years after initiation of the second treatment period. In some embodiments, the set time in the second treatment period falls within another range starting no lower than 2 weeks and ending no higher than 3 years after initiation of the second treatment period.

[0193] In some embodiments, the threshold amount of spleen size reduction is a percentage between twenty-five percent and fifty percent relative to a first baseline spleen size measurement in the corresponding first set of baseline spleen size measurements. In some embodiments, the threshold amount of spleen size reduction is at least thirty-five percent from the first baseline relative to a first baseline spleen size measurement in the corresponding first set of baseline measurements. In some embodiments, the threshold amount of spleen size reduction is a percentage between twenty-five percent and fifty percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements. In some embodiments, the threshold amount of spleen size reduction is at least thirty-five percent relative to a second baseline spleen volume measurement from a corresponding second set of baseline spleen volume measurements.

[0194] In some embodiments, the threshold amount of spleen size reduction is at least 1%, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 60%, or at least 70% reduction. In some embodiments, the threshold amount of spleen size reduction is no more than 80%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, or no more than 3% reduction. In some embodiments, the threshold amount of spleen size reduction is from 1% to 20%, from 10% to 40%, from 25% to 60%, or from 50% to 80%. In some embodiments, the threshold amount of spleen size reduction falls within another range starting no lower than 1% and ending no higher than 80% reduction.

[0195] In some embodiments, the one or more endpoints comprises an improvement in a quality of life score (e.g., a total symptom score) between the first arm and the second arm (e.g., a coprimary endpoint). In some embodiments, the one or more endpoints comprises a total symptom score (TSS) or a reduction thereof.

[0196] In some embodiments, an endpoint in the one or more endpoints is a comparison of: a proportion of subjects in the first arm that exhibit an improvement in a quality of life assessment score, between the run-in period and a set time in the second treatment period,that is greater than a threshold amount of improvement, and a proportion of subjects in the second arm that exhibit an improvement in a quality of life assessment score, between the run-in period and a set time in the second treatment period, that is greater than the threshold amount of improvement.

[0197] In some embodiments, the first treatment period is between 12 weeks and 36 weeks, and the set time in the second treatment period is between 12 weeks and 36 weeks after initiation of the second treatment period. In some embodiments, the first treatment period is between 12 weeks and 36 weeks, and the set time in the second treatment period is 24 weeks after initiation of the second treatment period.

[0198] In some embodiments, the set time in the second treatment period is at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 4 months, at least 6 months, at least 1 year, or at least 2 years after initiation of the second treatment period. In some embodiments, the set time in the second treatment period is no more than 3 years, no more than 2 years, no more than 1 year, no more than 6 months, no more than 4 months, no more than 2 months, no more than 4 weeks, or no more than 2 weeks after initiation of the second treatment period. In some embodiments, the set time in the second treatment period is from 2 weeks to 2 months, from 1 month to 6 months, from 6 months to 1 year, or from 1 year to 3 years after initiation of the second treatment period. In some embodiments, the set time in the second treatment period falls within another range starting no lower than 2 weeks and ending no higher than 3 years after initiation of the second treatment period.

[0199] In some embodiments, for a subject in the subset of subjects: the corresponding first set of baseline measurements includes a first score derived from a quality of life assessment form, the corresponding second response set includes a second score derived from the quality of life assessment form, and the improvement in the quality of life assessment score between the run-in period and the set time in the second treatment period is a difference between the first score and the second score.

[0200] In some embodiments, the quality of life assessment form is the myelofibrosis symptom assessment form or the Myeloproliferative Neoplasm Symptom Assessment Form v2.0. In some embodiments, the quality of life assessment form is the general quality of life questionnaire (EQ-5D), eHEALS, EORTC QLG Core Questionnaire (EORTC QLQ-C30), Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale (e.g., Promis Fatigue Questionnaire), and / or patient activation measure (PAM-13).

[0201] In some embodiments, the quality of life assessment form is the Myeloproliferative Neoplasm Symptom Assessment Form v4.0 (MFSAF v4.0). The MFSAF- TSS v4.0 is composed of 7 items and measures symptoms related to MPN disease, including fatigue (weariness, tiredness), night sweats (or feeling hot or flushed), itching, abdominal discomfort (feeling pressure or bloating), pain under ribs on left side, feeling of fullness after beginning to eat, and bone pain (not joint or arthritis pain). Each item is scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MFSAF-TSS is computed as the sum of the observed symptoms. The MFSAF v4.0 thus has a possible score range of 0 to 70.

[0202] The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients.

[0203] The PROMIS Fatigue questionnaire measures the frequency and of a range of symptoms from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion with 7 questions. Each of the question uses a 5-point response option with scores of 1 (never) to 5 (always).

[0204] In some embodiments, the quality of life assessment form is the Patient Global Impression of Change (PGIC). The PGIC is composed of a single question intended to measure a patient’s perspective of improvement or deterioration over time relative to treatment. The PGIC uses a seven-point scale where one equals very much improved and seven equals very much worse.

[0205] In some embodiments, the quality of life assessment form is the Myeloproliferative Neoplasm Symptom Assessment Form (e.g., v2.0 and / or v4.0) and the threshold amount of improvement is at least a sixty percent reduction in the quality of life assessment score. In some embodiments, the quality of life assessment form is the Myeloproliferative Neoplasm Symptom Assessment Form (e.g., v2.0 and / or v4.0) and the threshold amount of improvement is at least a fifty percent reduction in the quality of life assessment score.

[0206] In some embodiments, the reduction in the quality of life assessment score is at least 1%, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 60%, or at least 70% reduction. In some embodiments, the reduction in the quality of life assessment score is no more than 80%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, or no more than 3% reduction. In some embodiments, the reduction in the quality of life assessmentscore is from 1% to 20%, from 10% to 40%, from 25% to 60%, or from 50% to 80%. In some embodiments, the reduction in the quality of life assessment score falls within another range starting no lower than 1% and ending no higher than 80% reduction.

[0207] In some embodiments, the one or more endpoints comprises an overall survival metric (e.g., a secondary endpoint).

[0208] In some embodiments, an endpoint in the one or more endpoints is a comparison of a first overall survival value calculation to a second overall survival calculation, wherein the first overall survival value calculation is a measure of central tendency of a difference between (i) a time of enrollment in the run-in period, and (ii) a time of death from any cause, across subjects in the first arm, and the second overall survival value calculation is a measure of central tendency of a difference between (i) a time of enrollment in the run-in period, and (ii) a time of death from any cause, across subjects in the second arm.

[0209] In some embodiments, overall survival (OS) is defined as the time from date of enrollment into the run-in period until date of death due to any cause. In some embodiments, subjects who have not died by the analysis data cutoff date will be censored at the last date known to be alive before the cutoff date. In some embodiments, subjects known to be alive or dead after the data cutoff date will be censored at the data cutoff date. In some embodiments, a stratified log-rank test adjusted for stratification factors will be used for the comparison of OS between the first arm and the second arm.

[0210] In some embodiments, the measure of central tendency is a mean, a median, a mode, a weighted mean, a weighted median, and / or a weighted mode.

[0211] In some embodiments, the one or more endpoints comprises a progression-free survival metric (e.g., a secondary endpoint).

[0212] In some embodiments, an endpoint in the one or more endpoints is a comparison of a first progression-free survival value calculation to a second progression-free survival calculation, wherein: the first progression-free survival value calculation is a measure of central tendency of a difference between (i) a time of enrollment in the run-in period, and (ii) a time of first occurrence of (a) a spleen size that exceeds a spleen size at a start of the run-in period by a threshold percent spleen volume, (b) a leukemic transformation, or (c) death from any cause, across subjects in the first arm; and the second progression-free survival value calculation is a measure of central tendency of a difference between (i) a time of enrollment in the run-in period, and (ii) a time of first occurrence of (a) an increase in spleen size above athreshold amount (e.g., a threshold percent spleen volume) over a spleen size at a start of the run-in period, (b) a leukemic transformation, or (c) death from any cause, across subjects in the second arm.

[0213] In some embodiments, the threshold percent spleen volume is between 15 percent and 35 percent relative to a first baseline spleen volume measurement in the corresponding first set of baseline spleen volume measurements. In some embodiments, the threshold percent spleen volume is 25 percent relative to a first baseline spleen volume measurement in the corresponding first set of baseline spleen volume measurements. In some embodiments, the threshold percent spleen volume is between 15 percent and 35 percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements. In some embodiments, the threshold percent spleen volume is 25 percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements.

[0214] In some embodiments, the threshold percent spleen volume is at least 1%, at least 2%, at least 5%, at least 10%, at least 20%, at least 30%, at least 50%, at least 60%, or at least 70% (e.g., relative to a first or a second baseline spleen volume measurement). In some embodiments, the threshold percent spleen volume is no more than 80%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, or no more than 3% (e.g., relative to a first or a second baseline spleen volume measurement). In some embodiments, the threshold percent spleen volume is from 1% to 20%, from 10% to 40%, from 25% to 60%, or from 50% to 80% (e.g., relative to a first or a second baseline spleen volume measurement). In some embodiments, the threshold percent spleen volume falls within another range starting no lower than 1% and ending no higher than 80% (e.g., relative to a first or a second baseline spleen volume measurement).

[0215] In some embodiments, the leukemic transformation comprises: (i) a bone marrow blast count of ≥ 20% above a bone marrow blast count at a time of enrollment in the run-in period associated with an absolute blast count of more than 1x109 / L that lasts for at least 2 weeks, and / or (ii) a peripheral blood blast content of ≥ 20% above a peripheral blood blast content at the time of enrollment in the run-in period associated with an absolute blast count of more than 1x109 / L that lasts for at least 2 weeks.

[0216] In some embodiments, the bone marrow blast count is at least 10%, at least 20%, at least 30%, or at least 50% above a bone marrow blast count at a time of enrollment in the run-in period. In some embodiments, the bone marrow blast count is no more than 60%, no more than 50%, no more than 40%, no more than 30%, or no more than 20% above a bone marrow blast count at a time of enrollment in the run-in period. In some embodiments, the bone marrow blast count is from 10% to 20%, from 20% to 40%, or from 40% to 60% above a bone marrow blast count at a time of enrollment in the run-in period. In some embodiments, the bone marrow blast count falls within another range starting no lower than 10% and ending no higher than 60% above a bone marrow blast count at a time of enrollment in the run-in period. Alternately or additionally, in some embodiments, the bone marrow blast count at the time of enrollment in the run-in period is associated with an absolute blast count of at least 10 x 108 / L, at least 100 x 108 / L, at least 1 x 109 / L, or at least 10 x 109 / L. In some embodiments, the bone marrow blast count at the time of enrollment in the run-in period is associated with an absolute blast count of no more than 100 x 109 / L, no more than 10 x 109 / L, no more than 1 x 109 / L, or no more than 100 x 108 / L. In some embodiments, the bone marrow blast count at the time of enrollment in the run-in period is associated with an absolute blast count of from 10 x 108 / L to 1 x 109 / L, from 1 x 109 / L to 10 x 109 / L, or from 10 x 109 / L to 100 x 109 / L. In some embodiments, the bone marrow blast count at the time of enrollment in the run-in period is associated with an absolute blast count that falls within another range starting no lower than 10 x 108 / L and ending no higher than 100 x 109 / L.

[0217] In some embodiments, the measure of central tendency is a mean, a median, a mode, a weighted mean, a weighted median, and / or a weighted mode.

[0218] In some embodiments, the one or more endpoints comprises duration of spleen response between the first arm and the second arm (e.g., a secondary endpoint).

[0219] In some embodiments, an endpoint in the one or more endpoints is a comparison of a first average amount of time to a second average amount of time, where the first average amount of time is between (i) a time of first observance of a reduction in spleen size after the run-in period of at least a threshold percent spleen volume, and (ii) a time of observation of disease progression or death across subjects in the first arm; and the second average amount of time is between (i) a time of first observance of a reduction in spleen size after the run-in period of at least the threshold percent and (ii) a time of observation of disease progression or death across subjects in the second arm.

[0220] In some embodiments, the threshold percent spleen volume is between 35 percent and 45 percent relative to a first baseline spleen volume measurement in the corresponding first set of baseline spleen volume measurements. In some embodiments, the threshold percent spleen volume is 35 percent relative to a first baseline spleen volume measurement in the corresponding first set of baseline spleen volume measurements. In some embodiments, the threshold percent spleen volume is between 35 percent and 45 percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements. In some embodiments, the threshold percent spleen volume is 35 percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements. In some embodiments, the threshold percent spleen volume is any of the values for threshold percent spleen volume disclosed elsewhere herein.

