Compositions and methods for treating cancer

Abstract

The disclosure relates to methods of treating glioblastoma and other EGFR mediated cancers. For example, the disclosure related to methods of treating glioblastoma in a subject by administering a dose of Compound 1 between about 100 mg per day and about 260 mg per day.

Description

[0001] COMPOSITIONS AND METHODS FOR TREATING CANCER

[0002] CROSS-REFERENCES TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisonal Patent Application No. 63 / 602,976 filed on November 27, 2023, the disclosure of which is incorporated by reference herein in its entirety, including any drawings.

[0004] BACKGROUND

[0005] Glioblastoma (glioblastoma multiforme; GBM) accounts for most primary malignant brain tumors in adults. Amplification and mutation of the epidermal growth factor receptor (EGFR) gene is a signature genetic abnormality encountered in GBM (Sugawa, et al. (1990) Proc. Natl. Acad. Sci. SI 8602-8606; Ekstrand, et al. (1992) Proc. Natl. Acad. Sci. 89: 4309- 4313). A range of potential therapies that target EGFR or its mutant constitutively active form, AEGFR, including tyrosine kinase inhibitors (TKIs), monoclonal antibodies, vaccines, and RNA-based agents, are currently in development or in clinical trials for the treatment of GBM. However, to date their efficacy in the clinic has so far been limited by both upfront and acquired drug resistance (Taylor, et al. (2012) Curr. Cancer Drug Targets. 12:197-209). A major limitation is that current therapies such as erlotinib, lapatinib, gefitinib and afatinib are poorly brain penetrant (Razier, et al. (2010) Neuro-Oncology 12:95-103; Reardon, et al. (2015) Neuro-Oncology 17:430-439; Thiessen, et al. (2010) Cancer Chemother. Pharmacol. 65:353-361). Another limitation is that some subjects may not respond to therapy administered. The presence of a specific genetic alteration is often insufficient to predict efficacy to targeted therapies.

[0006] In view of the foregoing, there is an urgent need for treatment of glioblastoma and other cancers.

[0007] SUMMARY

[0008] The present embodiments are directed to methods of treating cancer. In some aspects, there is provided a method of treating a cancer, the method including administering to a subject having cancer a dose of Compound 1 : or pharmaceutically acceptable salt thereof, wherein the dose is between about 100 mg and about 260 mg. In embodiments, the dose is between about 160 mg and about 240 mg. In embodiments, the dose is about 160 mg. In embodiments, the dose is about 240 mg. In embodiments, the dose is between about 160 mg and about 240 mg per day.

[0009] In some aspects, there is provided a method of treating a cancer including (a) selecting a patient having a cancer comprising a wild type or mutant EGFR, a mutation that results in increased EGFR expression relative to a normal control, or an EGFR with an altered copy number, and (b) administering to the subject a dose of Compound 1 : or pharmaceutically acceptable salt thereof, wherein the dose is between about 100 mg and about 260 mg. In embodiments, the dose is between about 160 mg and about 240 mg. In embodiments, the dose is about 160 mg. In embodiments, the dose is about 240 mg. In embodiments, the dose is between about 160 mg and about 240 mg per day.

[0010] In embodiments, the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi’s sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, or prostate cancer. In embodiments, the cancer is glioma, astrocytoma or glioblastoma. In embodiments, the cancer is brain cancer. In embodiments, the brain cancer is glioblastoma multiforme.

[0011] In embodiments, the cancer comprises a wild type or mutant EGFR, a mutation that results in increased EGFR expression relative to a normal control, or an EGFR with an altered copy number. In embodiments, the cancer comprises a wild type EGFR. In embodiments, the cancer comprises a mutant EGFR. In embodiments, the cancer comprises a mutation that results in increased EGFR expression relative to a normal control. In embodiments, the cancer comprises an EGFR with an altered copy number. In embodiments, the altered copy number of EGFR is caused by amplification of the EGFR or by polysomy. In embodiments, the mutant EGFR comprises an extracellular domain mutation.

[0012] In embodiments, the dose is administered orally.

[0013] In embodiments, Compound 1 or pharmaceutically acceptable salt thereof is administered once daily. In embodiments, Compound 1 is administered twice daily.

[0014] In embodiments, Compound 1 or pharmaceutically acceptable salt thereof is administered for 1 day to about 40 days. In embodiments, Compound 1 or pharmaceutically acceptable salt thereof is administered for about 7 days to about 28 days.

[0015] In embodiments, the cancer is a metabolic responder. In embodiments, the method includes selecting a subject having a cancer which is a metabolic responder.

[0016] In some aspects, there is provided a unit dose comprising between about 80 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose includes a pharmaceutically acceptable excipient. In embedments, the unit dose is formulated for oral administration.

