WO2016109426A1

WO2016109426A1 - Oral dosing regimen of a dual mtor and pi3 inhibitor

Info

Publication number: WO2016109426A1
Application number: PCT/US2015/067671
Authority: WO
Inventors: Mahesh Padval
Original assignee: Verastem, Inc.
Priority date: 2014-12-29
Filing date: 2015-12-28
Publication date: 2016-07-07

Abstract

The present invention relates to a method of treating a human subject having cancer, the method comprising administering to the subject a course of treatment comprising three (e.g., three, five) administrations of a compound of Formula (I) over a seven day period, wherein the compound is administered on days 1, 3, and 5 (e.g., 1, 3, and 5; 1, 2, 3, 4, and 5) of the seven day period, thereby treating the subject.

Description

ORAL DOSING REGIMEN OF A DUAL MTOR AND PI3 INHIBITOR

RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, U.S. S.N. 62/097,394, filed December 29, 2014, which is incorporated herein by reference in its entirety.

BACKGROUND OF INVENTION

mTOR and PI3K have been identified as protein kinases that are involved in a number of disorders, and compounds that target one or more of these kinases should display useful biological activity. Accordingly, compounds that are mTOR or PI3K inhibitors have the potential to provide further biologically active compounds that would be expected to have useful, improved pharmaceutical properties in the treatment of proliferative disorders such as cancer, immune and inflammatory diseases, diseases supported by excessive neovascularisation and organ transplant rejection.

Compounds that inhibit both mTOR and PI3K simultaneously may be expected to provide powerful anti-proliferative, anti- angiogenic and anti-tumor activity since these compounds may act at multiple points in the P13K/Akt/mTOR pathway. A number of inhibitors of this type are now being investigated in a clinical setting (e.g. , VS-5584, BEZ235, XL765, GDC0941, PX866, SF1126). Recently, PCT/SG2008/000379 and PCT/SG2009/000124 described 2-(morpholin-4-yl), 6-(pyrimidin-5-yl) substituted purine compounds that may be useful for the use in the treatment of certain kinase related disorders/conditions.

Described herein are methods of treating a subject, e.g. , a subject having cancer, with a compound that may inhibit both mTOR and PI3K. SUMMARY OF INVENTION

The present invention describes, in one aspect, a method of treating a human subject having cancer, the method comprising administering to the subject a course of treatment comprising three administrations of a compound of Formula (I) over a seven day period, wherein the compound is administered on days 1, 3, and 5 of the seven day period, thereby treating the subject.

In some embodiments, the administrations are delivered orally.

In some embodiments, the method comprises a plurality of courses of treatment. In some embodiments, the method comprises two courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, and 12). In some embodiments, the method comprises three courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, 12, 15, 17, and 19). In some embodiments, the method comprises six courses of treatment (e.g. , on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33, 36, 38, and 40).

In another aspect, described herein is a method of treating a human subject having cancer, the method comprising administering to the subject a course of treatment comprising five administrations of a compound of Formula (I) over a seven day period, wherein the compound is administered on days 1, 2, 3, 4, and 5 of the seven day period, thereby treating the subject.

In some embodiments, the administrations are delivered orally.

In some embodiments, the method comprises a plurality of courses of treatment. In some embodiments, the method comprises two courses of treatment (e.g., administrations on days 1, 2, 3, 4, 5, 8, 9, 10, 11, and 12). In some embodiments, the method comprises three courses of treatment (e.g., administrations on days 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 22, 23, 24, 25 and 26).

In some embodiments, the cancer is an advanced non-hematologic malignancy or lymphoma (e.g. , malignant lymphoma, FDG-avid lymphoma, FDG-avidity unknown, diffuse large B-cell lymphoma [DLBCL], Hodgkin's lymphoma, follicular lymphoma, mantle-cell lymphoma; large-cell lymphoma, small neoplastic B cell lymphoma, pulmonary lymphoma).

In some embodiments, the oral dosage form is a capsule (e.g. , a 5 mg, 10 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 100 mg, 200 mg or more capsule). In some embodiments, the oral dosage form comprises about 5 to 70%, about 10 to 50%, or about 10 to 40% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered at least 1, 2.5, 5, 10, or 20 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, daily (e.g., once daily). In some embodiments, the subject is administered from about 0.5 to about 50 mg (e.g., about 0.5 to about 30 mg, about 0.5 to about 20 mg, about 0.5 to about 10 mg, about 0.5 to about 5 mg, about 0.5 to about 1 mg, about 0.75 to about 30 mg, about 0.75 to about 20 mg, about 0.75 to about 10 mg, about 0.75 to about 5 mg, about 0.75 to about 1 mg, about 1 to about 25 mg, about 1 to about 20 mg, about 1 to about 10 mg, about 1 to about 5 mg, about 1 to about 2.5 mg) of compound daily (e.g., once daily).

In some embodiments, the duration of the course of treatment is at least 21 days.

In some embodiments, each administration occurs as in a single dose.

In some embodiments, the subject has failed (e.g. , relapsed from, insensitive to, received no or little benefit from) conventional or standard cancer treatment (e.g. , surgery, first-line therapy for cancer). In some embodiments, the subject has failed (e.g. , relapsed from, insensitive to, received no or little benefit from) first- line treatment (e.g. , first- line therapy for cancer).

In some embodiments, the method further comprises administration of an additional agent (e.g. , therapeutic agent, drug). In some embodiments, the additional agent is selected from a chemotherapeutic agent, an anti-inflammatory agent, an immunotherapy, an analgesic agent, a FAK inhibitor, a targeted therapy, or an antiemetic agent. In some embodiments, the additional agent is a FAK inhibitor (e.g., a FAK inhibitor described herein). In some embodiments, the additional agent is a first or second line therapy for cancer.

In some embodiments, the course of treatment is administered (e.g. , about 5, 15, 30, 60 minutes; about 1, 2, 3, 5, 6, 8, 10, 12, 15, 18, 20 hours; about 1, 2, 3, 4, 5, 6 days; about 1, 2, 3, 4 weeks) before the administration of the additional agent.

In some embodiments, the course of treatment is administered (e.g. , about 5, 15, 30, 60 minutes; about 1, 2, 3, 5, 6, 8, 10, 12, 15, 18, 20 hours; about 1, 2, 3, 4, 5, 6 days; about 1, 2, 3, 4 weeks) after the administration of the oral dosage form comprising a compound of Formula (I).