[0221] In some embodiments, the one or more endpoints comprises spleen size improvement as measured by palpation between the first arm and the second arm (e.g., a secondary endpoint).

[0222] In some embodiments, an endpoint in the one or more endpoints is a comparison of a proportion of subjects in the first arm that exhibit an amount of reduction in spleen size, between the run-in period and a set time in the second treatment period, as measured by palpation, that is greater than a threshold amount of spleen size reduction, and a proportion of subjects in the second arm that exhibit an amount of reduction in spleen size, between the run-in period and a set time in the second treatment period, as measured by palpation, that is greater than the threshold amount of spleen size reduction.

[0223] In some embodiments, the corresponding first set of baseline measurements comprises a first measurement of an organ of the respective subject, and the corresponding second response set includes a second measurement of the organ of the respective subject.

[0224] In some embodiments, the organ is the spleen of the respective subject.

[0225] In some embodiments, the first measurement of the organ of the respective subject is a first measurement of the size of the spleen of the respective subject, and the second measurement of the organ of the respective subject is a second measurement of the size of the spleen of the respective subject.

[0226] Various methods for performing spleen measurements are contemplated for use in the present disclosure, including measurement of spleen length by palpation and / or measurement of spleen volume by imaging.

[0227] In some embodiments, spleen length is assessed by palpation and measured with a ruler in centimeters (cm). The edge of the spleen is determined by palpation and the length is measured from the left lower costal margin to the point of greatest splenic protrusion.

[0228] In some embodiments, the one or more endpoints comprise secondary efficacy endpoints. In some embodiments, a secondary efficacy endpoint is determined by comparing the corresponding second response set to a corresponding second set of baseline measurements obtained for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo (e.g., between pre-randomization baseline and post-randomization periods).

[0229] In some embodiments, an endpoint in the one or more endpoints is a primary or secondary efficacy endpoint selected from the group consisting of SVR25, TSS30, SVR35, and TSS50, determined by comparing the corresponding second response set to a corresponding first set of baseline measurements prior to the treatment with the first composition and a corresponding second set of baseline measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo. SVR25 measures a proportion of subjects in each study arm with SVR of ≥ 25% after the second treatment period relative to the start of the second treatment period. TSS30 measures a proportion of subjects in each study arm with TSS reduction of ≥ 30% after the second treatment period relative to the start of the second treatment period. SVR35 measures a proportion of subjects in each study arm with SVR of ≥ 35% after the second treatment period relative to the start of the first treatment period. TSS50 measures a proportion of subjects in each study arm with TSS reduction of ≥ 50% after the second treatment period relative to the start of the first treatment period. In some embodiments, SVR25 is spleen volume reduction more than 25% after the second treatment period relative to the start of the second treatment period. In some embodiments, SVR35 is spleen volume reduction more than 35% after the second treatment period relative to the start of the first treatment period. In some embodiments, TSS30 is total symptom score reduction more than 30% after the second treatment period relative to the start of the second treatment period. In some embodiments,TSS50 is total symptom score reduction more than 50% after the second treatment period relative to the start of the first treatment period. In some embodiments, the first treatment period refers to the monotherapy period. In some embodiments, the first treatment period refers to Ruxolitinib monotherapy period. In some embodiments, the second treatment period refers to the combination therapy period, when the first composition and the second composition are concurrently administered to the patients. In some embodiments, the second treatment period refers to the combination therapy period, when the first composition and the second composition are concurrently administered to the patients, wherein the first composition comprises Ruxolitinib; the second composition comprises navtemadlin.

[0230] In some embodiments, the primary endpoints are SVR25, TSS30, SVR35, and TSS50. In some embodiments, the primary endpoints are SVR25 and TSS30. In some embodiments, the primary endpoints are SVR35 and TSS50. In some embodiments, the primary endpoints are SVR25 and SVR35. In some embodiments, the primary endpoints are TSS30 and TSS50.

[0231] In some embodiments, the endpoints are SVR25 and SVR35, where SVR25 is determined by comparing the corresponding second response set to a corresponding second set of baseline spleen volume measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition; where SVR35 is determined by comparing the corresponding second response set to a corresponding first set of baseline spleen volume measurements obtained for the respective subject prior to treatment with the first composition. In some embodiments, the endpoints are TSS30 and TSS50; where TSS30 are determined by comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition; where TSS50 are determined by comparing the corresponding second response set to a corresponding first set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition. In some embodiments, the endpoints are SVR25, SVR35, TSS30, and TSS50; where SVR25 and TSS30 are determined by comparing the corresponding second response set to a corresponding second set of baseline measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition; where SVR35 and TSS50 are determined by comparing the corresponding second response set to a corresponding firstset of baseline measurements obtained for the respective subject prior to treatment with the first composition.

[0232] Table 3: Example Endpoints Objectives Endpoints Coprimary To compare SVR between Arm 1 The proportion of subjects in each arm with SVR of ≥ and Arm 2 35% by MRI / CT scan (central review) 24 weeks after the start of the randomized period compared to the baseline spleen volume at the start of the run-in period To compare improvement in TSS The proportion of subjects in each arm with TSS between Arm 1 and Arm 2 improvement of ≥ 50% by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.024 weeks after the start of the randomized period compared to the baseline TSS at the start of the run-in period Secondary To compare OS between Arm 1 Time from enrollment into the run-in period to death and Arm 2 from any cause in patients randomized to each arm To compare progression-free Time from enrollment into the run-in period to survival (PFS) between Arm 1 progression (≥ 25% increase in spleen volume versus and Arm 2 baseline at the start of the run-in period in patients randomized in each arm, or leukemic transformation [bone marrow blast count of ≥ 20% or a peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1x109 / L that lasts for at least 2 weeks]) or death from any cause in patients randomized to each arm To compare duration of spleen Time from initial SVR of ≥ 35% by MRI / CT scan response between Arm 1 and Arm (central review) until disease progression or death in 2 in suboptimal responders each arm in the randomized period To compare spleen response rate The proportion of subjects with SVR of ≥ 35% at any between Arm 1 and Arm 2 time in each arm in the randomized period by MRI / CT scan (central review) compared to the baseline spleen volume at the start of the run-in period To compare spleen size The proportion of subjects in each arm with spleen improvement as measured by size reduction of ≥ 50% as measured by palpation 24 palpation between Arm 1 and weeks after the start of the randomized period Arm 2 compared to the baseline spleen size at the start of the run-in period To compare the safety and Analyses of the safety endpoints will include the tolerability of navtemadlin versus following measurements or assessments in each arm in placebo as add-on therapy to the randomized period: physical examinations, ruxolitinib laboratory tests, adverse events (AEs), serious Aes (SAEs), electrocardiograms (ECGs), and vital signsTo monitor the pharmacokinetics Navtemadlin and acyl glucuronide metabolite (M1) (PK) of navtemadlin and concentrations will be monitored with sparse samples navtemadlin glucuronide collected in Cycles 1 and 2 in the randomized period Exploratory To compare time to SVR and TSS • Time from enrollment in the run-in period to responses between Arm 1 and first observation of ≥ 35% SVR in each arm of Arm 2 the randomized period • Time from enrollment in the run-in period to first observation of ≥ 50% TSS reduction in each arm of the randomized period To compare quality of life Change in scores after the start of the randomized between Arm 1 and Arm 2 period compared to the baseline score for each assessment at the start of the run-in period: • European Organization for Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) • Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale • Patient Global Impression of Change (PGIC) To compare the efficacy and Biomarkers including but not limited to: safety of navtemadlin versus placebo as add-on therapy to • TP53 mutation status by central laboratory ruxolitinib as correlated with analysis selected PK and • CD34+count in peripheral blood pharmacodynamic (PD) markers • Molecular profile including driver genes, high molecular risk genes, and other myeloproliferative neoplasm (MPN)-related genetic alterations • Blood inflammatory markers To compare changes in bone Bone marrow will be assessed between arms during marrow between Arm 1 and Arm the randomized period and compared to the run-in 2 period baseline by central review for changes in: • Percent blasts • Fibrosis grade • Cellularity • Myeloid to erythroid (M:E) ratio • Other changes in marrow histomorphic features

[0233] In some embodiments, the one or more endpoints includes bone marrow biopsy (e.g., by pathology review). In some embodiments, the one or more endpoints includes endpoints for evaluating cancer. In some embodiments, the one or more endpoints includes a percent blast of bone marrow, a fibrosis grade of bone marrow, a cellularity of bone marrow, a myeloid to erythroid ratio of bone marrow, and / or other changes in bone marrow histomorphic features.

[0234] In some embodiments, the one or more endpoints includes one or more biomarker assessments, as listed in Table 4. In some embodiments the one or more endpoints includes one, two, three, four, five or six or more biomarker assessments listed in Table 4.

[0235] Table 4: Example Biomarker Assessments Time Points Measurement Sample Ruxolitinib Run-in RandTypePeriodomized PeriodMutational status • Sample to be • Testing by central Blood of TP53 and obtained at laboratory must be other MPN screening. performed prior to related genes randomization • At EOT visit. CD34+count • Screening • Cycle 1 Day 1 pre-dose Blood • Week 12 • Week 24 and every 24 weeks thereafter on study treatment MolecularNA• Cycle 1 Day 1 pre-doseBlood profiling • Week 12 • Week 24 and every 24 weeks thereafter on study treatment BloodNA• Cycle 1: Day 1 pre-doseBlood inflammatory and Day 8 markers • Cycle 2: Day 1 pre-dose • Week 12 • Week 24 and every 24 weeks thereafter on study treatment Blood forNA• Cycle 1: Day 1BloodoptionalTime Points Measurement Sample Ruxolitinib Run-in RaTypePeriodndomized Periodexploratory ADMET genotyping Abbreviation: ADMET, absorption, distribution, metabolism, excretion, toxicity; EOT, end of treatment.

[0236] Additional Endpoints

[0237] In some embodiments, contribution effect of navtemadlin will be characterized relative to historical SVR and TSS response thresholds.

[0238] In some embodiments, the one or more endpoints comprises a multi-component endpoint. In some embodiments, the one or more endpoints is a co-primary multi-component endpoint.

[0239] In some embodiments, a multi-component endpoint comprises a plurality of component endpoints. In some embodiments, each respective component endpoint in the plurality of component endpoints comprises any of the endpoints disclosed herein (see, for example, the section entitled “Endpoints,” above). In some embodiments, the plurality of component endpoints comprises at least 2, at least 3, at least 4, at least 5, at least 6, or at least 10 component endpoints. In some embodiments, the plurality of component endpoints comprises no more than 20, no more than 10, no more than 5, or no more than 3 component endpoints. In some embodiments, the plurality of component endpoints consists of from 2 to 5, from 3 to 8, from 5 to 12, or from 10 to 20 component endpoints. In some embodiments, the plurality of component endpoints falls within another range starting no lower than 2 component endpoints and ending no higher than 20 component endpoints.

[0240] In some embodiments, a multi-component endpoint comprises at least a total symptom score. In some embodiments, a multi-component endpoint comprises two or more total symptom scores. In some embodiments, a multi-component endpoint comprises a spleen volume reduction. In some embodiments, a multi-component endpoint comprises a plurality of spleen volume reduction.

[0241] In some embodiments, a multi-component endpoint comprises: one or more total symptom scores, one or more changes in spleen volume, and / or one or more quality of life scores.

[0242] In some embodiments, the multi-component endpoint comprises a spleen volume reduction (SVR) that satisfies a threshold value of at least ≥ 5% (SVR5), at least ≥ 10% (SVR10), at least ≥ 15% (SVR15), at least ≥ 20% (SVR20), at least ≥ 25% (SVR25), at least ≥ 30% (SVR30), at least ≥ 35% (SVR35), at least ≥ 40% (SVR40), at least ≥ 45% (SVR45), at least ≥ 50% (SVR50), at least ≥ 55% (SVR55), at least ≥ 60% (SVR60), at least ≥ 65% (SVR65), at least ≥ 70% (SVR70), at least ≥ 75% (SVR75), at least ≥ 80% (SVR80), at least ≥ 85% (SVR85), at least ≥ 90% (SVR90), at least ≥ 95% (SVR95), or at least ≥ 100% (SVR100).