[0017] BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 is a graph showing plasma concentrations (ng / mL) of Compound 1 at the indicated timepoints after oral administration of Compound 1. Serial plasma PK samples were collected following single- and multiple-doses of Compound 1 administration over the dose range of 20 mg to 320 mg QD. The steady-state PK exposure of Compound 1 increased in a dose dependent manner. Steady-state PK exposures at doses of 160 mg QD and above exceeded the concentration at which 90% tumor growth inhibition was achieved in the GBM patient-derived orthotopic xenograft (PDOX) mouse model (effective concentration, Ceff).

[0019] DETAILED DESCRIPTION

[0020] The present disclosure is based, at least in part, on the discovery that a dose of Compound 1 or pharmaceutically acceptable salt thereof between about 100 mg and about 260 mg, for example between about 160 mg and about 240 mg, is efficacious for treatment of certain cancers (e.g., glioblastoma), while avoiding most serious side effects.

[0021] Gliomas are the most commonly occurring form of brain tumor, with glioblastoma multiforme (GBM) being most malignant form, causing 3^4% of all cancer-related deaths (Louis et al. (2007) Acta. Neuropathol. 114: 97-109.). The World Health Organization defines GBM as a grade IV cancer characterized as malignant, mitotically active, and predisposed to necrosis. GBM has a very poor prognosis with a 5-year survival rate of 4—5% with the median survival rate of GBM being 12.6 months (McLendon et al. (2003) Cancer. 98 : 1745-1748.). This can be attributed to unique treatment limitations such as a high average age of onset, tumor location, and poor current understandings of the tumor pathophysiology (Louis et al. (2007) Acta. Neuropathol. 114: 97-109). The standard current standard of care for GBM includes tumor resection with concurrent radiotherapy and chemotherapy and in recent years there have been few marked improvements that increase survival rates (Stewart, et al. (2002) Lancet. 359:1011-1018.).

[0022] The standard for GBM chemotherapy is temozolomide (TMZ), which is a brainpenetrant alkylating agent that methylates purines (A or G) in DNA and induces apoptosis (Stupp, et al. (2005) N. Engl. J. Med. 352:987-996). However, TMZ use has drawbacks in that significant risk arises from DNA damage in healthy cells and that GBM cells can rapidly develop resistance towards the drug (Carlsson, et al. (2014) EMBO. Mol. Med. 6: 1359- 1370).

[0023] Epidermal growth factor receptor (EGFR) is a member of the HER superfamily of receptor tyrosine kinases together with ERBB2, ERBB3, and ERBB4. A common driver of GBM progression is EGFR amplification (amp), which is found in nearly 40% of all GBM cases (Hynes et al. (2005) Nat. Rev. Cancer. 5: 341-354; Hatanpaa et al. (2010) Neoplasia. 12 :675-684). Additionally, EGFR amplification is associated with the presence of EGFR protein variants: in 68% of EGFR mutants, there is a deletion in the N-terminal ligandbinding region between amino acids 6 and 273. These deletions in the ligand-binding domains of EGFR can lead to ligand-independent activation of EGFR (Y amazaki et al. (1990) Jpn. J. Cancer Res. 81: 773-779.).

[0024] Small molecule tyrosine kinase inhibitors (TKIs) are the most clinically advanced of the EGFR-targeted therapies, and both reversible and irreversible inhibitors are in clinical trials. Examples of the reversible inhibitors and irreversible inhibitors include erlotinib, gefitinib, lapatinib, PKI166, canertinib and pelitinib (Mischel et al. (2003) Brain Pathol. 13: 52-61). Mechanistically, these TKIs compete with ATP for binding to the tyrosine kinase domain of EGFR; however, these EGFR-specific tyrosine kinase inhibitors have been relatively ineffective against gliomas, with response rates only reaching as high as 25% in the case of erlotinib (Mischel et al. (2003) Brain Pathol. 13: 52-61; Gan et al. (2009) J. Clin. Neurosci. 16: 748-54). Although TKIs are well tolerated and display some antitumor activity in GBM patients, the recurrent problem of resistance to receptor inhibition limits their efficacy (Learn et al. (2004) Clin. Cancer. Res. 10: 3216-3224; Rich et al. (2004) Nat. Rev. DrugDiscov. 3: 430-446). Additionally, recent studies have shown that brain plasma concentrations of gefitinib and erlotinib following therapy were only 6-11% of the starting dose, suggesting that these compounds may be failing to cross the blood-brain barrier as illustrated in table 1 (Karpel-Massler et al. (2009) Mol. Cancer Res. 7 : 1000-1012). Thus, insufficient delivery to the target may be another cause of the disappointing clinical results.