In some embodiments, the first or second line therapy comprises administering multiple therapeutic agents (e.g. , a combination of therapeutic agents).

In some embodiments, the duration of the method is at least 4, 5, 6 weeks; 1, 2, 3, 4, 5, 6 months (e.g. , 6 weeks).

In some embodiments, the method further comprises an additional course of treatment (e.g., administrations on days 1, 3, and 5). In some embodiments, the method further comprises an additional two courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, and 12). In some embodiments, the method further comprises an additional three courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, 12, 15, 17, and 19). In some embodiments, the administration is performed by self-administration (e.g., outside the clinic).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts exemplary effects of the compound of Formula (I) on animal body weight. Figure 2 depicts exemplary effects of the compound of Formula (I) on tumor volume.

Figure 3 depicts exemplary effects of the compound of Formula (I) on tumor weight.

Figure 4 depicts exemplary effects of the vehicle control and cisplatin/etoposide treatment on tumor weight.

Figure 5 depicts exemplary effects of the vehicle control and cisplatin/etoposide treatment on body weight.

Figure 6 depicts exemplary effects of the vehicle control, cisplatin/etoposide, and

cisplatin/etoposide with the compound of Formula (I) treatment on tumor weight.

Figure 7 depicts exemplary effects of the vehicle control, cisplatin/etoposide, and

cisplatin/etoposide with the compound of Formula (I) treatment on body weight.

DETAILED DESCRIPTION OF INVENTION

Applicants have discovered a method for treating a human subject having cancer comprising administration (e.g., a course of administration) of a compound of Formula (I) that is effective at treating the subject. The method comprises, in one aspect, administering to the subject a course of treatment comprising three administrations of a compound of Formula (I) over a seven day period, wherein the compound is administered on days 1, 3, and 5 of the seven day period. Course of administration

The present invention describes a method of treating a human subject having cancer, the method comprising a course of therapy or administration of an oral dosage form comprising an active agent, e.g. , an active therapeutic agent, e.g. , a compound of Formula (I). Course of therapy or administration, as referred to herein, comprises one or more separate administrations of a therapeutic agent.

In one aspect, the present invention describes a method of treating a human subject having cancer, the method comprising administering to the subject a course of treatment comprising three administrations of a compound of Formula (I) over a seven day period, wherein the compound is administered on days 1, 3, and 5 of the seven day period, thereby treating the subject.

In some embodiments, the method comprises a plurality of courses of treatment. In some embodiments, the method comprises two courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, and 12). In some embodiments, the method comprises three courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, 12, 15, 17, and 19). In some embodiments, the method comprises six courses of treatment {e.g. , on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33, 36, 38, and 40).

In some embodiments, the administrations are delivered orally.

In some embodiments, the course of treatment comprises the administration of one or more separate administrations of a therapeutic agent (e.g., a compound of Formula (I))

administered in combination with a course of therapy of an additional drug or therapeutic agent, (e.g. , as described herein). In some embodiments, the course of treatment comprises administering one or more separate administrations of a therapeutic agent (e.g. , a compound of Formula (I)) administered after a course of therapy of an additional drug or therapeutic agent. In some embodiments, the course of treatment comprises administering one or more separate administrations of a therapeutic agent (e.g. , a compound of Formula (I)) administered before a course of treatment of an additional drug or agent, (e.g. , therapeutic agent).

Compound of the Invention

The present invention describes a method of treating a human subject having cancer, the method comprising administering an oral dosage form comprising an active agent, e.g. , an active therapeutic agent, e.g. , a compound of Formula (I). The compound of the invention is described in PCT/SG2009/000124, the contents of which are incorporated by reference. The active agent (e.g., active therapeutic agent, active ingredient) is the compound of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the composition in the amount of 5, 10, 1 1 , 12, 12.5, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60% w/w or greater. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the composition in the amount of about 10 to 50% w/w. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the composition in the amount of about 10% w/w. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the composition in greater than 10% w/w. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the composition in the amount of about 13% w/w. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the composition in the amount of about 25%' w/w. In some

embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is present in the composition in the amount of about 50% w/w.

Oral dosage forms

The methods described herein comprise administering an oral dosage form forming an active agent, e.g. , an active therapeutic agent, e.g. , a compound of Formula (I). The term, "oral dosage form," as used herein, refers to a composition or medium used to administer an agent, e.g., a therapeutic agent, e.g., compound of Formula (I), to a subject with cancer. Typically, an oral dosage form is administered via the mouth, however, "oral dosage form" is intended to cover any substance which is administered to a subject and is absorbed across a membrane, e.g., a mucosal membrane, of the gastrointestinal tract, including, e.g., the mouth, esophagus, stomach, small intestine, large intestine, and colon. For example, "oral dosage form" covers a solution which is administered through a feeding tube into the stomach.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin,

polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active compound can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Combination Therapy I Other Courses of Treatment

The methods of the invention may be used or administered in combination with one or more additional therapies {e.g., cancer treatment, e.g., surgery, additional drug(s) or therapeutic agents) for the treatment of the disorder/diseases mentioned. The additional therapies {e.g., cancer treatment, e.g., drug(s) or therapeutic agents described herein) can be administered in the same formulation or in separate formulations. If administered in separate formulations, the compounds of the invention may be administered sequentially or simultaneously with the other drug(s). Administered "in combination", as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject's affliction with the disorder, e.g. , the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as "simultaneous" or "concurrent delivery". In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g. , an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

In addition to being able to be administered in combination with one or more additional therapies (e.g. , cancer treatment, e.g. , surgery, additional drug(s) or therapeutic agents), methods of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.

Exemplary cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, immunotherapy, hormonal therapy, radiation therapy, antiinflammatory agents, analgesic agents, antiemetic agents, and surgery. Examples of each of these treatments are provided below.

Chemotherapy

In some embodiments, the methods of the invention are administered with a

chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g. , with the duplication of DNA or the separation of newly formed

chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.

The methods of the invention may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, hormonal therapy agents, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers. In this regard, the following is a non-limiting list of examples of secondary agents, e.g., secondary therapeutic agents, that may be used with the compound of the invention {e.g. , a compound of Formula (I)).