[0243] In some embodiments, the multi-component endpoint comprises a total symptom score (TSS) that satisfies a threshold value of at least ≥ 5% (TSS5), at least ≥ 10% (TSS10), at least ≥ 15% (TSS15), at least ≥ 20% (TSS20), at least ≥ 25% (TSS25), at least ≥ 30% (TSS30), at least ≥ 35% (TSS35), at least ≥ 40% (TSS40), at least ≥ 45% (TSS45), at least ≥ 50% (TSS50), at least ≥ 55% (TSS55), at least ≥ 60% (TSS60), at least ≥ 65% (TSS65), at least ≥ 70% (TSS70), at least ≥ 75% (TSS75), at least ≥ 80% (TSS80), at least ≥ 85% (TSS85), at least ≥ 90% (TSS90), at least ≥ 95% (TSS95), or at least ≥ 100% (TSS100).

[0244] In some embodiments, the multi-component endpoint comprises any combination of the above mentioned thresholds of the spleen volume reduction (SVR) and total symptom score (TSS) (e.g., SVR25 and TSS30).

[0245] In some embodiments, a component endpoint in the plurality of component endpoints is measured as a comparison between a second response set and a first set of baseline measurements.

[0246] In some embodiments, the second response set is obtained from a first arm of subjects after treatment with the first composition and the second composition (e.g., after post-randomization treatment with ruxolitinib and navtemadlin). In some embodiments, the first composition is ruxolitinib. In some embodiments, the second composition comprises ruxolitinib and navtemadlin wherein ruxolitinib and navtemadlin are administered to the patient separately. In some embodiments, ruxolitinib and navtemadlin are administered to the patient at different interval or dosing regimen. In some embodiments, the second response set is obtained from a second arm of subjects after treatment with the first composition and aplacebo (e.g., after post-randomization treatment with ruxolitinib and placebo). In some embodiments, the first set of baseline measurements is obtained from each subject in the plurality of subjects prior to any treatment (e.g., at the pre-ruxolitinib baseline). For instance, in some embodiments, a component endpoint in the plurality of component endpoints is measured as a comparison between a post-randomization treatment and a pre-ruxolitinib baseline.

[0247] In some embodiments, the component endpoint in the plurality of component endpoints is measured as a comparison between a second response set and a second set of baseline measurements.

[0248] In some embodiments, the second response set is obtained from a first arm of subjects after treatment with the first composition and the second composition (e.g., after post-randomization treatment with ruxolitinib and navtemadlin). In some embodiments, the second response set is obtained from a second arm of subjects after treatment with the first composition and a placebo (e.g., after post-randomization treatment with ruxolitinib and placebo). In some embodiments, the second set of baseline measurements is obtained from each subject in the plurality of subjects after randomization (e.g., after division of the subset of subjects between the first arm and the second arm) and prior to post-randomization treatment (e.g., after treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo prior to any treatment) (e.g., a pre-randomization baseline). For instance, in some embodiments, a component endpoint in the plurality of component endpoints is measured as a comparison between a post-randomization treatment and a pre-randomization baseline.

[0249] In some embodiments, the one or more endpoints is the proportion of patients who achieve an SVR of any of the following endpoints ≥5% (SVR5), ≥10% (SVR10), ≥ 15% (SVR15), ≥ 20% (SVR20), ≥ 25% (SVR25), ≥ 30% (SVR30), ≥ 35% (SVR35), ≥ 40% (SVR40), ≥ 45% (SVR45), ≥ 50% (SVR50), ≥ 55% (SVR55), ≥ 60% (SVR60), ≥ 65% (SVR65), ≥ 70% (SVR70), ≥ 75% (SVR75), ≥ 80% (SVR80), ≥ 85% (SVR85), ≥ 90% (SVR90), ≥ 95% (SVR95) and ≥ 100% (SVR100), from the second set of baseline measurements (e.g., pre-randomization baseline) and any of the following SVR endpoints of any of the following endpoints ≥5% (SVR5), ≥10% (SVR10), ≥ 15% (SVR15), ≥ 20% (SVR20), ≥ 25% (SVR25), ≥ 30% (SVR30), ≥ 35% (SVR35), ≥ 40% (SVR40), ≥ 45% (SVR45), ≥ 50% (SVR50), ≥ 55% (SVR55), ≥ 60% (SVR60), ≥ 65% (SVR65), ≥ 70% (SVR70), ≥ 75% (SVR75), ≥ 80% (SVR80), ≥ 85% (SVR85), ≥ 90% (SVR90), ≥ 95%(SVR95) and ≥ 100% (SVR100), from the first set of baseline measurements (e.g., pre- ruxolitinib baseline).

[0250] In some embodiments, the one or more endpoints is the proportion of patients who achieve TSS reduction of any of the following endpoints ≥5% (TSS5), ≥10% (TSS10), ≥ 15% (TSS15), ≥ 20% (TSS20), ≥ 25% (TSS25), ≥ 30% (TSS30), ≥ 35% (TSS35), ≥ 40% (TSS40), ≥ 45% (TSS45), ≥ 50% (TSS50), ≥ 55% (TSS55), ≥ 60% (TSS60), ≥ 65% (TSS65), ≥ 70% (TSS70), ≥ 75% (TSS75), ≥ 80% (TSS80), ≥ 85% (TSS85), ≥ 90% (TSS90), ≥ 95% (TSS95) and ≥ 100% (TSS100) from the second set of baseline measurements (e.g., pre-randomization baseline) and any of the following TSS endpoints TSS reduction endpoints ≥5% (TSS5), ≥10% (TSS10), ≥ 15% (TSS15), ≥ 20% (TSS20), ≥ 25% (TSS25), ≥ 30% (TSS30), ≥ 35% (TSS35), ≥ 40% (TSS40), ≥ 45% (TSS45), ≥ 50% (TSS50), ≥ 55% (TSS55), ≥ 60% (TSS60), ≥ 65% (TSS65), ≥ 70% (TSS70), ≥ 75% (TSS75), ≥ 80% (TSS80), ≥ 85% (TSS85), ≥ 90% (TSS90), ≥ 95% (TSS95) and ≥ 100% (TSS100) from the first set of baseline measurements (e.g., pre-ruxolitinib baseline).

[0251] In some embodiments spleen volume reduction (SVR) will be evaluated at any of the following time periods: 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 1.25 years, 1.5 years, 1.75 years and 2 years after randomization (e.g., by MRI / CT scan).

[0252] In some embodiments total symptom score (TSS) will be evaluated at any of the following time periods 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 1.25 years, 1.5 years, 1.75 years and 2 years after randomization (e.g., using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0).

[0253] In some embodiments, assessment of symptom benefits will be supported by evaluation of multiple concurrent anchor scales (e.g., Patient Global Impression of Change) collected from time of randomization (e.g., within a clinical trial study).

[0254] In some embodiments, the one or more endpoints is the proportion of patients who achieve an SVR of ≥ 25% (SVR25) from the pre-randomization baseline and an SVR of ≥ 35% (SVR35) from the pre-ruxolitinib baseline.

[0255] In some embodiments, the one or more endpoints is proportion of patients who achieve a TSS reduction of ≥ 30% (TSS30) from the pre-randomization baseline and a TSS reduction of ≥ 50% (TSS50) from the pre-ruxolitinib baseline.

[0256] In some embodiments, the one or more endpoints are the response thresholds of SVR25 and TSS30, as measured from the pre-randomization baseline, serving to demonstrate the contribution effect of navtemadlin.

[0257] In some embodiments, the one or more endpoints is the response thresholds of any of the following SVR5, SVR10, SVR15, SVR20, SVR25, SVR30, SVR35, SVR40, SVR45, SVR50, SVR55, SVR60, SVR65, SVR70, SVR75, SVR80, SVR85, SVR90, SVR95 and SVR100 and any of the following TSS5, TSS10, TSS15, TSS20, TSS25, TSS30, TSS35, TSS40, TSS45, TSS50, TSS55, TSS60, TSS65, TSS70, TSS75, TSS80, TSS85, TSS90, TSS95 and TSS100, as measured from the second set of baseline measurements (e.g., the pre- randomization baseline), serving to demonstrate the contribution effect of the second composition (e.g., navtemadlin).

[0258] In some embodiments, to be considered an endpoint an SVR or TSS responder within a plurality of subjects or a subset thereof (e.g., a clinical trial study), each subject in the plurality of subjects, or the subset thereof, satisfies within-patient thresholds determined for both the first set of baseline measurements and the second set of baseline measurements (e.g., meets any of the multi-component or component endpoint thresholds disclosed above from both the pre-randomization baseline and the pre-ruxolitinib baseline).

[0259] In some embodiments, the plurality of component endpoints in a multi-component endpoint comprises component endpoints determined at a first time point (e.g., before ruxolitinib monotherapy) and at a second time point (e.g., at a later time period after randomization to either add-on navtemadlin or add-on placebo).

[0260] In some embodiments, the one or more endpoints are before ruxolitinib monotherapy treatment, at Week 18 (when it is determined if the subject is a suboptimalresponder), and 24 weeks after randomization to either add-on navtemadlin or add-on placebo.

[0261] In some embodiments, an endpoint and / or a component endpoint in a multi- component endpoint comprises a measure of central tendency for any of the endpoints disclosed herein. In some embodiments, a measure of central tendency is a mean, a median, a mode, a weighted mean, a weighted median, and / or a weighted mode. In some embodiments, an endpoint and / or a component endpoint thereof comprises a mean SVR that satisfies any of the above thresholds. In some embodiments, an endpoint and / or a component endpoint thereof comprises, for example, a mean TSS that satisfies any of the above threshold. In some embodiments, an endpoint and / or a component endpoint thereof comprises an additional improvement over a threshold measure of central tendency for the respective endpoint and / or component endpoint. In some embodiments, for example, an additional SVR of 25% to a mean SVR of 18% would result in a 39% effective response threshold from the pre- ruxolitinib baseline.

[0262] Additional Embodiments

[0263] Another aspect of the present disclosure includes a computing system comprising: computer memory configured to store clinical data. In some embodiments, the clinical data involves a plurality of subjects that have a myeloproliferative neoplasm, where the clinical data includes and associates for each respective subject in the plurality of subjects (i) a corresponding first set of baseline measurements prior to treatment with a first treatment with a first composition or a second treatment with a second composition for the myeloproliferative neoplasm and (ii) a corresponding first response set after a first treatment period with the first composition.

[0264] In some embodiments, the computing system further includes one or more processors in communication with the computer memory and configured to execute program instructions to perform a method.

[0265] In some embodiments, the method includes identifying a subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold. In some embodiments, the method further includes dividing the subset of subjects between a first arm and a second arm on a randomized basis, where subjects in the first arm receive a combination of the first composition and the second composition and subjects in the secondarm receive a combination of the first composition and a placebo for a second treatment period.

[0266] In some embodiments, the method further includes, for each respective subject in the subset of subjects, obtaining a corresponding second response set upon completion of the second treatment period; and evaluating each respective subject in the subset of subjects by comparing the corresponding second response set to (a) the corresponding first set of baseline measurements for the respective subject and / or (b) an optional corresponding second set of baseline measurements obtained for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, thereby determining whether the combination of the first treatment and the second treatment of the first arm improves the one or more endpoints associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition.

[0267] In some embodiments, the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding first set of baseline measurements for the respective subject. In some embodiments, the method further includes obtaining the corresponding second set of baseline measurements for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, and the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding second set of baseline measurements for the respective subject.

[0268] Another aspect of the present disclosure includes a non-transitory computer readable storage medium, where the non-transitory computer readable storage medium stores instructions, which when executed by a computer system, cause the computer system to perform a method for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition.

[0269] In some embodiments, the method includes obtaining clinical data that involves a plurality of subjects that have the myeloproliferative neoplasm, where the clinical dataincludes and associates for each respective subject in the plurality of subjects (i) a corresponding first set of baseline measurements prior to treatment with the first composition for the myeloproliferative neoplasm and (ii) a corresponding first response set after a first treatment period with the first composition. In some embodiments, the method further includes identifying a subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold.

[0270] In some embodiments, the method further includes dividing the subset of subjects between a first arm and a second arm on a randomized basis, where subjects in the first arm receive a combination of the first composition and the second composition and subjects in the second arm receive a combination of the first composition and a placebo for a second treatment period. In some embodiments, the method further includes, for each respective subject in the subset of subjects, obtaining a corresponding second response set upon completion of the second treatment period.