[0025] It is demonstrated herein that a dose of Compound 1 between about 100 mg and about 260 mg, e.g. between about 160 mg and about 240 mg, is efficacious for treatment of cancer (e.g., glioblastoma). It is contemplated that a dose of Compound 1 between about 100 mg and about 260 mg, e.g. between about 160 mg and about 240 mg will provide treatment of the cancer while minimizing toxicity to the subject.

[0026] Definitions

[0027] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.

[0028] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0029] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985). All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0030] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known and those agents whose structure is not known.

[0031] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0032] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0033] “Administering” or “administration of’ a substance, a compound, or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, or transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. Appropriate methods of administering a substance, a compound, or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow-release formulation or administered using a device for such slow or extended release.

[0034] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer (e.g., a glioblastoma). The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0035] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “an optionally substituted alkyl” refers to a molecule or compound in which an alkyl may be substituted as well as where the alkyl is not substituted.

[0036] The term “modulate” as used herein includes the inhibition or suppression of a fimction or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0037] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term is used to describe compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0038] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt that is suitable for or compatible with the treatment of patients. Where Compound 1 is referred to herein, it is to be understood that a pharmaceutically acceptable salt of Compound 1 is also contemplated. The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of Compound 1. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfiiric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of Compound 1 are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of Compound 1 for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0039] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of Compound 1 or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

[0040] “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., Compound 1). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a fimctional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751; 7,585,851; and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce Compound 1. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0041] The terms “Log of solubility,” “LogS,” or “logS” are used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter.

[0042] Types and stages of Gliomas

[0043] Primary malignant brain tumors are tumors that start in the brain or spine and are known collectively as gliomas. Gliomas are not a specific type of cancer but rather a term used to describe tumors that originate in glial cells. Examples of primary malignant brain tumors include astrocytomas, pilocytic astrocytomas, pleomorphic xanthoastrocytomas, diffuse astrocytomas, anaplastic astrocytomas, glioblastoma multiformes (GBMs), gangliogliomas, oligodendrogliomas, ependymomas. According to the WHO classification of brain tumors, astrocytomas have been categorized into four grades, determined by the underlying pathology. The characteristics that are used to classify gliomas include mitoses, cellular or nuclear atypia, and vascular proliferation and necrosis with pseudopalisading features. Malignant (or high-grade) gliomas include anaplastic glioma (WHO grade III) as well as glioblastoma multiforme (GBM; WHO grade IV). These are the most aggressive brain tumors with the worst prognosis.

[0044] GBMs is the most common, complex, treatment resistant, and deadliest type of brain cancer, accounting for 45% of all brain cancers, with nearly 11,000 men, women, and children diagnosed each year. GBM (also known as grade-4 astrocytoma and glioblastoma multiforme) are the most common types of malignant (cancerous) primary brain tumors. They are extremely aggressive for a number of reasons. First, glioblastoma cells multiply quickly, as they secrete substances that stimulate a rich blood supply. They also have an ability to invade and infiltrate long distances into the normal brain by sending microscopic tendrils of tumor alongside normal cells. Two types of glioblastomas are known. Primary GBM are the most common form; they grow quickly and often cause symptoms early. Secondary glioblastomas are less common, accounting for about 10 percent of all GBMs. They progress from low-grade diffuse astrocytoma or anaplastic astrocytoma and are more often found in younger patients. Secondary GBMs are generally located in the frontal lobe and carry a better prognosis.

[0045] GBM is usually treated by combined multi-modal treatment plan including surgical removal of the tumor, radiation, and chemotherapy. First, as much tumor as possible is removed during surgery. The tumor’s location in the brain often determines how much of it can be safely removed. After surgery, radiation and chemotherapy slow the growth of remaining tumor cells. The oral chemotherapy drug, temozolomide, is most often used for six weeks, and then monthly thereafter. Another drug, bevacizumab (Avastin®), is also used during treatment. This drug attacks the tumor’s ability to recruit blood supply, often slowing or even stopping tumor growth.

[0046] Novel investigational treatments are also used and these may involve adding treatments to the standard therapy or replacing one part of the standard therapy with a different treatment that may work better. Some of these treatments include immunotherapy such as vaccine immunotherapies, or low-dose pulses of electricity to the area of the brain where the tumor exists and nano therapies involving spherical nucleic acids (SNAs), such as NU-0129. In some embodiments, the methods of the current disclosure are used in combination with one or more of the aforementioned therapies.

[0047] Embodiments of the methods and compositions discussed herein are also contemplated to be applicable to other types of cancers including, but not limited to, lung cancer, non-CNS cancers, CNS cancers, and CNS metastases, such as brain metastases, leptomeningeal metastases, choroidal metastases, spinal cord metastases, and others.