• Alkylating agents include, but are not limited to, nitrogen mustard N-oxide,

cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinated alkylating compounds include but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satrplatin;

• Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S- l, gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4- oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid;

•Antibiotics include but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin;

•Hormonal therapy agents, e.g. , exemestane (Aromasin), Lupron, anastrozole

(Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano- 3-(4-iluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide) and combinations thereof;

• Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel;

• Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HC1 (Camptosar), edotecarin, epirubicin

(Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof;

• Immunologicals include but are not limited to, interferons and numerous other immune enhancing agents. Interferons include but are not limited to, interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma- la or interferon gamma-nl. Other agents include but are not limited to, filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, and Provenge;

• Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include but are not limited to, krestin, lentinan, sizofiran, picibanil, or ubenimex;

• Other anticancer agents include but are not limited to, alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, Bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, 1-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286, Velcade, Tarceva, or tretinoin;

• Other anti-angiogenic compounds include but are not limited to, acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain and Vitaxin;

• Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin;

• Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, and topotecan;

• Tyrosine kinase inhibitors include but are not limited to, Focal Adhesion Kinase (FAK) inhibitors (e.g., the FAK inhibitors as described herein), Iressa or SU5416;

• Antibodies include but are not limited to, Herceptin, Erbitux, Avastin, or Rituximab; and

• Interferons include but are not limited to, interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma- la or interferon gamma-nl.

Because some drugs work better together than alone, two or more drugs are often given at the same time or sequentially. Often, two or more chemotherapy agents are used as combination chemotherapy. In some embodiments, the chemotherapy agents (including combination chemotherapy) can be used in combination with the methods described herein.

Targeted therapy

In some embodiments, the methods of the invention are administered with a targeted therapy. Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.

Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin-depdendent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include but are not limited to, the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies. Other exemplary anbitodies include but are not limited to, Ctuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusion proteins include but are not limited to, Aflibercept and Denileukin diftitox. Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®. In some embodiments, the targeted therapy can be used in combination with the methods of the invention.

FAK Inhibitors

In some embodiments, the methods of the invention are administered with (e.g., in combination with) a FAK inhibitor. Exemplary FAK inhibitors include, but shall not be construed to be limited to:

Compounds VS-4718 and VS-5095 Exemplary FAK inhibitors include but are not limited to VS-4718, VS-5095, and related compounds, or a pharmaceutically acceptable salt thereof. Compounds VS-4718, VS-5095, and related compounds are described in PCT/US2010/045359 and US20110046121, the contents of each of which are incorporated herein in their entirety. In some embodiments, the FAK inhibitor is a compound of Formula (Il-a) or (Il-b):

Formula (Il-a) Formula (Il-b)

GSK2256098

Exemplary FAK inhibitors also include but are not limited to GSK2256098 and related compounds, or a pharmaceutically acceptable salt thereof. GSK2256098 and related compounds are described in US20100113475, US20100317663, US20110269774, US20110207743, US20140155410, and US20140107131, the contents of which are incorporated herein in their entirety. In some embodiments, the FAK inhibitor is a compound of Formula (Ill-a), (Ill-b), (III-c), (Ill-d), or (Ill-e):

Formula (III-a) Formula

Formula (III-c)

Formula (Ill-d) Formula (IH-e)

Compound VS-6063 and VS-6062

Exemplary FAK inhibitors also include but are not limited to VS-6063, VS-6062, and related compounds, or a pharmaceutically acceptable salt thereof (e.g., VS-6063 hydrochloride, VS-6062 hydrochloride). VS-6063, VS-6062, and related compounds are also disclosed in, e.g., US Pat. No. 7,928,109, EP1578732, PCT/IB2004/202744, PCT/IB2003/005883, PCT/IB2005/001201, and PCT/IB2006/003349, the contents of each of which are incorporated herein by reference. VS-6063 is also known as defactinib and PF-04554878. VS-6062 is also known as PF-00562271. In some embodiments, the FAK inhibitor is a compound of Formula (IV-a) or (IV-b):

Formula (IV-a) or Formula (IV-b)

Other FAK inhibitors

Exemplary FAK inhibitors also include but are not limited to a compound of Formula (V) and related compounds, or a pharmaceutically acceptable salt thereof. A compound of Formula (V) and related compounds are described in US Pat. No. 8,569,298, the contents of which are incorporated herein in their entirety. In some embodiments, the FAK inhibitor is 2-[[2[(l,3- dimethylpyrazol-4-yl)amino]-5-(trifluoromethyl)-4-pyridyl] amino] -5-fluoro-N-methoxy- benzamide, or a compound of Formula (V):

Formula (V) Immunotherapy

In some embodiments, the methods of the invention are administered with an

immunotherapy {e.g., cancer immunotherapy). Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient's own immune system to fight the tumor. This may include, but is not limited to, antibodies against immune checkpoints (PD-1, PD-L1, CTLA-4, etc.), antibodies to induce costimulatory responses (OX40, 4- IBB, CD40, etc.), vaccines and adoptive T-cell therapies (e.g. CAR T-cell therapy). Additional methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in subjects with renal cell carcinoma and melanoma.

Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor's immune cells will often attack the tumor in a graft-versus- tumor effect. In some embodiments, the immunotherapy agents can be used in combination with the methods of the invention.

Anti-Inflammatory Agents

The methods of the invention can be administered with an anti-inflammatory agent. Antiinflammatory agents include, but are not limited to, non-steroidal anti-inflammatory agents {e.g., Salicylates (Aspirin (acetylsalicylic acid), Diflunisal, Salsalate), Propionic acid derivatives (Ibuprofen, Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen), Acetic acid derivatives (Indomethacin, Sulindac, Etodolac, Ketorolac, Diclofenac, Nabumetone), Enolic acid (Oxicam) derivatives (Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam), Fenamic acid derivatives ( Fenamates )(Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid), Selective COX-2 inhibitors (Coxibs) (Celecoxib), Sulphonanilides (Nimesulide). Steriods (e.g. Hydrocortisone (Cortisol), Cortisone acetate, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, Fludrocortisone acetate, Deoxycorticosterone acetate, Aldosterone).