[0271] In some embodiments, the method further includes evaluating each respective subject in the subset of subjects by comparing the corresponding second response set to (a) the corresponding first set of baseline measurements for the respective subject and / or (b) an optional corresponding second set of baseline measurements obtained for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, thereby determining whether the combination of the first treatment and the second treatment of the first arm improves the one or more endpoints associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition.

[0272] In some embodiments, the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding first set of baseline measurements for the respective subject. In some embodiments, the method further includes obtaining the corresponding second set of baseline measurements for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, and the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding second set of baseline measurements for the respective subject.

[0273] Yet another aspect of the present disclosure includes a system including a memory; one or more processors; and one or more modules stored in the memory and configured for execution by the one or more processors, the one or more modules including instructions for performing any of the methods disclosed herein.

[0274] Still another aspect of the present disclosure includes a non-transitory computer readable storage medium, the non-transitory computer readable storage medium storing one or more programs for execution by one or more processors of a computer system, the one or more computer programs including instructions for performing any of the methods disclosed herein.

[0275] EXAMPLES

[0276] Example 1 – Randomized double-blind study evaluating safety and efficacy of navtemadlin plus ruxolitinib vs. placebo plus ruxolitinib in myelofibrosis patients who have a suboptimal response to ruxolitinib

[0277] This is a Phase 3, randomized, double-blind, placebo-controlled study of navtemadlin or placebo as add-on therapy to ruxolitinib in subjects with MF who have a suboptimal response after ≥ 18 weeks of treatment with ruxolitinib monotherapy.

[0278] Subjects with JAKi-naïve MF will be enrolled into a ruxolitinib monotherapy run- in period (Figure 3). Those subjects that meet suboptimal response criteria and have TP53WTMF will be randomized in a double-blind, placebo-controlled method to receiveor placebo as add-on therapy to ruxolitinib treatment. Each portion of the study design is described below.

[0279] Approximately 630 JAKi-naïve subjects with MF are expected to be enrolled to attain 180 randomized suboptimal response subjects (Harrison 2012; Verstovsek 2012; Mesa 2017). Subjects will receive ruxolitinib monotherapy at a dose ≥ 5 mg twice per day (BID) chosen at the discretion of the Investigator during the run-in period. After ≥ 18 weeks and < 25 weeks of treatment, response to therapy will be assessed in subjects that have had a stable dose of ruxolitinib for ≥ 6 consecutive weeks (e.g., a dose ≥ 5 mg BID that has not required a treatment hold or dose adjustment). Subjects that have a suboptimal response to a stable dose of ruxolitinib monotherapy and meet eligibility criteria (including a stable dose of ruxolitinib ≥ 8 consecutive weeks) will be randomized in a double-blind, placebo-controlled method to receive navtemadlin or placebo as add-on therapy to ruxolitinib treatment. Note, a stable dose of ruxolitinib ≥ 8 consecutive weeks is set as a baseline for randomization; however, in someimplementations, response assessment during the run-in period is allowed earlier, after a stable dose of ≥ 6 consecutive weeks.

[0280] Suboptimal response to ruxolitinib monotherapy is defined as > 0% but < 35% reduction in spleen volume by MRI / CT scan (central review) and > 0% but < 50% reduction in TSS by MFSAF v4.0. Subjects that do not meet criteria for randomization may continue receiving commercially available ruxolitinib as per standard of care treatment and will be discontinued from this study.

[0281] Approximately 180 evaluable subjects with a suboptimal response to ruxolitinib monotherapy will be randomized 2:1 to receive either navtemadlin as add-on therapy to ruxolitinib (N = 120; Arm 1) or placebo as add-on therapy to ruxolitinib (N = 60; Arm 2). Navtemadlin / placebo will be administered 240 mg once daily on Days 1-7 on a 28-day treatment cycle and will not be administered on Days 8-28 on the 28-day treatment cycle.

[0282] In both treatment arms, ruxolitinib will continue to be administered at the subject’s stable dose (e.g., a dose ≥ 5 mg BID that did not require a treatment hold or dose adjustment in the 8 weeks prior to study treatment in the randomized period). For each subject, dose escalation or any dose increases of ruxolitinib during the randomized period above the stable dose are not allowed before the primary efficacy assessment.

[0283] A stratified, permuted-block randomization scheme will be used for treatment allocation, and will be based on one or more (e.g., at least 4) stratification factors: - SVR > 0% but < 20%, - SVR ≥ 20% but < 35%, - TSS reduction > 0% but < 30%, - TSS reduction ≥ 30% but < 50%, - Optionally, International Prognostic Scoring System (IPSS; (Cervantes 2009) (Intermediate-1 vs Intermediate-2 or High), and / or - Optionally, total daily ruxolitinib dose at randomization (< 20 mg vs ≥ 20 mg).

[0284] Radiological assessment of disease will be performed at specified time points.

[0285] The study will include a screening period, a run-in period, and for subjects who are eligible, a randomization period, and a follow-up period.

[0286] Screening period assessments will be performed within 28 days prior to initiation of the run-in period. Subjects who satisfy all eligibility criteria are eligible to enroll in the study.

[0287] The run-in period will follow subjects from the initiation of treatment on Cycle 1 Day 1 with ruxolitinib monotherapy until randomization to navtemadlin / placebo treatment as add-on therapy to ruxolitinib, or study discontinuation for subjects who are ineligible for participation in the randomized period of the study.

[0288] The randomization period consists of 28-day cycles and will extend from the first dose of add-on study treatment in the navtemadlin / placebo period of the study until the end of treatment (EOT) visit which should occur within 28 days from the last dose of study drug. Initiation of navtemadlin / placebo treatment should be performed as early as possible or within 3 days following randomization approval. In the randomized period, all subjects will continue study treatment until criteria for permanent discontinuation of study drug are met. These criteria include disease progression, or where the study drug is no longer tolerated by the subject, or study end. Efficacy evaluations will be performed, including but not limited to SVR25, TSS30, SVR35, and / or TSS50.

[0289] The follow-up period will begin once a subject discontinues study treatment in the randomized period of the study, and will continue until death, lost to follow-up, consent withdrawal, or study end, whichever occurs first. The follow-up period may include both response follow-up and long-term follow-up periods.

[0290] The response follow-up period will occur for randomized subjects who discontinue treatment for reasons other than disease progression and will include efficacy assessments at a minimum of every 12 weeks ± 7 days until disease progression, withdrawal of consent, or start of subsequent anticancer therapy.

[0291] The long-term follow-up period will occur for randomized subjects with disease progression who will be followed for survival and subsequent anti-cancer therapy every 12 weeks ± 14 days until study end.

[0292] Example 2 – Navtemadlin Combined with Ruxolitinib Synergistically Increase Apoptosis in a JAK2 V617F Cell Line

[0293] Apoptosis induced by navtemadlin, ruxolitinib, or the combination was assessed in the UKE-1 cell line, a TP53WTJAK2 V617F cell line derived from a patient with essential thrombocytopenia that transformed into acute leukemia (Fiedler 2000). Addition ofnavtemadlin to ruxolitinib synergistically increased apoptosis (P < 0.001) at 24 hours (data not shown). Quantitative comparison using Combenefit software of the combination versus single agent results using a highest single agent (HSA) model showed statistically significant synergy at clinically meaningful concentrations (Clevenger 2023).

[0294] Example 3 – Navtemadlin Combined with Ruxolitinib Synergize in Apoptosis of Chronic Phase MF Patient-Derived Progenitor Cells

[0295] Because the UKE-1 cell line does not fully represent myeloid cells in chronic phase myelofibrosis (MF cell lines cannot be used because they are TP53MUT), the combination effect was confirmed in myeloid cells from MF patients. The effects of navtemadlin and ruxolitinib were assessed in apoptosis assays using peripheral blood mononuclear cells collected from patients with chronic phase MF. MF-cells were co-cultured with a stromal support layer to mimic the supportive signals more closely from the tumor microenvironment present in vivo.

[0296] After 24 and 72 hours of co-culture, in the presence of clinically relevant concentrations of navtemadlin, ruxolitinib or the combination of the two drugs, progenitor cells were identified by flow cytometry (CD45+mid, SSClow, CD14-), and examined for markers of apoptosis (cleaved PARP). The combination of navtemadlin and ruxolitinib resulted in significantly more apoptosis of MF progenitor cells than from either drug alone at 72 hours (Figure 4A).

[0297] Activation of p53 also activates p21, a critical p53 induced cell cycle checkpoint that regulates cell cycle arrest and antagonizes apoptosis. As expected, navtemadlin alone markedly increased p21 expression in MF patient cells, whereas, as expected, ruxolitinib alone did not. Unexpectedly, the combination of navtemadlin and ruxolitinib significantly reduced levels of navtemadlin-induced p21 activation, evident as early as 24 hours after initial exposure. At 72 hours of combination exposure, p21 expression was nearly completely suppressed compared to navtemadlin alone (Figure 4B). These results demonstrated that MF patient cells treated with the combination of navtemadlin and ruxolitinib still induce p21 activation, but at a significantly lower apoptotic threshold needed to overcome the p21- mediated cell cycle arrest and apoptotic resistance. Surprisingly, in addition to the lowered apoptotic threshold of MF-cells, another synergistic mechanism of the combination was observed – significantly lowered expression of the BCL-2 family protein MCL-1, animportant pro-survival, cell death escape pathway utilized by cancer cells in myeloid and B cell diseases (Figure 5).

[0298] Example 4 – Cytotoxicity of Navtemadlin as Monotherapy or As Add-On Therapy to Ruxolitinib is Correlated with Spleen Volume Reduction

[0299] In MF, there is not a “true” cytotoxic target at the blast level to define clinical response, like in AML. However, ex vivo results demonstrate that navtemadlin, both as monotherapy in study KRT-232-101A (see study design in Example 6), and as add-on therapy to ruxolitinib in study KRT-232-109 (Example 7), robustly decreased circulating CD34+cells (Figure 6A and Figures 6B-C, respectively). Importantly, in both studies, reduction in CD34+cells correlated with SVR – patients with the largest decreases in peripheral CD34+cell count had the largest reductions in spleen volume.

[0300] In study KRT-232-101A, from baseline Cycle 1 Day 1 to Week 24, the median reduction in circulating CD34+cells in subjects treated with 240 mg on Days 1-7 of a 28-day treatment cycle was 89.02% (range: -98.5% to 103.7%; (Vachhani 2021). Analysis of all evaluable subjects showed that change in CD34+cell count was positively and significantly correlated with the magnitude of SVR (Figure 6A).

[0301] In study KRT-232-109, the addition of navtemadlin to ongoing ruxolitinib treatment decreased CD34+cell count at both Week 12 and Week 24, with a larger median reduction at Week 24 (Figure 6B). Indeed, four out of five subjects with the largest CD34+reductions from baseline Cycle 1 Day 1 to Week 24 were SVR35 responders (Figure 6C).

[0302] These results provide compelling evidence that navtemadlin-induced cytotoxicity of malignant CD34+cells improve the clinically important outcome of SVR and establishes the relevance of a cytotoxic mechanism for disease modifying outcomes in patients with MF. In addition, these results further support the relevance of MF-cell killing models demonstrating synergy in preclinical experiments (see, e.g., Examples 2 and 3). Importantly, this cytotoxicity-mediated mechanism is distinct from, and complementary to, the mechanisms through which ruxolitinib monotherapy acts (e.g., inhibition of the JAK-STAT signaling pathway).

[0303] Example 5 – KRT-232-114: Navtemadlin Monotherapy has Efficacy in Treatment- Naïve Myelofibrosis

[0304] KRT-232-114 was a Phase 2 open-label study in which the safety and efficacy of navtemadlin monotherapy was assessed in treatment-naïve patients with MF. A total of 14subjects were treated with navtemadlin 240 mg on Days 1-7 on a 28-day cycle. Median treatment duration was 183.0 days (range, 7-539). A total of 14.3% of subjects (2 / 14) had SVR of ≥ 35% at the Week 24 assessment by central review, while 28.6% (4 / 14) had a TSS reduction of ≥ 50% by MFSAF v4.0 at the same time point.