[0048] Methods of Treatment

[0049] In one aspect of the present disclosure, a method is provided for a method of treating a cancer, the method including administering to a subject having cancer a dose of Compound 1: or pharmaceutically acceptable salt thereof, wherein the dose is between about 100 mg and about 260 mg. In embodiments, the dose is between about 160 mg and about 240 mg. In embodiments, the dose is about 160 mg. In embodiments, the dose is about 240 mg. In embodiments, the dose is between about 160 mg and about 240 mg per day.

[0050] In some aspects, there is provided a method of treating a cancer including (a) selecting a patient having a cancer comprising a wild type or mutant EGFR, a mutation that results in increased EGFR expression relative to a normal control, or an EGFR with an altered copy number, and (b) administering to the subject a dose of Compound 1 : or pharmaceutically acceptable salt thereof, wherein the dose is between about 100 mg and about 260 mg. In embodiments, the dose is between about 160 mg and about 240 mg. In embodiments, the dose is about 160 mg. In embodiments, the dose is about 240 mg. In embodiments, the dose is between about 160 mg and about 240 mg per day.

[0051] In embodiments, the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi’s sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, or prostate cancer. In embodiments, the cancer is glioma, astrocytoma or glioblastoma. In embodiments, the cancer is brain cancer. In embodiments, the brain cancer is glioblastoma multiforme.

[0052] In embodiments, the cancer comprises a wild type or mutant EGFR, a mutation that results in increased EGFR expression relative to a normal control, or an EGFR with an altered copy number. In embodiments, the cancer comprises a wild type EGFR. In embodiments, the cancer comprises a mutant EGFR. In embodiments, the cancer comprises a mutation that results in increased EGFR expression relative to a normal control. In embodiments, the cancer comprises an EGFR with an altered copy number. In embodiments, the altered copy number of EGFR is caused by amplification of the EGFR or by polysomy. In embodiments, the mutant EGFR comprises an extracellular domain mutation.

[0053] In embodiments, the dose is administered orally. In embodiments, Compound 1 or pharmaceutically acceptable salt thereof is administered once daily. In embodiments, Compound 1 is administered twice daily.

[0054] In embodiments, Compound 1 or pharmaceutically acceptable salt thereof is administered for 1 day to about 40 days. In embodiments, Compound 1 or pharmaceutically acceptable salt thereof is administered for about 7 days to about 28 days.

[0055] In embodiments, the cancer is a metabolic responder. In embodiments, the method includes selecting a subject having a cancer which is a metabolic responder. Pharmaceutical Dosing

[0056] The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A clinical practitioner can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disease or disorder.

[0057] The daily oral dosage of Compound 1 (or pharmaceutically acceptable salt thereof), when used for the indicated effects, will range between about 100 mg to about 260 mg. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 110 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 120 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 130 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 140 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 150 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 160 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 170 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 180 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 190 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 200 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 210 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 220 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 230 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 240 mg / day and about 260 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 250 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 240 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 230 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 220 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 210 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 200 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 190 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 180 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 170 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 100 mg / day and about 160 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 150 mg / day and about 250 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 160 mg / day and about 250 mg / day. In embodiments, Compound 1 may be administered at a dose of between about 160 mg / day and about 240 mg / day.

[0058] In embodiments, Compound 1 (or pharmaceutically acceptable salt thereof) may be administered at a dose of about 100 mg / day. In embodiments, Compound 1 may be administered at a dose of about 105 mg / day. In embodiments, Compound 1 may be administered at a dose of about 1 lOmg / day. In embodiments, Compound 1 may be administered at a dose of about 115 mg / day. In embodiments, Compound 1 may be administered at a dose of about 120 mg / day. In embodiments, Compound 1 may be administered at a dose of about 125 mg / day. In embodiments, Compound 1 may be administered at a dose of about 130 mg / day. In embodiments, Compound 1 may be administered at a dose of about 135 mg / day. In embodiments, Compound 1 may be administered at a dose of about 140 mg / day. In embodiments, Compound 1 may be administered at a dose of about 145 mg / day. In embodiments, Compound 1 may be administered at a dose of about 150 mg / day. In embodiments, Compound 1 may be administered at a dose of about 155 mg / day.In embodiments, Compound 1 may be administered at a dose of about 160 mg / day. In embodiments, Compound 1 may be administered at a dose of about 165 mg / day. In embodiments, Compound 1 may be administered at a dose of about 170 mg / day. In embodiments, Compound 1 may be administered at a dose of about 175 mg / day. In embodiments, Compound 1 may be administered at a dose of about 180 mg / day. In embodiments, Compound 1 may be administered at a dose of about 185 mg / day. In embodiments, Compound 1 may be administered at a dose of about 190 mg / day. In embodiments, Compound 1 may be administered at a dose of about 195 mg / day. In embodiments, Compound 1 may be administered at a dose of about 200 mg / day. In embodiments, Compound 1 may be administered at a dose of about 205 mg / day. In embodiments, Compound 1 may be administered at a dose of about 210 mg / day. In embodiments, Compound 1 may be administered at a dose of about 215 mg / day. In embodiments, Compound 1 may be administered at a dose of about 220 mg / day. In embodiments, Compound 1 may be administered at a dose of about 225 mg / day. In embodiments, Compound 1 may be administered at a dose of about 230 mg / day. In embodiments, Compound 1 may be administered at a dose of about 235 mg / day. In embodiments, Compound 1 may be administered at a dose of about 240 mg / day. In embodiments, Compound 1 may be administered at a dose of about 245 mg / day. In embodiments, Compound 1 may be administered at a dose of about 250 mg / day. In embodiments, Compound 1 may be administered at a dose of about 255 mg / day. In embodiments, Compound 1 may be administered at a dose of about 260 mg / day. The dose may be any value or subrange within the recited ranges, including endpoints, and fractional amounts as well.