Analgesic Agents

The methods of the invention can be administered with analgesic agents. Analgesics include but are not limited to, opiates (e.g. morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetomal and nonsteroidal anti-inflammatory agents (e.g., Salicylates (Aspirin (acetylsalicylic acid), Diflunisal, Salsalate), Propionic acid derivatives (Ibuprofen, Naproxen, Fenoprofen, Ketoprofen,

Flurbiprofen, Oxaprozin, Loxoprofen), Acetic acid derivatives (Indomethacin, Sulindac, Etodolac, Ketorolac, Diclofenac, Nabumetone), Enolic acid (Oxicam) derivatives (Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam), Fenamic acid derivatives (

Fenamates )(Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid), Selective COX-2 inhibitors (Coxibs) (Celecoxib), Sulphonanilides (Nimesulide).

Antiemetic agents

The methods of the invention can be administered with an antiemetic agent. Antiemetic agents include, but are not limited to, 5-HT3 receptor antagonists (Dolasetron (Anzemet), Granisetron (Kytril, Sancuso), Ondansetron (Zofran), Tropisetron (Navoban), Palonosetron (Aloxi), Mirtazapine (Remeron)), Dopamine antagonists (Domperidone, Olanzapine, Droperidol, Haloperidol, Chlorpromazine, Promethazine, Prochlorperazine, Metoclopramide (Reglan), Alizapride, Prochlorperazine (Compazine, Stemzine, Buccastem, Stemetil, Phenotil), NK1 receptor antagonist (Aprepitant (Emend), Antihistamines (Cyclizine, Diphenhydramine

(Benadryl), Dimenhydrinate (Gravol, Dramamine), Meclozine (Bonine, Antivert), Promethazine (Pentazine, Phenergan, Promacot), Hydroxyzine), benzodiazapines (Lorazepam, Midazolam), Anticholinergics (hyoscine), steriods (Dexamethasone).

Radiation therapy

The methods of the invention are can be used in combination with directed energy or particle, or radioisotope treatments, e.g. , radiation therapies, e.g. , radiation oncology, for the treatment of proliferative disease, e.g. , cancer, e.g. , cancer associated with cancer stem cells. The methods of the invention may be administered to a subject simultaneously or sequentially along with the directed energy or particle, or radioisotope treatments. For example, the methods of the invention may be administered before, during, or after the directed energy or particle, or radioisotope treatment, or a combination thereof. The directed energy or particle therapy may comprise total body irradiation, local body irradiation, or point irradiation. The directed energy or particle may originate from an accelerator, synchrotron, nuclear reaction, vacuum tube, laser, or from a radioisotope. The therapy may comprise external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, systemic radioisotope therapy, or unsealed source radiotherapy. The therapy may comprise ingestion of, or placement in proximity to, a radioisotope, e.g. , radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon.

External beam radiation may comprise exposure to directed alpha particles, electrons (e.g. , beta particles), protons, neutrons, positrons, or photons (e.g. , radiowave, millimeter wave, microwave, infrared, visible, ultraviolet, X-ray, or gamma-ray photons). The radiation may be directed at any portion of the subject in need of treatment.

Surgery

The methods of the invention can be used in combination with surgery, e.g. , surgical exploration, intervention, biopsy, for the treatment of proliferative disease, e.g. , cancer, e.g. , cancer associated with cancer stem cells. The methods of the invention may be administered to a subject simultaneously or sequentially along with the surgery. For example, the methods of the invention may be administered before (pre-operative), during, or after (post-operative) the surgery, or a combination thereof. The surgery may be a biopsy during which one or more cells are collected for further analysis. The biopsy may be accomplished, for example, with a scalpel, a needle, a catheter, an endoscope, a spatula, or scissors. The biopsy may be an excisional biopsy, an incisional biopsy, a core biopsy, or a needle biopsy, e.g., a needle aspiration biopsy. The surgery may involve the removal of localized tissues suspected to be or identified as being cancerous. For example, the procedure may involve the removal of a cancerous lesion, lump, polyp, or mole. The procedure may involve the removal of larger amounts of tissue, such as breast, bone, skin, fat, or muscle. The procedure may involve removal of part of, or the entirety of, an organ or node, for example, lung, throat, tongue, bladder, cervix, ovary, testicle, lymph node, liver, pancreas, brain, eye, kidney, gallbladder, stomach, colon, rectum, or intestine. In one embodiment, the cancer is breast cancer, e.g., triple negative breast cancer, and the surgery is a mastectomy or lumpectomy.

First-line therapy

The present invention describes a method of treating a human subject having cancer, wherein the subject has failed {e.g., relapsed from, insensitive to, received no or little benefit from) first- line treatment {e.g., first- line therapy for cancer). The present invention also describes a method of treating a human subject having cancer, wherein the methods of the invention are administered with an additional agent. In some embodiments, the additional agent is a first-line therapy for cancer. First- line therapy is typically the first treatment given for a disease (e.g. , cancer as described herein). It is often part of a standard set of treatments, such as surgery followed by chemotherapy and radiation. When used by itself, first-line therapy is generally the one accepted as the best treatment. If it does not cure the disease or it causes severe side effects, other treatment(s) may be added or used instead. First-line therapy is also called induction therapy, primary therapy, and primary treatment.

For example, first- line-therapy, e.g. , for Hodgkin lymphoma may include: Adcetris (Brentuximab Vedotin), Adriamycin PFS (Doxorubicin Hydrochloride), Adriamycin RDF (Doxorubicin Hydrochloride), Ambochlorin (Chlorambucil), Amboclorin (Chlorambucil), Blenoxane (Bleomycin), Bleomycin, Brentuximab Vedotin, Chlorambucil, Clafen

(Cyclophosphamide), Cyclophosphamide, Cytoxan (Cyclophosphamide), Dacarbazine,

Doxorubicin Hydrochloride, DTIC-Dome (Dacarbazine), Leukeran (Chlorambucil), Linfolizin (Chlorambucil), Lomustine, Matulane (Procarbazine Hydrochloride), Neosar

(Cyclophosphamide), Procarbazine Hydrochloride, Velban (Vinblastine Sulfate), Velsar (Vinblastine Sulfate), Vinblastine Sulfate, Vincasar PFS (Vincristine Sulfate), and Vincristine Sulfate.