[0305] Example 6 – KRT-232-101A: Navtemadlin Monotherapy has Efficacy and Results in Disease-Modification in Ruxolitinib-Relapsed / Refractory Myelofibrosis

[0306] KRT-232-101A is a Phase 2 open-label, dose-finding study designed to evaluate the safety and efficacy of navtemadlin in subjects with MF who were relapsed or refractory to JAK inhibitor treatment. Subjects were treated with one of four dosing schedules to determine the optimal Phase 2 dose and schedule: navtemadlin 120 mg QD for Days 1-7 on a 21-cycle; navtemadlin 240 mg QD for Days 1–7 on a 21-day cycle; navtemadlin 240 mg QD for Days 1–7 on a 28-day cycle; or navtemadlin 240 mg QD for Days 1–5 on a 28-day cycle.

[0307] A total of 32 subjects were treated with navtemadlin 240 mg on Days 1-7 on a 28- day cycle. Fourteen (14) of these subjects had ruxolitinib washout of ≥ 28 days prior to the baseline imaging assessment; efficacy results are reported for this subset of patients to control for the effects on the spleen after ruxolitinib discontinuation prior to Cycle 1 Day 1. Median treatment duration for all 32 subjects was 175.5 days (range, 2-469). A total of 14.3% of subjects (2 / 14) had SVR of ≥ 35% at the Week 24 assessment by central review, while 14.3% (2 / 14) had a TSS reduction of ≥ 50% by MFSAF v4.0 at the same time point.

[0308] Navtemadlin Monotherapy Results in Disease-Modification of MF. Pharmacodynamic (PD) analysis showed disease modification with navtemadlin treatment, including reduced CD34+cell count, and VAF reductions.

[0309] Reduction in CD34+Cell Count: Reduction in CD34+cell count was correlated with progression-free survival (PFS) and OS (Figure 7) (Vachhani 2023). Subjects in which CD34+cell count normalized (e.g., had < 7 cells / μL), had significantly longer PFS and OS than subjects in which CD34+cell counts remained elevated.

[0310] Reductions in Driver Gene VAF: Across all evaluable subjects, the magnitude of best VAF reduction was positively and significantly correlated (p < 0.001) with the magnitude of best change in spleen volume. Similar to CD34+count, reduction of VAF was correlated with PFS and OS (Figure 8) (Vachhani 2023). Subjects with VAF reduction ≥ 20% had longer PFS and longer OS when compared with those with VAF reduction < 20%.

[0311] Improvement in Bone Marrow Fibrosis: Across all evaluable subjects, 27.3% (12 / 44) demonstrated improvement in fibrosis grade from baseline to Week 24.

[0312] Example 7 – KRT-232-109: Addition of Navtemadlin to Ongoing Therapy with a Stable Dose of Ruxolitinib Results in Synergistic Efficacy Responses

[0313] KRT-232-109 is an ongoing, Phase 1 / 2 study of the safety and efficacy of navtemadlin as add-on therapy to ruxolitinib in MF patients with a suboptimal response to ruxolitinib monotherapy. Patients eligible for this study did not have a spleen response per IWG-MRT criteria and did not show signs of progression after prior treatment with a stable dose of ruxolitinib. In the dose escalation Phase 1 study, subjects were treated with navtemadlin 120 mg, 180 mg, or 240 mg on Days 1-7 on a 28-day cycle. In the Phase 2 dose expansion, additional subjects were treated at the Recommended Phase 2 Dose (RP2D) of 240 mg on Days 1-7 on a 28-day treatment cycle. As of 2 May 2023, a total of 28 subjects had been treated with the RP2D. Subjects had been treated with prior ruxolitinib monotherapy for a median duration of 21.6 months (range, 7-129) before the addition of navtemadlin. It is important to note that the ruxolitinib dose was not increased in any subjects after initiation of navtemadlin. Median treatment duration with navtemadlin as add-on therapy to an ongoing stable dose of ruxolitinib was 143 days (range, 3-449). Nineteen (19) subjects had reached Week 24 or discontinued prior to that time point and were evaluable for efficacy. A total of 31.6% of subjects (6 / 19) had SVR of ≥ 35% at the Week 24 assessment by central review (Figure 9), while 31.6% (6 / 19) had a TSS reduction of ≥ 50% by MFSAF v4.0 at the same time point (Figure 10).

[0314] Navtemadlin Add-On Therapy to Ruxolitinib Results in Disease-Modification of MF. Navtemadlin add-on therapy to ruxolitinib reduced driver gene VAF and improved bone marrow fibrosis scores (Figure 11). A total of 71% (5 of 7 evaluable subjects) had ≥ 20% reduction in driver VAF at Week 24, and 57% (4 / 7) had improvement in bone marrow fibrosis scores comparing baseline to Week 24. These preliminary results are a substantial improvement from changes observed at similar time points in ruxolitinib (Kvasnicka 2018), or navtemadlin monotherapy studies.

[0315] Example 8 – Clinical Evidence of Synergy with Addition of Navtemadlin to Ongoing Ruxolitinib

[0316] Clinical evidence of synergy resulting from the addition of navtemadlin to ruxolitinib demonstrated when comparing results from navtemadlin monotherapy studiesKRT-232-114 and KRT-232-101A versus add-on study KRT-232-109 (Table 5). Study results demonstrated the efficacy of navtemadlin as add-on treatment to ongoing therapy with ruxolitinib was greater than efficacy achieved with navtemadlin alone, as measured by SVR and TSS reductions.

[0317] In studies KRT-232-114 and KRT-101A, patients with ruxolitinib-naïve or ruxolitinib relapsed / refractory MF were treated with navtemadlin monotherapy. In each of these studies, 14.3% of patients treated with navtemadlin monotherapy had a spleen response (SVR ≥ 35%) at Week 24. In KRT-232-109, patients that did not have a spleen response per IWG-MRT criteria nor disease progression while on ruxolitinib monotherapy but on a stable dose of ruxolitinib for ≥ 8 weeks, (median treatment duration 21.6 months of ruxolitinib monotherapy), were treated with navtemadlin as add-on therapy to their ongoing ruxolitinib treatment. In this study, 31.6% of patients had SVR ≥ 35% and TSS ≥ 50% at Week 24, markedly better than responses reported in the navtemadlin monotherapy studies KRT-232- 114 and KRT-232-101A.

[0318] Table 5: Clinical Evidence for Synergy of Navtemadlin and Ruxolitinib KRT-232-114 KRT-232-101A KRT-232-109 (n=14) (n=14) (n=19) Indication Rux-naïve MF Rux- MF with suboptimal relapsed / refractory response to MF Rux monotherapy Treatment Navtemadlin Navtemadlin Navtemadlin added monotherapy monotherapy to an ongoing stable dose of ruxolitinib SVR35 at Week 24 14.3% (2 / 14) 14.3% (2 / 14) 31.6% (6 / 19) by Central Review TSS50 at Week 24 28.6% (4 / 14) 14.3% (2 / 14) 31.6% (6 / 19) by MFSAF v4.0 KRT-232-114KRT-232-101A KRT-232-109 (n=14)(n=14) (n=19) Rux- MF with suboptimal Indication Rux-naïve MF relapsed / refractory response to MF Rux monotherapy Navtemadlin Navtemadlin Navtemadlin added Treatment monotherapy monotherapy to an ongoing stable dose of ruxolitinib SVR35 at Week 24 by Central Review14.3% (2 / 14) 14.3% (2 / 14) 31.6% (6 / 19)TSS50 at Week 24 by MFSAF v4.028.6% (4 / 14) 14.3% (2 / 14) 31.6% (6 / 19)Abbreviations: Rux = ruxolitinib; SVR35 = spleen volume reduction of ≥ 35% at Week 24; TSS50 = total symptom score reduction of ≥ 50% at Week 24. Navtemadlin dose: All navtemadlin dosing was 240 mg on Days 1-7 of a 28-day cycle.

[0319] Of note, the novel SVR ≥ 35% and TSS ≥ 50% responses occurred in a patient population where ongoing ruxolitinib monotherapy did not provide further response benefit since SVR and TSS responses to ruxolitinib plateau after the initial 12 weeks of single agent ruxolitinib therapy (Verstovsek 2012). Thus, efficacy results observed in study KRT-232-109 were due to the addition of navtemadlin to ongoing ruxolitinib therapy. Together, these clinical results provide strong support for further development of navtemadlin as add-on therapy to ruxolitinib for patients with a suboptimal response to ruxolitinib monotherapy in study KRT-232-115. In addition, the magnitude of response after addition of navtemadlin to ongoing ruxolitinib (31.6% of patients with SVR ≥ 35%) exceeded the magnitude observed in monotherapy trials (14.3% in frontline and in relapsed refractory settings) by ~2.2 fold, strongly suggestive of a synergistic effect of this drug combination.

[0320] The addition of navtemadlin to ruxolitinib treatment resulted in novel SVR ≥ 35%; however, many other subjects had clinically relevant decreases in spleen volume of ≥ 25% to < 35% (Figure 9). While numerically smaller than SVR ≥ 35%, an SVR of ≥ 25% is associated with clinically meaningful increases in overall survival. Pooled analysis of results from COMFORT-1 and COMFORT-2 reported that an SVR of ≥ 25% was associated with meaningful improvements in survival that were similar in magnitude to those associated with SVR ≥ 35% (Vannucchi 2015). In the pooled analysis, the hazard ratio for survival in ruxolitinib-treated patients with SVR ≥ 25% to < 35% was 0.25 (95% CI: 0.11-0.61), representing a 75% reduction in risk of death versus patients that had SVR < 10%. Most importantly, this hazard ratio was numerically similar to patients who achieved SVR ≥ 35% to < 50% (0.24 [95%CI: 0.11-0.56).

[0321] In study KRT-232-109, the addition of navtemadlin did not negatively affect ruxolitinib dosing. Dose reductions of ruxolitinib prior to Week 24 were rare, occurring in only 15.8% (3 / 19) of patients and all three of these patients achieved at least a 25% reduction in spleen volume at Week 24, providing clinical evidence that ruxolitinib dose reductions did not have a negative effect on patients’ ability to achieve additional clinical benefit.

[0322] The safety profile of navtemadlin add-on therapy to ruxolitinib in study KRT-232- 109 was acceptable. A total of 19.4% of subjects had a serious adverse event (SAE) and 8.3% of subjects had navtemadlin-related SAEs. Anemia was the only SAE that occurred in > 1 subject (occurring in 2 subjects, 5.6%). Navtemadlin-related grade 3 / 4 TEAEs were reported in 44.4% of subjects. The most frequently reported navtemadlin-related Grade 3 / 4 TEAEs (> 5%) were thrombocytopenia / platelet count decreased (25%), anemia (13.9%), nausea (11.1%), and diarrhea, neutrophil count decreased, and leukocytosis (5.6% each).

[0323] Example 9 – Study KRT-232-115: A Phase 3, Randomized, Double-blind, Add-on Study Evaluating the Safety and Efficacy of Navtemadlin Plus Ruxolitinib vs Placebo Plus Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib

[0324] The study includes a ruxolitinib monotherapy run-in period of ≥ 18 weeks but < 25 weeks during which subjects will receive standard of care ruxolitinib treatment. After completion of the run-in period, eligible subjects identified as suboptimal responders to ruxolitinib monotherapy will be randomized 2:1 in a double-blind, placebo-controlled manner to receive either add-on navtemadlin (Arm 1) or add-on placebo (Arm 2) in the setting of continuous ruxolitinib use. All subjects assessed as refractory or optimally responding to ruxolitinib monotherapy will be discontinued from the study.

[0325] The run-in period will extend from the initiation of treatment with ruxolitinib monotherapy until randomization to navtemadlin / placebo as add-on therapy to ruxolitinib treatment (or study discontinuation for subjects who are ineligible for participation in the randomized period of the study). During the run-in period, eligible subjects with JAK inhibitor-naïve MF will receive ruxolitinib monotherapy at a dose ≥ 5 mg twice per day (BID) chosen at the discretion of the Investigator. Spleen volume and MF symptoms before and after ≥ 18 weeks but < 25 weeks of ruxolitinib monotherapy will be assessed in subjects who have had a stable dose of ruxolitinib for ≥ 6 consecutive weeks (ie, a dose ≥ 5 mg BID that did not require a treatment hold or dose adjustment). These assessments should be performed within 14 days prior to randomization.