[0059] Depending on the patient’s condition and the intended therapeutic effect, the dosing frequency for Compound 1 (or pharmaceutically acceptable salt thereof) may vary, for example, from once per day to six times per day. That is, the dosing frequency may be QD, i.e., once per day, BID, i.e., twice per day; TID, i.e., three times per day; QID, i.e., four times per day; five times per day, or six times per day. In another embodiment, dosing frequency may be BIW, i.e., twice weekly, TIW, i.e., three times a week, or QIW, i.e. four times a week. In embodiments, dosing frequency is once per day. In embodiments, dosing frequency is twice per day.

[0060] Depending on the patient’s condition and the intended therapeutic effect, the treatment cycle may have a period of time where no therapeutic agent (Compound 1) is administered. As used herein, “interval administration” refers to administration of the therapeutic agent followed by void days or void weeks. For example, the treatment cycle may be 3 weeks long which includes 2 weeks of dosing of the therapeutic agent(s) followed by 1 week where no therapeutic agent is administered. In some embodiments, the treatment cycle is 4 weeks long which includes 3 weeks of dosing followed by 1 week where no therapeutic agent is administered. In some embodiments, the treatment cycle is 5 weeks long which includes 4 weeks of dosing followed by 1 week where no therapeutic agent is administered.

[0061] The term “treatment cycle” as used herein, means a pre-determined period of time for administering the therapeutic agent. Typically, the patient is examined at the end of each treatment cycle to evaluate the effect of the therapy.

[0062] In one embodiment, each of the treatment cycle has about 3 or more days. In another embodiment, each of the treatment cycle has from about 3 days to about 60 days. In another embodiment, each of the treatment cycle has from about 5 days to about 50 days. In another embodiment, each of the treatment cycle has from about 7 days to about 28 days. In another embodiment, each of the treatment cycle has 28 days. In one embodiment, the treatment cycle has about 29 days. In another embodiment, the treatment cycle has about 30 days. In another embodiment, the treatment cycle has about 31 days. In another embodiment, the treatment cycle has about a month-long treatment cycle. In another embodiment, the treatment cycle is any length of time from 3 weeks to 8 weeks. In another embodiment, the treatment cycle is any length of time from 3 weeks to 6 weeks. In yet another embodiment, the treatment cycle is 3 weeks. In another embodiment, the treatment cycle is one month. In another embodiment, the treatment cycle is 4 weeks. In another embodiment, the treatment cycle is 5 weeks. In another embodiment, the treatment cycle is 6 weeks. In another embodiment, the treatment cycle is 7 weeks. In another embodiment, the treatment cycle is 8 weeks. The duration of the treatment cycle may include any value or subrange within the recited ranges, including endpoints.

[0063] As used herein, the term “co-administration” or “coadministration” refers to administration of (a) an additional therapeutic agent and (b) Compound 1, or a salt, solvate, ester and / or prodrug thereof, together in a coordinated fashion. For example, the coadministration can be simultaneous administration, sequential administration, overlapping administration, interval administration, continuous administration, or a combination thereof. In embodiments, the dosing regimen for Compound 1 is once daily over a continuous 28-day cycle. In embodiments, the dosing regimen for Compound 1 is twice daily over a continuous 28-day cycle.

[0064] In embodiments, the dosing regimen for Compound 1 may be once daily, anywhere from 100 mg to 260 mg per day for two weeks, followed by a one week break over a period of 6 weeks (e.g. 2 weeks on, 1 week off). In embodiments, the dosing regimen for Compound 1 may be twice daily, anywhere from 50 mg to 130 mg twice a day for two weeks, followed by a one week break over a period of 6 weeks (e.g. 2 weeks on, 1 week off).