In some embodiments, first-line-therapy, e.g. , for Hodgkin lymphoma comprises administration of a combination of therapeutic agents, e.g. , therapeutic agents as described herein. For example, the combination may comprise Doxorubicin Hydrochloride (Adriamycin), Bleomycin, Vinblastine Sulfate, and Dacarbazine (i.e., ABVD). As another example, the combination may comprise Doxorubicin Hydrochloride (Adriamycin), Bleomycin, Vinblastine Sulfate, and Etoposide (i.e., ABVE). In some embodiments, the combination comprises Doxorubicin Hydrochloride (Adriamycin), Bleomycin, Vinblastine Sulfate, Etoposide, Prednisone, and Cyclophosphamide (i.e., ABVE-PC). In some embodiments, the combination comprises Vincristine Sulfate, Doxorubicin Hydrochloride (Adriamycin), Methotrexate, and Prednisone (i.e., VAMP).

Approved therapeutic agents and combinations for different types of cancer can be found on the National Cancer Institute at the National Institutes of Health Cancer website at http://www.cancer.gov/cancertopics/druginfo/drug-page-index

Second-line therapy

The present invention describes a method of treating a human subject having cancer, wherein the subject has failed (e.g. , relapsed from, insensitive to, received no or little benefit from) second-line treatment (e.g. , second-line therapy for cancer). The present invention also describes a method of treating a human subject having cancer, wherein the methods of the invention are administered with an additional agent. In some embodiments, the additional agent is a first or second line therapy for cancer. Second-line therapy generally refers to treatment that is given when initial treatment (e.g. , first- line therapy) does not achieve a desired result, e.g. , does not work, is not efficacious; stops working. Second-line therapy is typically considered or given when a subject does not respond or develops a resistance to initial treatment (e.g. , first-line therapy). For example, second-line therapy is typically considered or given to a subject with relapsed or refractory disease.

Cancer

As used herein, the term "cancer" is a general term intended to encompass the vast number of conditions that are characterized by uncontrolled abnormal growth of cells. Abnormal cell growth, as used herein and unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate, for example, by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases, for example, in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate, for example, by receptor tyrosine kinases; (4) any tumors that proliferate, for example, by aberrant serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases, for example, in which aberrant serine/threonine kinase activation occurs. Abnormal ceil growth can refer to cell growth in epithelial (e.g., carcinomas, adenocarcinomas); mesenchymal (e.g., sarcomas (e.g.

leiomyosarcoma, Ewing's sarcoma)); hematopoetic (e.g., lymphomas, leukemias,

myelodysplasias (e.g., pre-malignant)); or other (e.g., melanoma, mesothelioma, and other tumors of unknown origin) cells.

It is anticipated that the methods of the invention will be useful in treating various cancers including but not limited to bone cancers, brain and CNS tumours, breast cancers, colorectal cancers, endocrine cancers including adrenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, gastrointestinal cancers, Liver cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers, gynaecological cancers, head and neck cancers, leukemias, myelomas, hematological disorders, lung cancers, lymphomas, eye cancers, skin cancers, soft tissue sarcomas, adult soft tissue sarcoma, Kaposi' s sarcoma, urinary system cancers.

Exemplary cancers that may be treated by compounds of this invention include but are not limited to, Hematologic cancer such as myeloproliferative disorders (idiopathic

myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes, plasma cell disorder, hairy cell leukemia, kaposi' s sarcoma, lymphoma and hyperproliferative conditions such as psoriasis and restenosis;

gynaecologic cancer such as breast carcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer, endometrial hyperplasia; gastrointestinal tract cancer such as colorectal carcinoma, polyps, liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer; urinary tract cancer such as prostate cancer, kidney and renal cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer such as melanoma; brain tumour such as glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such as nasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancer such as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease such as retinoblastoma; musculo-skeleton diseases such as osteosarcoma, musculo skeleletal neoplasm; Squamous cell carcinoma and fibroid tumour.

Methods of this invention may also be used to treat precancer conditions or hyperplasia including familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasia, benign prostatic hyperplasia, papillomas of the larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.

In some embodiments, the cancer is an advanced non-hematologic malignancy or lymphoma (e.g. , malignant lymphoma, FDG-avid lymphoma, FDG-avidity unknown, diffuse large B-cell lymphoma [DLBCL], Hodgkin's lymphoma, follicular lymphoma, mantle-cell lymphoma; large-cell lymphoma, small neoplastic B cell lymphoma, pulmonary lymphoma). The inventive methods of the present invention may be useful in the prevention and treatment of cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof. The disclosed methods are also useful in treating non-solid cancers. Exemplary solid tumors include but are not limited to, malignancies (e.g. , sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid,

gastrointestinal (e.g. , colon), and genitourinary (e.g. , renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary. Exemplary adenocarcinomas include but are not limited to, colorectal cancers, renal-cell carcinoma, liver cancer (e.g. , Hepatocellular carcinoma), non-small cell carcinoma of the lung, pancreatic (e.g. , metastatic pancreatic adenocarcinoma) and cancer of the small intestine.

The cancer can include mesothelioma; neurofibromatosis; e.g. , neurofibromatosis type 2, neurofibromatosis type 1 ; renal cancer; lung cancer, non small cell lung cancer; liver cancer; thyroid cancer; ovarian; breast cancer; a nervous system tumor; schwannoma; meningioma; schwannomatosis; neuroma acoustic; adenoid cystic carcinoma; ependymoma; or ependymal tumors. In some embodiments, the cancer exhibits decreased merlin expression and/or mutation, and/or deletion and/or promotor hypermethylation of the NF-2 gene. In some embodiments, the cancer is renal cancer.

The cancer can include cancers characterized as comprising cancer stem cells, cancer associated mesenchymal cells, or tumor initiating cancer cells. The cancer can include cancers that have been characterized as being enriched with cancer stem cells, cancer associated mesenchymal cells, or tumor initiating cancer cells (e.g. , a tumor enriched with cells that have undergone an epithelial-to-mesenchymal transition or a metastatic tumor). The cancer can be a primary tumor, i.e. , located at the anatomical site of tumor growth initiation. The cancer can also be metastatic, i.e. , appearing at least a second anatomical site other than the anatomical site of tumor growth initiation. The cancer can be a recurrent cancer, i.e. , cancer that returns following treatment, and after a period of time in which the cancer was undetectable. The recurrent cancer can be anatomically located locally to the original tumor, e.g. , anatomically near the original tumor; regionally to the original tumor, e.g. , in a lymph node located near the original tumor; or distantly to the original tumor, e.g. , anatomically in a region remote from the original tumor.