[0326] The randomized period consists of 28-day treatment cycles and will extend from the first dose of add-on navtemadlin / placebo until the end of treatment (EOT) visit, which should occur within 28 days from the last dose of study drug. Approximately 180 subjects identified as suboptimal responders to ruxolitinib who meet eligibility criteria will berandomized (2:1) in a double-blind, placebo-controlled manner to receive either add-on navtemadlin (Arm 1; n = 120) or add-on placebo (Arm 2; n = 60) in the setting of continuous ruxolitinib treatment. Suboptimal response to ruxolitinib monotherapy is defined as > 0% but < 35% reduction in spleen volume by MRI / CT scan (central review) and > 0% but < 50% reduction in TSS by MFSAF v4.0. Key eligibility requirements are that subjects must be on a stable dose of ruxolitinib for ≥ 8 consecutive weeks (note that a response assessment during the monotherapy run-in period is allowed after a stable dose of ≥ 6 consecutive weeks) and have TP53WTMF. Subjects who do not meet the criteria for randomization will be discontinued from the study and may continue to receive commercially available ruxolitinib as per standard of care treatment.

[0327] A study of a plurality of subjects (Study KRT-232-115) will be performed to measure spleen size and symptoms for JAKi-naïve MF patients at three key time points: prior to treatment with the first composition (e.g., before ruxolitinib monotherapy treatment), at a second time point after a first treatment period (e.g., at least at Week 18 (when it is determined if the subject is a suboptimal responder)), and at a third time point after a second treatment period (e.g., 24 weeks after randomization to either add-on navtemadlin or add-on placebo). Efficacy evaluations will be performed, including but not limited to SVR25, TSS30, SVR35, and / or TSS50. This unique study design allows the evaluation of the contribution of effect of either the combination of the first composition and the second composition or the combination of the first composition and the placebo (e.g., add-on navtemadlin or add-on placebo) by comparing a multi-component endpoint comprising two component endpoints SVR25 and TSS30 as determined based on a comparison of a second response set to a second set of baseline measurements (e.g., from a pre-randomization baseline) to the established SVR35 and TSS50 thresholds from both a within-patient and overall population perspective. The multi-component endpoints ensure that only patients who achieve an SVR35 or TSS50 in the first set of baseline measurements (e.g., from the pre- ruxolitinib baseline) are defined as responders if achieving both SVR25 and TSS30 in the second set of baseline measurements (e.g., from the pre-randomization baseline)), thereby attributing within-patient clinically meaningful benefit according to established thresholds (Figure 12, Figure 13). In one preferred embodiment, the multi-component endpoints comprise: 1. the proportion of patients in each arm who achieve an SVR of ≥ 25% (SVR25) from the pre-randomization baseline and an SVR of ≥ 35% (SVR35) from the pre-ruxolitinib baseline; and 2. the proportion of patients in each arm who achieve a TSS reduction of ≥ 30%(TSS30) from the pre-randomization baseline and a TSS reduction of ≥ 50% (TSS50) from the pre-ruxolitinib baseline.

[0328] Multi-component spleen response endpoints based on spleen volume reduction are shown in Figure 12. Patients achieving an SVR35 (spleen volume reduction ≥ 35%) from the pre-ruxolitinib baseline are defined as responders (despite achieving a SVR25 (spleen volume reduction ≥ 25%) from pre-randomization baseline). The multi-component spleen response endpoints based on spleen volume reduction are shown in Figure 13. Patients achieving a TSS50 (≥ 50% total symptom score reduction) from the pre-ruxolitinib baseline are defined as responders (despite achieving a TSS30 (≥ 30% total symptom score reduction) from pre- randomization baseline).

[0329] Taken together, the multi-component co-primary endpoints will isolate the contribution of add-on navtemadlin, while ensuring the magnitude of spleen and symptom benefit is clinically meaningful from the established SVR35 and TSS50 endpoints perspective.

[0330] Concordance Analysis of SVR25 and TSS30 to SVR35 and TSS50

[0331] To tie the response thresholds of SVR25 and TSS30, as measured from the pre- randomization baseline, with the historic thresholds for clinically meaningful benefit of SVR35 and TSS50 in the JAKi-naïve population (e.g., from the pre-ruxolitinib baseline), a three-step approach was taken.

[0332] Step One:

[0333] Data was pooled from published phase 3 studies for patients treated with ruxolitinib in the JAKi-naive MF setting (Verstovsek 2012; Mesa 2017; Pemmaraju 2023; Rampal 2023) to understand the natural history of patients with MF who achieve a suboptimal response to ruxolitinib, as defined in Study KRT-232-115 (e.g., a subject with an SVR > 0% but <35% and a TSS reduction > 0% but < 50%) (Figure 14).

[0334] Figure 14 illustrates suboptimal spleen and symptom responders from the pooled phase 3 ruxolitinib data, including patients treated with ruxolitinib monotherapy with and without placebo. SVR data was obtained for 465 subjects from the three studies COMFORT- 1, SIMPLIFY-1, and TRANSFORM-1(Verstovsek 2012; Mesa 2017; Pemmaraju 2023). TSS data was obtained for 528 subjects from the three studies. Week-24 data used as a proxy to Week-18 suboptimal response assessment.

[0335] Step Two:

[0336] From the pooled dataset, it was determined that among the JAKi-naive MF patients with a suboptimal response to ruxolitinib the mean SVR was 18% (Figure 15) and the mean TSS reduction was 28.5% (Figure 16).

[0337] The information was then incorporated with the pre-randomization thresholds of SVR25 and TSS30 to determine congruence with historical thresholds of clinical benefit (e.g., SVR35 and TSS50) established in JAKi-naïve MF patients, as measured from the pre- ruxolitinib baseline.

[0338] An additional SVR of 25% to a mean SVR of 18% would result in a 39% effective response threshold from the pre-ruxolitinib baseline, more than the current SVR35 standard. Similarly, an additional TSS reduction of 30% to a mean TSS reduction of 28.5% would establish a 50% effective response threshold from the pre-ruxolitinib baseline, at parity with the current standard of TSS50.

[0339] Step Three:

[0340] Lastly, a concordance analysis was performed comparing two sets of outcomes: SVR25 and TSS30 (measured from the pre-randomization baseline) with SVR35 and TSS50 (measured from the pre-ruxolitinib baseline). This was done to understand how well these outcomes align when assessing the effect of add-on navtemadlin or add-on placebo in suboptimal responders in study KRT-232-115.

[0341] To do this, suboptimal responder patient data was pooled from the published phase 3 studies in JAKi-naïve MF (Verstovsek 2012; Mesa 2017; Pemmaraju 2023; Rampal 2023), together with the results from KRT-232-109 (Figure 17, Figure 18), a phase 2 study of add-on navtemadlin in patients with a suboptimal response to ruxolitinib.

[0342] Figure 17 illustrates the spleen volume reduction after add-on navtemadlin to a stable dose of ruxolitinib for evaluable subjects with spleen volume assessments at baseline and Week 24. Baseline spleen volume magnetic resonance imaging / computed tomography scans were taken while subjects were on a stable dose of ruxolitinib for ≥ 8 weeks (e.g., no ruxolitinib wash-out). Figure 18 illustrates the total symptom score reduction after add-on navtemadlin to a stable dose of ruxolitinib, with baseline TSS assessments taken while subjects were on the same period of a stable dose of ruxolitinib for ≥ 8 weeks (e.g., no ruxolitinib wash-out). For both Figures 17 and 18, no dose increases of ruxolitinib above the stable baseline dose occurred during the 24-week assessment period. The median duration ofruxolitinib treatment prior to the addition of navtemadlin was 21.6 months (range: 7 to 129). Six subjects discontinued treatment prior to Week 24.

[0343] In these analyses, the contribution effect of navtemadlin on SVR and TSS from study KRT-232-109 were modeled onto the pooled suboptimal responder data to establish the add-on benefit of navtemadlin from the perspective of the pre-ruxolitinib baseline. This model permitted an estimate of the proportion of suboptimal responder patients who would achieve an SVR25 or TSS30 from the pre-randomization baseline.

[0344] Based on this model, 55% of patients receiving add-on navtemadlin were expected to achieve an SVR35 from the pre-ruxolitinib baseline and 50% an SVR25 from the pre- randomization baseline compared to 8% and 0% for patients receiving add-on placebo, respectively (Figure 19, Figure 20). Figure 19 illustrates the expected SVR for add-on navtemadlin to ruxolitinib, with spleen volume reductions modeled from KRT-232-109 and published phase 3 myelofibrosis studies. Light gray bars depict the baseline distribution of SVR based on pooled, extractable data from published phase 3 JAKi-naïve MF studies for patients with suboptimal spleen response to ruxolitinib monotherapy (± placebo); COMFORT-1, SIMPLIFY-1, and TRANSFORM-1 (Verstovsek 2012; Mesa 2017; Pemmaraju 2023). Blue bars, regardless of shade, show the expected additional benefit of treating patients with add-on navtemadlin. Darkest blue bars depict SVR25 responders from a pre-randomization baseline that also cross the SVR35 threshold from a pre-ruxolitinib baseline (e.g., multi-component SVR endpoint). Figure 20 illustrates the expected SVR for add-on placebo to ruxolitinib. Dark gray bars show the expected additional benefit of treating patients with add-on placebo. No patients (0% of patients) were modeled to achieve the multi-component SVR endpoint of SVR25 from a pre-randomization baseline AND SVR35 from a pre-ruxolitinib baseline.

[0345] Similarly, 45% of patients receiving add-on navtemadlin were expected to achieve a TSS50 from the pre-ruxolitinib baseline and 45% a TSS30 from the pre-randomization baseline compared to 9% and 2% for add-on placebo (Figure 21, Figure 22).

[0346] Figure 21 illustrates the expected TSS reduction add-on navtemadlin to ruxolitinib. Light gray bars depict the baseline distribution of TSS reductions based on pooled extractable data from published phase 3 JAKi-naïve MF studies for patients with suboptimal symptom response to ruxolitinib monotherapy (± placebo). Green bars, regardless of shade, show the expected additional symptom improvement benefit of treating patients with add-onnavtemadlin. Darkest green bars depict TSS30 responders from a pre-randomization baseline that also cross the TSS50 threshold from a pre-ruxolitinib baseline (multi-component TSS endpoint). Figure 22 illustrates the expected TSS reductions for placebo add-on to ruxolitinib. Light gray bars depict the baseline distribution of TSS reductions based on pooled extractable data from published phase 3 JAKi-naïve MF studies for patients with suboptimal symptom response to ruxolitinib monotherapy (± placebo). Darker gray bars show the expected additional benefit of treating patients with add-on placebo. Black bars depict TSS30 responders from a pre-randomization baseline that also cross the TSS50 threshold from a pre- ruxolitinib baseline (e.g., multi-component TSS endpoint).

[0347] A 93% concordance was observed between the expected SVR25 from the pre- randomization baseline and the expected SVR35 from the pre-ruxolitinib baseline (e.g., 93% of SVR25 responders would also achieve SVR35 from the pre-ruxolitinib baseline). Similarly, a 90% concordance was observed between the expected TSS30 from the pre- randomization baseline and the expected TSS50 from the pre-ruxolitinib baseline (e.g., 90% of TSS30 responders from would also achieve a TSS50 from the pre-ruxolitinib baseline).

[0348] References

[0349] Al-Ali HK, Vannucchi AM. Managing patients with myelofibrosis and low platelet counts. Ann Hematol. Apr 2017;96(4):537-548.

[0350] Aubrey BJ, Kelly GL, Janic A, et al. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. Jan 2018;25(1):104- 113.

[0351] Barosi G, Mesa RA, Thiele J, et al. Proposed criteria for the diagnosis of post- polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. Feb 2008;22(2):437-8.

[0352] Canon J, Osgood T, Olson SH, et al. The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents. Mol Cancer Ther. Mar 2015;14(3):649-58.

[0353] Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. Mar 262009;113(13):2895-901.

[0354] Clevenger T, Cheung J, Krantz F, et al. Adding Navtemadlin (nvtm) to Ruxolitinib (rux) Potentiates Apoptosis in Myeloblasts from Patients (pts) with Myelofibrosis (MF). presented at: EHA2023 Congress; 2023; Frankfurt, Germany.

[0355] Erba HP, Becker PS, Shami PJ, et al. Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed / refractory acute myeloid leukemia. Blood Adv. Jul 92019;3(13):1939-1949.

[0356] Fiedler W, Henke RP, Ergun S, et al. Derivation of a new hematopoietic cell line with endothelial features from a patient with transformed myeloproliferative syndrome: a case report. Cancer. Jan 152000;88(2):344-51.

[0357] Food and Drug Administration. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation.2009.