[0065] In embodiments, the dosing regimen for Compound 1 may be once daily, anywhere from 100 mg to 260 mg per day for three weeks, followed by a one week break over a period of 8 weeks (e.g. 3 weeks on, 1 week off). In embodiments, the dosing regimen for Compound 1 may be twice daily, anywhere from 50 mg to 130 mg twice a day for three weeks, followed by a one week break over a period of 8 weeks (e.g. 8 weeks on, 1 week off).

[0066] When Compound 1 is administered multiple times a week, the dose may be administered on any day or combination of days within the week. For example, administration three times per week may include administration on days 1, 3, and 5; days 1, 2, and 3; 1, 3, and 5; and so on. Administration two days per week may include administration on days 1 and 2; days 1 and 3; days 1 and 4; days 1 and 5; days 1 and 6; days 1 and 7; and so on.

[0067] Predictive Medicine

[0068] One aspect of the present embodiments relates to seletion of a subject for treatment using diagnostic assays for determining the amount and / or activity level of a metabolic process described herein in the context of a glioblastoma to thereby determine whether an individual afflicted with a glioblastoma is likely to respond to inhibitors of one or more metabolic process. Such assays can be used for prognostic or predictive purpose alone, or can be coupled with a therapeutic intervention to thereby prophylactically treat an individual prior to the onset or after recurrence of a glioblastoma. In some aspects the predictive or diagnostic assays can be conducted at the outset of a treatment with an inhibitor, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or within 1 week, 2 weeks, 3 weeks or 4 weeks of initially administering the inhibitor. In some aspects, the predictive or diagnostic assays are conducted without assessing impact of the inhibitor on tumor volume, for example. In some instances both predictive and diagnostic assays for metabolism are assessed and tumor volume also is assessed. Another aspect of the present embodiments pertains to monitoring the influence of agents (e.g., drugs, compounds, and small nucleic acid-based molecules) on the expression or activity of a glioblastoma. For example, imaging of a glioblastoma (e.g., magnetic resonance imaging (MRI)) during a course of treatment to determine changes in tumor volume during the course of treatment. In some embodiments, a first image of the glioblastoma is acquired at or near the time treatment is commenced, and the tumor volume determined from this first image serves as a reference to which later-acquired images can be compared. A reduction in tumor volume during the course of treatment indicate a positive therapeutic response to the selected treatment. The present invention provides for both prophylactic and therapeutic methods of preventing and / or treating glioblastoma that would benefit from a decrease in at least one metabolic process (e.g., glucose metabolism) and an early determination of the effectiveness of such an inhibitor. In some embodiments, which includes both prophylactic and therapeutic methods, the agent is administered in a pharmaceutically acceptable formulation.

[0069] One method of selecting a subject with glioblastoma for treatment includes use of a metabolic assay to determine whether the glioblastoma is a metabolic responder. For example, a method of treating a glioblastoma, the method comprising administering to a subject in need thereof a first dose of an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), administering to the subject a detectably labeled substrate for a metabolic process, measuring an amount of the detectably labeled substrate in the glioblastoma after administering the EGFR TKI, wherein a decrease in the amount of detectably labeled substrate relative to a reference level indicates that the glioblastoma is a metabolic responder to the inhibitor; and if the glioblastoma is identified as a metabolic responder, treating the subject with the metabolic process inhibitor for a period of time and imaging the glioblastoma to assess a change tumor volume over the period of time, wherein a decrease in tumor volume identifies the inhibitor as an effective treatment for the glioblastoma.

[0070] Non-limiting examples of methods for selecting a patient can be found in WO 2022 / 061299, which is incorporated herein by reference in its entirety.

[0071] Pharmaceutical Compositions

[0072] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection, or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0073] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0074] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0075] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0076] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0077] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0078] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0079] Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0080] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0081] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), or a surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0082] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0083] Liquid dosage forms usefiil for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofiiryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

[0084] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0085] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0086] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0087] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0088] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0089] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0090] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection, and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0091] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0092] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifimgal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0093] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0094] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0095] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0096] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0097] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt, or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0098] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0099] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0100] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0101] The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.

[0102] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.

[0103] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxy-2 -naphthoic acid, 2,2-dichloroacetic acid, 2 -hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fiunaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1-malic acid, malonic acid, mandelic acid, methanesulfonic acid , naphthalene- 1,5 -disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, 1- pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfiiric acid, 1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid acid salts.

[0104] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0105] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the compositions.