The cancer can also include for example, but is not limited to, epithelial cancers, breast, lung, pancreatic, colorectal {e.g. , metastatic colorectal, e.g. , metastatic K Ras mutated), prostate, head and neck, melanoma {e.g. , N Ras mutated locally advanced or metastatic malignant cutaneous melanoma), acute myelogenous leukemia, and glioblastoma. Exemplary breast cancers include triple negative breast cancer, basal-like breast cancer, claudin-low breast cancer, invasive, inflammatory, metaplastic, and advanced Her-2 positive or ER-positive cancers resistant to therapy.

Other cancers include but are not limited to, brain, abdominal, esophagus,

gastrointestinal, glioma, liver, tongue, neuroblastoma, osteosarcoma, ovarian, retinoblastoma, Wilm' s tumor, multiple myeloma, skin, lymphoma, blood and bone marrow cancers {e.g. , advanced hematological malignancies, leukemia, e.g. , acute myeloid leukemia {e.g. , primary or secondary), acute lymphoblastic leukemia, acute lymphocytic leukemia, T cell leukemia, hematological malignancies, advanced myeloproliferative disorders, myelodysplastic syndrome, relapsed or refractory multiple myeloma, advanced myeloproliferative disorders), retinal, bladder, cervical, kidney, endometrial, meningioma, lymphoma, skin, uterine, lung, non small cell lung, nasopharyngeal carcinoma, neuroblastoma, solid tumor, hematologic malignancy, squamous cell carcinoma, testicular, thyroid, mesothelioma, brain vulval, sarcoma, intestine, oral, endocrine, salivary, spermatocytic seminoma, sporadic medulalry thyroid carcinoma, non- proliferating testes cells, cancers related to malignant mast cells, non-Hodgkin' s lymphoma, and diffuse large B cell lymphoma.

Exemplary cancers include: Acute Lymphoblastic Leukemia, Adult; Acute

Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical

Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar

Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male;

Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primaiy; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor;

Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer,

Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary);

Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer;

Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer,

Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS- Related; Lymphoma, Central Nervous System (Primary);

Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's,

Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non- Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer,

Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer;

Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor;

Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;

Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma;

Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer,

Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant;

Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood;

Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma,

Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor. Metastases of the aforementioned cancers can also be treated and/or prevented in accordance with the methods described herein.

In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is refractory (e.g. , resistant) after standard therapy (e.g. , first-line therapy).

Methods described herein can reduce, ameliorate or altogether eliminate the disorder, and/or its associated symptoms, to keep it from becoming worse, to slow the rate of progression, or to minimize the rate of recurrence of the disorder once it has been initially eliminated (i.e. , to avoid a relapse). A suitable dose and therapeutic regimen may vary depending upon the specific compounds, combinations, and/or pharmaceutical compositions used and the mode of delivery of the compounds, combinations, and/or pharmaceutical compositions. In some embodiments, the method increases the average length of survival, increases the average length of progression-free survival, and/or reduces the rate of recurrence, of subjects treated with the combinations described herein in a statistically significant manner.

In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutant SCLC; metastatic cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer (e.g., unresectable low-grade ovarian, advanced or metastatic ovarian cancer), rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer (e.g., triple- negative breast cancer (e.g., breast cancer which does not express the genes for the estrogen receptor, progesterone receiptor, and Her2/neu)), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgical resectable malignant pleural mesothelioma) or a combination of one or more of the foregoing cancers. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurring (e.g., the subject has a locally recurrent disease, e.g., cancer). Methods of this invention may also be used to treat cancers that fail to respond to first- line therapy (e.g. , relapsed or refractory disease).

In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined:

Definitions

As used herein, the articles "a" and "an" refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.

"About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

As used herein, an amount of a compound (e.g. , a compound as described herein, e.g., a compound of Formula (I)) effective to treat a disorder (e.g., a disorder as described herein), "effective amount" or " effective course" refers to an amount of the compound which is effective, upon single or multiple dose administration(s) to a subject, in treating a subject, or in curing, alleviating, relieving or improving a subject with cancer (e.g., a cancer as described herein) beyond that expected in the absence of such treatment (e.g., placebo treatment).

The term "pharmaceutically acceptable," as used herein._, refers to a compound or carrier (e.g., excipient) that may be administered to a subject, together with a compound described herein (e.g., a compound of Formula (I)), and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. The term, "pharmaceutically acceptable salts," as used herein, refers to derivatives of a compound described herein (e.g., a compound of Formula (I)), wherein the compound is modified by converting an existing acid or base moiety to its salt form. Examples of

pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the disclosure include the conventional non-toxic salts of a compound described herein (e.g., a compound of Formula (I)), formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the disclosure can be synthesized from a compound described herein (e.g., a compound of Formula (I)), which contains a basic or acidic moiety by conventional chemical methods.

Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

The term, "treat" or "treatment," as used herein, refers to the application or administration of a compound, alone or in combination with, an additional agent, e.g., an additional therapeutic agent, to a subject, e.g., a subject who has cancer (e.g., a cancer as described herein), a symptom of cancer, or a predisposition toward cancer, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the cancer.

Co-administration, co-administering or co-providing, as used herein in the context of the administration of therapies, refers to administration at the same time, administration of one therapy before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72 or more hours before), or administration of one therapy after (e.g., immediately after, less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72 or more hours after), administration of a secondary therapy.

Course of therapy, as referred to herein, comprises one or more separate administrations of a therapeutic agent. A course of therapy can comprise one or more cycles of a therapeutic agent.

A cycle, as used herein in the context of a cycle of administration of a drug, refers to a period of time for which a drug is administered to a patient. For example, if a drug is administered for a cycle of 21 days, the periodic administration, e.g., daily or twice daily, is given for 21 days. A drug can be administered for more than one cycle. In some embodiments, a first and second or subsequent cycle are the same in terms of one or both of duration and periodic administration. In embodiments, a first and second or subsequent cycle differ in terms of one or both of duration and periodic administration. Rest periods may be interposed between cycles. A rest cycle may be 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 or more weeks in length.

Numerous ranges, e.g., ranges for the amount of a drug administered per day, are provided herein. In some embodiments, the range includes both endpoints. In other embodiments, the range excludes one or both endpoints. By way of example, the range can exclude the lower endpoint. Thus, in such an embodiment, a range of 250 to 400 mg/day, excluding the lower endpoint, would cover an amount greater than 250 that is less than or equal to 400 mg/day. As used herein, the term "subject" is intended to include human subjects. Exemplary human subjects include a human subject having cancer, e.g., a cancer described herein. The term "non-human animals" of the invention includes all vertebrates, e.g., non-mammals.

This invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having," "containing", "involving", and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

As used herein, an amount of a compound effective to treat a disorder, or a

"therapeutically effective amount" refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder, e.g. , a subject with cancer, beyond that expected in the absence of such treatment.

As used herein, "a prophylactically effective amount" of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in reducing at least one symptom of the disorder or to delay onset of at least one symptom of the disorder.

Examples

Example 1. Preclinical Study Protocol: Efficacy of an Oral Dosing Regimen of Formula (I) using a Xenograft Mouse Model of Human Breast Adenocarcinoma

Study Design A subcutaneous xenograft tumor model of breast cancer was used to evaluate the antitumor efficacy of Formula (I). SUM159 human breast adenocarcinoma cells (ATCC, Manassas, VA) were maintained in vitro as a monolayer culture in RPMl-1640 medium supplemented with 10% fetal bovine serum. Cells were cultured at 37 °C and 5% C0₂ in a tissue culture incubator. The tumor cells were routinely subcultured twice weekly with trypsin-EDTA treatment. Cells in an experimental growth phase were harvested and counted for tumor inoculation.

Female NOD SCID mice between 5-6 weeks old and 18-22 g were utilized in this study. The mouse model was established by the transplantation of SUM159 cells (2xl0⁶, 1: 1 with Matrigel) subcutaneously in the right flank of each animal (0.1 mL/mouse). When the average tumor size reached approximately 150 mm , 30 NOD SCID mice were selected based on tumor volume and randomly assigned into one of three treatment groups (10 per group) according to Table 1 below.

Table 1. Treatment groups and dosing schedule of NOD SCID mice with Formula (I)

22, 24, 26, 29, 31,

33)

The dosing solutions of Formula (I) were prepared in 0.5% CMC, 0.1% Tween-80, and 99.4% sterile water and administered orally using a 22-gauge oral gavage needle. During the treatment period, the implanted tumors were measured using calipers twice per week. The tumors were measured for the maximum width (X) and length (Y) and the tumor volumes (V) were calculated using the formula V = (X Y)/2. The differences in tumor volume between the control and treatment groups were analyzed for significance using the unpaired two-tailed Student's t-test, where a P value < 0.05 was considered to be statistically significant. In addition, the animals were weighed and body weights recorded twice a week.

Study Results

Effects on Animal Body Weight: Figure 1 summarizes the changes in body weight of mice in this study. For mice treated with the vehicle, the average body weight decreased 12.77% (2.97 g) by Day 25 compared to Day 1. Similarly, animals treated with either 15 mg/kg or 25 mg/kg of Formula (I) exhibited a reduction in body weight of 10.84% (2.27 g) or 14.03% (3.11 g) on Day 25 compared to Day 1. Animals tolerated treatment with Formula (I) well, with no apparent side effects observed.

Effects on Tumor Growth: Figure 2 depicts the effects of treatment of Formula (I) on tumor volume. Compared to the vehicle control group, treatment with 15 mg/kg of Formula (I) reached statistical significance by Day 4 of treatment with a tumor growth inhibitor (TGI) value of 74.22% (P < 0.001), and a maximal TGI value of 91.29% (P < 0.001) on Day 14. This statistically significant difference in tumor growth continued throughout the treatment period.

Similarly, the oral treatment of mice with 25 mg/kg of Formula (I) had statistically significant anti-tumor activity on the growth of SUM159 human breast adenocarcinomas. The average tumor volume was statistically significant by Day 4 with a TGI value of 74.59% (P < 0.001). Furthermore, this difference in tumor volume was sustained for the duration of the study, with a maximum TGI of 95.77% (P < 0.001) on Day 22.

Effects on Tumor Weight: All animals in Formula (I)-treated groups were sacrificed after the final tumor measurements on Day 35. Tumors from these animals were dissected, cleaned, and weighed. The average tumor weight for mice that received 15 mg/kg of Formula (I) was 0.258 g and the average tumor weight for mice that received 25 mg/kg of Formula (I) was 0.165 g. The effects of Formula (I) treatment on tumor growth are shown in Figure 3.

Example 2. Preclinical Study Protocol: Efficacy of Formula (I) in Combination with Cisplatin/Etoposide in a Xenograft Mouse Model of Human Small Cell Lung Cancer

Study Design

A subcutaneous xenograft tumor model of small cell lung cancer was used to evaluate the anti-tumor efficacy of Formula (I) in combination with both cisplatin and etoposide. The H69 human small cell lung tumor cell line (ATCC, Manassas, VA) was maintained in RPMI-1640, supplemented with fetal bovine serum and housed in a 5% C02 atmosphere. The cultures were expanded in tissue culture flasks at a 1:5 split ratio until a sufficient amount of cells were harvested. Femal athymic nude mice (Hsd:Athymic Nude-Foxnl^nu, supplied by Harlan, Indianapolis, IN) were received at 4-5 weeks of age and acclimated prior to handling. The mouse model was established by subcutaneous inoculation of H69 tumor cells (5.0 x 10⁶ cells, 1: 1 with Matrigel) in the right flank of each animal (0.1 mL/mouse).

Fourteen days after inoculation, tumors weights were measured using calipers and the animal study management software Study Director. Forty mice with tumor sizes ranging from 79-187 mg were randomized into one group of 10 mice and one group of 30 mice, each with a mean tumor weight of approximately 106 mg. Body weights were recorded when the mice were randomized and were taken three times for the first 11 days and twice a week thereafter in conjunction with tumor measurements. Dosing was performed as outlined in Table 2.

Table 2. Treatment groups and dosing schedule of athymic nude mice with cisplatin and etoposide in the (Days 1-10)

On Day 11, tumors weights were measured and 23 of the mice in Group 2 (Table 2) with tumor sizes ranging from 62-139 mg were randomized and further divided into three subgroups (Groups 3-5). Body weights were recorded when the mice were randomized and were taken twice a week thereafter in conjunction with tumor measurements. Dosing in the second phase of the experiment was performed as described in Table 3.