[0358] Greenfield G, McPherson S, Mills K, et al. The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms. J Transl Med. Dec 172018;16(1):360.

[0359] Guy W. ECDEU assessment manual for psychopharmacology. US Department of Health, Education, and Welfare; 1976.

[0360] Gwaltney C, Paty J, Kwitkowski VE, et al. Development of a harmonized patient- reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials. Leuk Res. Aug 2017;59:26-31.

[0361] Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. Mar 12012;366(9):787-98.

[0362] Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. Aug 2016;30(8):1701-7.

[0363] Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. Feb 2018;5(2):e73- e81.

[0364] Harutyunyan A, Klampfl T, Cazzola M, et al. p53 lesions in leukemic transformation. N Engl J Med. Feb 32011;364(5):488-90.

[0365] Hussein K, Van Dyke DL, Tefferi A. Conventional cytogenetics in myelofibrosis: literature review and discussion. Eur J Haematol. May 2009;82(5):329-38.

[0366] Jakafi Prescribing Information. Jakafi® (ruxolitinib) prescribing information. Available on the Internet at jakafi.com / pdf / prescribing-information.pdf

[0367] Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. J Hematol Oncol. Mar 152018;11(1):42.

[0368] Lussana F, Rambaldi A. Inflammation and myeloproliferative neoplasms. J Autoimmun. Dec 2017;85:58-63.

[0369] Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients with Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. May 12018;4(5):652-659.

[0370] Mascarenhas J, Jain T, Otoukesh S, et al. An Open-Label, Global, Phase 1B / 2 Study Adding Navtemadlin (NVTM) to Ruxolitinib (RUX) in Patients (PTS) with Primary or Secondary Myelofibrosis (MF) Who Have a Suboptimal Response to RUx. presented at: EHA2023 Congress; 2023; Frankfurt, Germany.

[0371] Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on myelofibrosis- related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. Apr 12013;31(10):1285-92.

[0372] Mesa RA, Kiladjian J-J, Catalano JV, et al. SIMPLIFY-1: A Phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor–naïve patients with myelofibrosis. Journal of Clinical Oncology.2017;35(34):3844-3850.

[0373] Nakatake M, Monte-Mor B, Debili N, et al. JAK2(V617F) negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms. Oncogene. Mar 82012;31(10):1323-33.

[0374] National Institute of Mental Health (NIMH). Patient global impression of change (PGIC).2017. Available on the Internet at eprovide.mapi-trust.org / instruments / patient- global-impression-of-change.

[0375] Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. Aug 312017;130(9):1125-1131.

[0376] Orvain C, Luque Paz D, Dobo I, et al. Circulating CD34+ cell count differentiates primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms: a pragmatic study. Ann Hematol. Oct 2016;95(11):1819-23.

[0377] Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer. Mar 152020;126(6):1243-1252.

[0378] Pardanani A, Harrison C, Cortes JE, et al. Safety and Efficacy of Fedratinib in Patients with Primary or Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. Aug 2015;1(5):643-51.

[0379] Pemmaraju N, Mead AJ, Somervaille TC, et al. Transform-1: A randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood.2023 Nov 28;142:620.

[0380] Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. Jul 2006;3(7):e270.

[0381] Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Patients with Myelofibrosis: Results of the MANIFEST-2 Randomized, Double-Blind, Phase 3 Study. Blood.2023;142(1):628.

[0382] Raza S, Viswanatha D, Frederick L, et al. TP53 mutations and polymorphisms in primary myelofibrosis. Am J Hematol. Feb 2012;87(2):204-6.

[0383] Sun D, Li Z, Rew Y, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. Feb 27 2014;57(4):1454-72.

[0384] Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG- MRT) and European LeukemiaNet (ELN) consensus report. Blood. Aug 22 2013;122(8):1395-8.

[0385] Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. Aug 152007;110(4):1092-7.

[0386] Thiele J, Kvasnicka HM, Facchetti F, et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. Aug 2005;90(8):1128-32.

[0387] Vachhani P, Lange A, Delgado RG, et al. Potential Disease-Modifying Activity of Navtemadlin (KRT-232), a First-in-Class MDM2 Inhibitor, Correlates with Clinical Benefits in Relapsed / Refractory Myelofibrosis (MF). Blood.2021;138:3581-3584.

[0388] Vachhani P, Perkins A, Mascarenhas J, et al. Disease-modifying activity of navtemadlin correlated with survival outcomes in Janus kinase inhibitor (JAKi) relapsed or refractory myelofibrosis patients. presented at: European Hematology Association; 2023; Frankfurt.

[0389] Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. Sep 2015;100(9):1139-45.

[0390] Vaseva AV, Moll UM. The mitochondrial p53 pathway. Biochim Biophys Acta. May 2009;1787(5):414-20.

[0391] Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo- controlled, phase 3 COMFORT-I trial. J Hematol Oncol. Feb 222017;10(1):55.

[0392] Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. Mar 12012;366(9):799-807.

[0393] Vousden KH, Lane Dp. p53 in health and disease. Nat Rev Mol Cell Biol. Apr 2007;8(4):275-83.

[0394] CONCLUSION

[0395] All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0396] The present invention can be implemented as a computer program product that comprises a computer program mechanism embedded in a non-transitory computer readable storage medium. For instance, the computer program product could contain the program modules shown in any combination of Figures 1A-C or 2A-C. These program modules can bestored on a CD-ROM, DVD, magnetic disk storage product, USB key, or any other non- transitory computer readable data or program storage product.

[0397] Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated. The invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

What is claimed is:

1. A method for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition, the method comprising: obtaining clinical data that involves a plurality of subjects that have the myeloproliferative neoplasm, wherein the clinical data includes and associates for each respective subject in the plurality of subjects (i) a corresponding first set of baseline measurements prior to treatment with the first composition for the myeloproliferative neoplasm and (ii) a corresponding first response set after a first treatment period with the first composition; identifying a subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold; dividing the subset of subjects between a first arm and a second arm on a randomized basis, wherein subjects in the first arm receive a combination of the first composition and the second composition and subjects in the second arm receive a combination of the first composition and a placebo for a second treatment period; for each respective subject in the subset of subjects, obtaining a corresponding second response set upon completion of the second treatment period; and evaluating each respective subject in the subset of subjects by comparing the corresponding second response set to: (a) the corresponding first set of baseline measurements for the respective subject and / or (b) an optional corresponding second set of baseline measurements obtained for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, thereby determining whether the combination of the first treatment and the second treatment of the first arm improves the one or more endpoints associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition.

2. The method of claim 1, wherein the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding first set of baseline measurements for the respective subject.

3. The method of claim 1, further comprising obtaining the corresponding second set of baseline measurements for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, and the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding second set of baseline measurements for the respective subject.

4. The method of claim 1, wherein an endpoint in the one or more endpoints is a comparison of: a proportion of subjects in the first arm that exhibit an amount of reduction in spleen size as measured by magnetic resonance imaging or computed tomography, between the run- in period and a set time in the second treatment period, that is greater than a threshold amount of spleen size reduction, and a proportion of subjects in the second arm that exhibit an amount of reduction in spleen size as measured by magnetic resonance imaging or computed tomography, between the run-in period and a set time in the second treatment period, that is greater than the threshold amount of spleen size reduction.

5. The method of claim 4, wherein the first treatment period is between 12 weeks and 36 weeks, and the set time in the second treatment period is between 12 weeks and 36 weeks after initiation of the second treatment period.

6. The method of claim 4, wherein the first treatment period is between 12 weeks and 36 weeks, and the set time in the second treatment period is 24 weeks after initiation of the second treatment period.

7. The method of any one of claims 4-6, wherein the threshold amount of spleen size reduction is a percentage between twenty-five percent and fifty percent relative to a firstbaseline spleen size measurement in the corresponding first set of baseline spleen size measurements.

8. The method of any one of claims 4-6, wherein the threshold amount of spleen size reduction is at least thirty-five percent relative to a first baseline spleen size measurement from the corresponding first set of baseline spleen size measurements.

9. The method of any one of claims 1-8, wherein an endpoint in the one or more endpoints is a comparison of: a proportion of subjects in the first arm that exhibit an improvement in a quality of life assessment score, between the run-in period and a set time in the second treatment period, is greater than a threshold amount of improvement, and a proportion of subjects in the second arm that exhibit an improvement in a quality of life assessment score, between the run-in period and a set time in the second treatment period, is greater than the threshold amount of improvement.

10. The method of claim 9, wherein the first treatment period is between 12 weeks and 36 weeks, and the set time in the second treatment period is between 12 weeks and 36 weeks after initiation of the second treatment period.

11. The method of claim 9, wherein the first treatment period is between 12 weeks and 36 weeks, and the set time in the second treatment period is 24 weeks after initiation of the second treatment period.

12. The method of any one of claims 9-11, wherein, for a subject in the subset of subjects: the corresponding first set of baseline measurements includes a first score derived from a quality of life assessment form, the corresponding second response set includes a second score derived from the quality of life assessment form, and the improvement in the quality of life assessment score between the run-in period and the set time in the second treatment period is a difference between the first score and the second score.

13. The method of claim 12, wherein the quality of life assessment form is the myelofibrosis symptom assessment form or the Myeloproliferative Neoplasm Symptom Assessment Form v2.

0.

14. The method of claim 12, wherein the quality of life assessment form is the general quality of life questionnaire (EQ-5D), eHEALS, EORTC QLG Core Questionnaire (EORTC QLQ-C30), Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and / or patient activation measure (PAM-13).

15. The method of any one of claims 7-13, wherein the quality of life assessment form is the Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and the threshold amount of improvement is at least a sixty percent reduction in the quality of life assessment score.

16. The method of any one of claims 7-13, wherein the quality of life assessment form is the Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and the threshold amount of improvement is at least a fifty percent reduction in the quality of life assessment score.

17. The method of any one of claims 1-16, wherein an endpoint in the one or more endpoints is a comparison of a first overall survival value calculation to a second overall survival calculation, wherein the first overall survival value calculation is a measure of central tendency of a difference between (i) a time of enrollment in the run-in period, and (ii) a time of death from any cause, across subjects in the first arm, and the second overall survival value calculation is a measure of central tendency of a difference between (i) a time of enrollment in the run-in period, and (ii) a time of death from any cause, across subjects in the second arm.

18. The method of any one of claims 1-17, wherein an endpoint in the one or more endpoints is a comparison of a first progression-free survival value calculation to a second progression-free survival calculation, wherein the first progression-free survival value calculation is a measure of central tendency of a difference between (i) a time of enrollment in the run-in period, and(ii) a time of first occurrence of (a) a spleen size that exceeds a spleen size at a start of the run-in period by a threshold percent spleen volume, (b) a leukemic transformation, or (c) death from any cause, across subjects in the first arm, and the second progression-free survival value calculation is a measure of central tendency of a difference between (i) a time of enrollment in the run-in period, and (ii) a time of first occurrence of (a) an increase in spleen size above a threshold amount over a spleen size at a start of the run-in period, (b) a leukemic transformation, or (c) death from any cause, across subjects in the second arm.

19. The method of claim 18, wherein the threshold percent spleen volume is between 15 percent and 35 percent relative to a first baseline spleen volume measurement in the corresponding first set of baseline spleen volume measurements.

20. The method of claim 18, wherein the threshold percent spleen volume is 25 percent relative to a first baseline spleen volume measurement in the corresponding first set of baseline spleen volume measurements.

21. The method of claim 18, wherein the leukemic transformation comprises: (i) a bone marrow blast count of ≥ 20% above a bone marrow blast count at a time of enrollment in the run-in period associated with an absolute blast count of more than 1x109 / L that lasts for at least 2 weeks, and / or (ii) a peripheral blood blast content of ≥ 20% above a peripheral blood blast content at the time of enrollment in the run-in period associated with an absolute blast count of more than 1x109 / L that lasts for at least 2 weeks.

22. The method of any one of claims 1-21, wherein an endpoint in the one or more endpoints is a comparison of a first average amount of time to a second average amount of time, wherein the first average amount of time is between (i) a time of first observance of a reduction in spleen size after the run-in period of at least a threshold percent spleen volume, and (ii) a time of observation of disease progression or death across subjects in the first arm, andthe second average amount of time is between (i) a time of first observance of a reduction in spleen size after the run-in period of at least the threshold percent and (ii) a time of observation of disease progression or death across subjects in the second arm.

23. The method of claim 22, wherein the threshold percent spleen volume is between 35 percent and 45 percent relative to a first baseline spleen volume measurement in the corresponding first set of baseline spleen volume measurements.