[0106] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0107] In some aspects, there is provided a unit dose comprising between about 50 mg and about 260 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 50 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 50 mg and about 120 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 80 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 80 mg and about 260 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 100 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 110 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 120 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 130 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 140 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 150 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 160 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 170 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 180 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 190 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 200 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 210 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 220 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 230 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof. In embodiments, the unit dose comprises between about 230 mg and about 250 mg of Compound 1 or pharmaceutically acceptable salt thereof. The dose may be any value or subrange within the recited ranges, including endpoints.

[0108] In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 50 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof at about 60 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 70 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 80 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 90 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 100 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 110 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 120 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 130 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 140 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 150 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 160 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 165 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 170 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 175 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 180 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 185 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 190 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 195 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 200 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 210 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 215 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 220 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 225 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 230 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 235 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about240 50 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 245 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 250 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 255 mg. In embodiments, the unit dose comprises Compound 1 (or pharmaceutically acceptable salt thereof) at about 260 mg.

[0109] In embodiments, the unit dose includes a pharmaceutically acceptable excipient. In embedments, the unit dose is formulated for oral administration. In embedments, the unit dose is formulated for administration once a day. In embedments, the unit dose is formulated for administration twice a day.

[0110] EXAMPLES

[0111] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

[0112] Example 1: Clinical Trial

[0113] This is a Phase 1, open-label, multicenter clinical study to evaluate the safety and tolerability of escalating doses of Compound 1 in study participants with recurrent glioblastoma multiforme (GBM) harboring mutations within epidermal growth factor receptor (EGFRm). These mutations may include EGFR gene amplification and alterations in the extracellular domain. The study initially commenced with dose escalation of Compound 1. Once the Maximum Tolerated Dose (MTD) and / or Recommended Dose (RD) has been determined from dose escalation, then dose expansion of Compound 1 may commence within the same patient population. Antitumor activity and pK profile of Compound 1 will also be determined.

[0114] In Part 1 of the study, Compound 1 was orally administered to study participants with EGFRm GBM in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent. Compound 1 was administered once daily for 28 days.

[0115] Primary outcomes measured include Dose Limiting Toxicities (DLT), MTD and RD were determined based on adverse events observed during dose escalation; and Adverse Events (AEs). Secondary outcomes measured or to be measured include: plasma concentration (Cmax, Maximum plasma or serum concentration of Compound 1) at Study Day 1 up to Day 29; time to achieve Cmax (Tmax) at Study Day 1 up to Day 29; area under the curve (Area under the plasma concentration-time curve of Compound 1) at Study Day 1 up to Day 29; half-life of Compound 1 at Study Day 1 up to Day 29; Objective Response Rate (ORR) based on assessment of radiographic imaging per modified RANO response assessment, assessed up to 24 months from time of first dose; Duration of Response (DOR) based on assessment of radiographic imaging per modified RANO response assessment, assessed up to 24 months from time of first dose; Time to Response (TTR) based on assessment of radiographic imaging per modified RANO response assessment, assessed up to 24 months from time of first dose.

[0116] Inclusion Criteria:

[0117] • Age > 18 years

[0118] • Willing and able to give written informed consent

[0119] • Diagnosis of Glioblastoma, IDH WT as defined by the WHO 2021 criteria

[0120] • Adequate organ function

[0121] • Willing to comply with all protocol-required visits, assessments, and procedures

[0122] • Able to swallow oral medication

[0123] Exclusion Criteria:

[0124] • Prior treatment with an EGFR inhibitor for Glioblastoma

[0125] • Currently enrolled in another therapeutic study

[0126] • History of clinically significant cardiovascular disease

[0127] • Gastrointestinal conditions that may affect administration / absorption of oral medications

[0128] • Have an active infection (bacterial, fungal, or viral) requiring systemic therapy

[0129] • Pregnant or breastfeeding women

[0130] • Any serious underlying medical or psychiatric condition or evidence of any other significant clinical disorder or laboratory finding that renders the patient inappropriate to participate in the study

[0131] • Known allergies, hypersensitivity, or intolerance to Compound 1 or its excipients

[0132] Example 2: Results and Maximum Tolerated Dose

[0133] A total of eight patients enrolled at 240mg QD. Six out of eight patients were deemed DLT-evaluable (two patients were deemed non-DLT evaluable due to not receiving at least 75% of study treatment).

[0134] One patient experienced G3 QTc, which was deemed a DLT. There were no DLTs observed in the other seven patients. SAE Grade 3 Dermatitis acneiform was observed in one patient. Overall treatment related AEs (TRAEs) experienced in two or more patients include: Dermatitis acneiform, Rash, maculo-popular Diarrhea, Nausea, Platelet count decreased / Thrombocytopenia, Electrocardiogram QT prolonged, Blood creatinine increased, Lymphocyte count decreased. Six out of eight patients receiving 240 mg QD experienced skin toxicity.