24. The method of claim 22, wherein the threshold percent spleen volume is 35 percent relative to a first baseline spleen volume measurement in the corresponding first set of baseline spleen volume measurements.

25. The method of any one of claim 1-24, wherein an endpoint in the one or more endpoints is a comparison of a proportion of subjects in the first arm that exhibit an amount of reduction in spleen size, between the run-in period and a set time in the second treatment period, as measured by palpation, that is greater than a threshold amount of spleen size reduction, and a proportion of subjects in the second arm that exhibit an amount of reduction in spleen size, between the run-in period and a set time in the second treatment period, as measured by palpation, that is greater than the threshold amount of spleen size reduction.

26. The method of any one of claims 1-25, wherein the corresponding first set of baseline measurements comprises a first measurement of an organ of the respective subject, and the corresponding second response set includes a second measurement of the organ of the respective subject.

27. The method of claim 26, wherein the organ is the spleen of the respective subject.

28. The method of claim 26, wherein the first measurement of the organ of the respective subject is a first measurement of the size of the spleen of the respective subject, and the second measurement of the organ of the respective subject is a second measurement of the size of the spleen of the respective subject.

29. The method of any one of claims 1-28, wherein the plurality of subjects comprises 200 subjects.

30. The method of any one of claims 1-28, wherein the plurality of subjects comprises 500 subjects.

31. The method of any one of claim 1-30, wherein less than eighty percent of the plurality of subjects satisfies the suboptimal response threshold.

32. The method of any one of claims 1-30, wherein less than forty percent of the plurality of subjects satisfies the suboptimal response threshold.

33. The method of any one of claims 1-32, wherein the myeloproliferative neoplasm is myelofibrosis.

34. The method of any one of claims 1-33, wherein the plurality of subjects is JAK- inhibitor treatment naïve.

35. The method of any one of claims 1-34, wherein each subject in the plurality of subjects has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 in the corresponding first set of baseline measurements.

36. The method of any one of claims 1-35, wherein each subject in the plurality of subjects has a spleen measuring greater than or equal to 450 cm3as determined by magnetic resonance imaging or computed tomography in the corresponding first set of baseline measurements.

37. The method of any one of claims 1-36, wherein each subject in the plurality of subjects has a platelet count of 100 x 109 / L or greater in the corresponding first set of baseline measurements.

38. The method of any one of claims 1-37, wherein the first treatment period is greater than 5 weeks and less than 40 weeks.

39. The method of any one of claims 1-37, wherein the first treatment period is equal to or greater than 12 weeks and less than 36 weeks.

40. The method of claim 38 or 39, wherein the first treatment period includes at least 5 weeks of daily administration of the first composition free of a treatment hold or a dose adjustment.

41. The method of claim 38 or 39, wherein the first treatment period includes at least 8 weeks of daily administration of the first composition free of a treatment hold or a dose adjustment.

42. The method of any one of claims 1-41, wherein the second treatment period is between 5 weeks and 100 weeks.

43. The method of any one of claims 1-41, wherein the second treatment period is between 12 weeks and 200 weeks.

44. The method of any one of claims 1-43, wherein an active ingredient of the first treatment composition is Ruxolitinib.

45. The method of claim 44, wherein the Ruxolitinib is administered at a total dose of ≥ 3 mg per day during the first treatment period and the second treatment period to the plurality of subjects.

46. The method of claim 44, wherein the Ruxolitinib is administered at a total dose of ≥ 5 mg per day during the first treatment period and the second treatment period to the plurality of subjects.

47. The method of claim 44, wherein the Ruxolitinib is administered at a total dose of ≥ 8 mg per day during the first treatment period and the second treatment period to the plurality of subjects.

48. The method of claim 44, wherein the Ruxolitinib is administered at a total dose of between 2 mg and 10 mg per day during the first treatment period and the second treatment period to the plurality of subjects.

49. The method of any one of claims 44-48, wherein the Ruxolitinib is administered twice a day.

50. The method of any one of claims 44-48, wherein the Ruxolitinib is administered once a day.

51. The method of any one of claims 1-50, wherein an active ingredient of the second treatment composition is Navtemadlin.

52. The method of claim 51, wherein the Navtemadlin is administered at a total dose of ≥ 100 mg per day during the second treatment period to each subject in the first arm.

53. The method of claim 51, wherein the Navtemadlin is administered at a total dose of ≥ 200 mg per day during the second treatment period to each subject in the first arm.

54. The method of claim 51, wherein the Navtemadlin is administered at a total dose of between 150 mg and 300 mg per day during the second treatment period to each subject in the first arm.

55. The method of claim 51, wherein the Navtemadlin is administered at a total dose of 240 mg per day during the second treatment period to each subject in the first arm.

56. The method of any one of claims 51-55, wherein the Navtemadlin is administered twice a day during the second treatment period to each subject in the first arm.

57. The method of any one of claims 51-55, wherein the Navtemadlin is administered once a day during the second treatment period to each subject in the first arm.

58. The method of any one of claims 1-57, wherein the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a 50 percent reduction in spleen size between the baseline measurement and after the first treatment period, and / or (ii) between a greater than 0 percent and a 70 percent reduction in total symptom score between the baseline measurement and after the first treatment period.

59. The method of any one of claims 1-57, wherein the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a 40 percent reduction in spleen size between the baseline measurement and after the first treatment period, and / or (ii) between a greater than 0 percent and a 60 percent reduction in total symptom score between the baseline measurement and after the first treatment period.

60. The method of any one of claims 1-57, wherein the corresponding first response set of the respective subject satisfies the suboptimal response threshold when there is: (i) between a greater than 0 percent and a 35 percent reduction in spleen size between the baseline measurement and after the first treatment period, and / or (ii) between a greater than 0 percent and a 50 percent reduction in total symptom score between the baseline measurement and after the first treatment period.

61. The method of any one of claims 1–60, wherein the dividing the subset of subjects between a first arm and a second arm on the randomized basis is in accordance with a stratified, permuted-block randomization scheme that balances representation in the first arm and the second arm for each block in a plurality of blocks, wherein a first block in the plurality of blocks is SVR > 0% but < 20%, and a second block in the plurality of blocks is SVR ≥ 20% but < 35%.

62. The method of claim 61, wherein a third block in the plurality of blocks is TSS reduction > 0% but < 30%, and a fourth block in the plurality of blocks is TSS reduction ≥ 30% but < 50%.

63. A computing system comprising: computer memory configured to store clinical data, wherein the clinical data involves a plurality of subjects that have a myeloproliferative neoplasm, wherein the clinical data includes and associates for each respective subject in the plurality of subjects (i) a corresponding first set of baseline measurements prior to treatment with a first treatment with a first composition or a second treatment with a second composition for the myeloproliferative neoplasm and (ii) a corresponding first response set after a first treatment period with the first composition; one or more processors in communication with the computer memory and configured to execute program instructions to: identifying a subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold; dividing the subset of subjects between a first arm and a second arm on a randomized basis, wherein subjects in the first arm receive a combination of the first composition and the second composition and subjects in the second arm receive a combination of the first composition and a placebo for a second treatment period, for each respective subject in the subset of subjects, obtaining a corresponding second response set upon completion of the second treatment period, and evaluating each respective subject in the subset of subjects by comparing the corresponding second response set to: (a) the corresponding first set of baseline measurements for the respective subject and / or(b) an optional corresponding second set of baseline measurements obtained for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, thereby determining whether the combination of the first treatment and the second treatment of the first arm improves the one or more endpoints associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition.

64. The computing system of claim 63, wherein the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding first set of baseline measurements for the respective subject.

65. The computing system of claim 63, further comprising: obtaining the corresponding second set of baseline measurements for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, wherein: the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding second set of baseline measurements for the respective subject.

66. A non-transitory computer readable storage medium, wherein the non-transitory computer readable storage medium stores instructions, which when executed by a computer system, cause the computer system to perform a method for determining whether treatment with a combination of a first composition and a second composition improves one or more endpoints associated with a myeloproliferative neoplasm relative to monotherapy with the first composition, the method comprising: obtaining clinical data that involves a plurality of subjects that have the myeloproliferative neoplasm, wherein the clinical data includes and associates for each respective subject in the plurality of subjects (i) a corresponding first set of baseline measurements prior to treatment with the first composition for the myeloproliferative neoplasm and (ii) a corresponding first response set after a first treatment period with the first composition; identifying a subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold;dividing the subset of subjects between a first arm and a second arm on a randomized basis, wherein subjects in the first arm receive a combination of the first composition and the second composition and subjects in the second arm receive a combination of the first composition and a placebo for a second treatment period, for each respective subject in the subset of subjects, obtaining a corresponding second response set upon completion of the second treatment period, and evaluating each respective subject in the subset of subjects by comparing the corresponding second response set to: (a) the corresponding first set of baseline measurements for the respective subject and / or (b) an optional corresponding second set of baseline measurements obtained for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, thereby determining whether the combination of the first treatment and the second treatment of the first arm improves the one or more endpoints associated with the myeloproliferative neoplasm relative to the monotherapy with the first composition.

67. The non-transitory computer readable storage medium of claim 66, wherein the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding first set of baseline measurements for the respective subject.

68. The non-transitory computer readable storage medium of claim 66, further comprising: obtaining the corresponding second set of baseline measurements for the respective subject after division of the subset of subjects between the first arm and the second arm and prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo, wherein the evaluating each respective subject in the subset of subjects is performed by comparing the corresponding second response set to the corresponding second set of baseline measurements for the respective subject.

69. The method of any one of claims 4-6, wherein the threshold amount of spleen size reduction is a percentage between twenty-five percent and fifty percent relative to a secondbaseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements.

70. The method of any one of claims 4-6, wherein the threshold amount of spleen size reduction is at least thirty-five percent relative to a second baseline spleen volume measurement from a corresponding second set of baseline spleen volume measurements.

71. The method of claim 18, wherein the threshold percent spleen volume is between 15 percent and 35 percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements.

72. The method of claim 18, wherein the threshold percent spleen volume is 25 percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements.

73. The method of claim 22, wherein the threshold percent spleen volume is between 35 percent and 45 percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements.

74. The method of claim 22, wherein the threshold percent spleen volume is 35 percent relative to a second baseline spleen volume measurement in a corresponding second set of baseline spleen volume measurements.

75. The method of any one of claims 1-62, wherein an endpoint in the one or more endpoints is a secondary efficacy endpoint selected from the group consisting of SVR25, TSS30, SVR35, and TSS50, determined by comparing the corresponding second response set to a corresponding first set of baseline measurements prior to the treatment with the first composition and a corresponding second set of baseline measurements prior to treatment with the combination of the first composition and the second composition or the combination of the first composition and the placebo.

76. The method of any one of claims 1-62, further comprising, after the identifying the subset of subjects in the plurality of subjects that each satisfies a suboptimal response threshold and before the dividing the subset of subjects between the first arm and the second arm: for a first block in a plurality of blocks, limiting the subset of subjects such that the first block represents a proportion of subjects in the subset of subjects that is no greater than an enrollment threshold.

77. The method of claim 76, wherein the first block is a spleen size reduction of between 30% and 35%, and the enrollment threshold is 15%.

78. The method of any one of claims 1-62, wherein the endpoints are SVR25 and SVR35, wherein SVR25 is determined by comparing the corresponding second response set to a corresponding second set of baseline spleen volume measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition; wherein SVR35 is determined by comparing the corresponding second response set to a corresponding first set of baseline spleen volume measurements obtained for the respective subject prior to treatment with the first composition.

79. The method of any one of claims 1-62, wherein the endpoints are TSS30 and TSS50; wherein TSS30 are determined by comparing the corresponding second response set to a corresponding second set of baseline TSS measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition; wherein TSS50 are determined by comparing the corresponding second response set to a corresponding first set of baseline TSS measurements obtained for the respective subject prior to treatment with the first composition.

80. The method of any one of claims 1-62, wherein the endpoints are SVR25, SVR35, TSS30, and TSS50; wherein SVR25 and TSS30 are determined by comparing the corresponding second response set to a corresponding second set of baseline measurements obtained for the respective subject prior to treatment with the combination of the first composition and the second composition; wherein SVR35 and TSS50 are determined by comparing the corresponding second response set to a corresponding first set of baseline measurements obtained for the respective subject prior to treatment with the first composition.

Images