[0135] There were two DLTs observed at the 320mg QD cohort (QTcF prolongation >60ms from baseline and Grade 3 rash). There were three DLTs observed at the 280mg QD cohort (QTcF prolongation >60ms from baseline).

[0136] The MTD for Compound 1 was identified as 240 mg QD.

[0137] Serial plasma PK samples were collected following single- and multiple-doses of Compound 1 administration over the dose range of 20 mg to 320 mg QD. As shown in FIG. 1 , the steady-state PK exposure of Compound 1 increased in a dose dependent manner. A lower dose within the efficactious range was identified as 160 mg QD. Steady-state PK exposures at doses of 160 mg QD and above exceeded the concentration at which 90% tumor growth inhibition was achieved in the GBM patient-derived orthotopic xenograft (PDOX) mouse model. Dosages of 160 mg QD and 240 mg QD are selected for further evaluation in the dose expansion phase of the FIH study.

[0138] Compound 1 has an acceptable safety profile based upon observed safety findings at MTD (240 mg) and 160 mg dose levels, consistent with the mechanism of action and non- clinical findings. Compound 1 exhibited well behaved pharmacokinetic (PK) characteristics: Compound 1 showed rapid absorption and had dose-dependent increases in PK exposure. Steady-state PK exposures at doses of 160 mg QD and above exceeded the concentration at which 90% tumor growth inhibition was achieved in the GBM patient-derived orthotopic xenograft (PDOX) mouse model. Steady state Tmaxvalues ranged from 2 - 6 h. Compound 1 accumulation ratio is approximately 3, consistent with terminal half life (ti / 2) > 30 h. Compound 1 plasma Cmaxand AUC0-24 increase with dose in a dose dependent manner from 20 mg QD to 320 mg QD.

[0139] Expansion cohorts at both 240 mg and 160 mg are open to enrollment for patients with GBM harboring EGFR amplifications to ensure identification of a Compound 1 dose with the optimal risk / benefit profile (including further evaluation of safety and efficacy in patients with EGFR amplified GBM), and in accordance keeping with guidance from the FDA initiative Project Optimus, which is designed to improve dose optimization and selection in oncology to maximize efficacy, safety, and tolerability. INCORPORATION BY REFERENCE

[0140] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0141] EQUIVALENTS

[0142] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations

Claims

WE CLAIM:

1. A method of treating a cancer, the method comprising administering to a subject having cancer a dose of Compound 1 :or pharmaceutically acceptable salt thereof, wherein the dose is between about 160 mg and about 240 mg.

2. The method of claim 1 , wherein the cancer comprises a wild type or mutant EGFR, a mutation that results in increased EGFR expression relative to a normal control, or an EGFR with an altered copy number.

3. A method of treating a cancer, the method comprising (a) selecting a patient having a cancer comprising a wild type or mutant EGFR, a mutation that results in increased EGFR expression relative to a normal control, or an EGFR with an altered copy number, and (b) administering to the subject a dose of Compound 1 :or pharmaceutically acceptable salt thereof, wherein the dose is between about 160 mg and about 240 mg.

4. The method of any one of the above claims, wherein the cancer is bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi’s sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer,testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, or prostate cancer.

5. The method of claim 4, wherein the cancer is glioma, astrocytoma or glioblastoma.

6. The method of claim 5, wherein the brain cancer is glioblastoma multiforme.

7. The method of any one of the above claims, wherein the altered copy number of EGFR is caused by amplification of the EGFR or by polysomy.

8. The method of any one of the above claims, wherein the mutant EGFR comprises an extracellular domain mutation.

9. The method of any one of claims 1 -8, wherein the dose is administered orally.

10. The method of any one of claims 1 -9, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered once daily.

11. The method of any one of claims 1 -9, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered twice daily.

12. The method of any one of claims 1-11, wherein Compound 1 or pharmaceutically acceptable salt thereof is administered for 1 day to about 40 days.

13. The method of claim 12, where Compound 1 or pharmaceutically acceptable salt thereof is administered for about 7 days to about 28 days.

14. The method of any one of the above claims, wherein the subject is a mammal.

15. The method of any one of the above claims, wherein the subject is human.

16. The method of any one of the above claims, wherein the cancer is a metabolic responder.

17. The method of any one of the above claims, comprising selecting a subject having a cancer which is a metabolic responder.

18. A unit dose comprising between about 80 mg and about 240 mg of Compound 1 or pharmaceutically acceptable salt thereof.

19. The unit dose of claim 18, farther comprising a pharmaceutically acceptable excipient.

20. The unit dose of claim 18 or 19 which is formulated for oral administration.

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