Table 3. Treatment groups and dosing schedule of athymic nude mice with Formula (I) (Days 11-64)

The dosing solution of Formula (I) were prepared in 0.5% CMC, 0.1% Tween-80, and 99.4% sterile water at concentrations of 1.5 mg/mL and 2.5 mg/mL. Cisplatin (APP Pharmaceuticals) and etoposide (Intas Pharmaceuticals) were diluted separately in a 0.9% NaCl solution to a concentration of 0.5 mg/mL and 2.25 mg/mL each to deliver doses of 5 mg/kg and 22.5 mg/kg, respectively. The vehicle control was dosed with a solution of 0.5% CMC and 0.1% Tween-80 in sterile water. All formulations were delivered in 10 mL/kg dose volumes.

Upon reaching the written endpoint of a group mean tumor weight of 1500 mg, Groups 1 and 3-5 were terminated on Days 25, 42, 61, and 64, respectively, and tumor samples were collected 2 hrs after the final dose. The tumors from each mouse were collected at the time of euthanization and were bisected. One half of the tumor was sliced approximately every 2-3 cm to ensure full penetration of formalin and was fixed in 10% neutral-buffered formalin for 24 hrs, followed by transfer to 70% ethanol and embedding in paraffin. The other half of each tumor was placed in a cryogenic vial and stored at -80 °C for further analysis. Mean tumor growth inhibition (TGI) was calculated and analyzed using the GraphPad Instat software suite.

Differences in Day 25 tumor weights were confirmed using Analysis of Variance (ANOVA) with Tukey's Comparison Test. A Student's t-test with Welch's correction was also used to confirm differences.

Study Results

Vehicle Control (Group 1): The vehicle control group (Group 1) reached a mean tumor weight of 1785.1 mg by Day 25. This group experienced no appreciable body weight loss throughout the study. Nine of ten mice exhibited slight to marked necrosis, first exhibited on Day 14. One mouse exhibited pallor skin on the whole body starting on Day 19 and recovering by Day 21. One mouse was found dead on Day 25 from an unknown cause of death. Cisplatin/Etoposide Treatment (Group 3): Treatment with cisplatin (5 mg/kg) and etoposide (22.5 mg/kg) (Group 3) resulted in a mean tumor weight of 319.3 mg by Day 25. This group produced a TGI of 87.4% when compared to the vehicle control group on Day 25. A statistically significant decrease in tumor weight (P < 0.05) was observed when compared to vehicle control on Day 25. This group experienced severe body weight loss with a maximum decrease of 26.3% on Day 8; however, body weights recovered by Day 18. Other notable observations of this group include hunched posture and emaciation. Five of seven mice exhibited slight to marked tumor necrosis, first observed on Day 32. Figures 4 and 5 summarize exemplary effects of both the vehicle control and combined cisplatin/etoposide treatment on tumor weight and body weight.

Cisplatin/Etoposide Treatment, followed by 15 mg/kg of Formula (I) (Group 4): After initial treatment of cisplatin/etoposide, follow-on dosing with 15 mg/kg Formula (I) (Group 4) resulted in a mean tumor weight of 253.5 mg by Day 25. This group produced a TGI of 90.8% when compared to the vehicle control group on Day 25. A statistically significant decrease in tumor weight (P < 0.05) resulted when compared to the vehicle control group (Group 1, Student's t-test and ANOVA) and Group 3 (ANOVA) on Day 25. This group experienced severe body weight loss with a maximum loss of 18.8% on Day 6; however, body weights recovered by Day 14. Other notable observations of this group include hunched posture and emaciation. Seven of eight mice exhibited slight to marked tumor necrosis, first observed on Day 25.

Cisplatin/Etoposide Treatment, followed by 25 mg/kg of Formula (I) (Group 5): After initial treatment of cisplatin/etoposide, follow-on dosing with 25 mg/kg Formula (I) (Group 5) resulted in a mean tumor weight of 218.2 mg by Day 25. This group produced a TGI of 93.3% when compared to the vehicle control group on Day 25. A statistically significant decrease in tumor weight (P < 0.05) resulted when compared to the vehicle control group (Group 1,

Student's t-test and ANOVA) and Group 3 (Student's t-test) on Day 25. This group experienced severe body weight loss with a maximum loss of 19.6% on Day 6; however, body weights recovered by Day 14. Other notable observations of this group include hunched posture and emaciation. Four of eight mice exhibited slight to marked tumor necrosis, first observed on Day 32. Figures 6 and 7 depict exemplary effects of the vehicle control, cisplatin/etoposide treatment alone, and cisplatin/etoposide treatment with Formula (I) on tumor weight and body weight.

Example 3. Clinical Study Protocol: Phase I Dose Escalation Study of a Dual PI3K/MTOR Inhibitor in Subjects with Advanced Non-Hematologic Malignancies or Lymphoma

Study Design

In a Phase I, open-label, multicenter, dose-escalation trial to evaluate the safety, pharmacokinetics and pharmacodynamics of the compound of Formula (I), in subjects with advanced non-hematologic malignancies or lymphoma. The clinical study is comprised of 2 sequential parts: Part 1 (Dose Escalation) and Part 2 (Expansion).

In Part I (Dose Escalation), the compound of Formula (I) will be administered on an intermittent dosing schedule in 21 day cycles. The compound of Formula (I) will be

administered orally once daily on Day 1, 3, 5, 8, 10, 12, 15, 17, and 19 of each cycle {e.g., Monday, Wednesday, and Friday). Subject enrollment will proceed according to a standard 3+3 design. In the absence of a dose limiting toxicity (DLT), each subject may continue to receive additional cycles of study treatment until disease progression has been documented or other treatment discontinuation criteria have been met. All subjects in a cohort must have completed at least one cycle (21 days) of dosing prior to escalating the dose in the next cohort. The proposed schedule may be modified based on clinical pharmacokinetics, pharmacodynamics, and any compound of Formula (I)-related toxicities observed during the conduct of the phase I study. These modifications may include increasing/decreasing the dosing frequency or introduction of delays between each cycle.

In Part 2 (Expansion), up to an additional 20 subjects will be treated at the recommended phase 2 dose (RP2D) and schedule established in the dose escalation portion of the study. A compound of Formula (I) will be administered at the RP2D and schedule in 21 day cycles until disease progression or other discontinuation criteria have been met.

Safety and tolerability will be assessed by the incidence and severity of adverse events (AEs) as determined by NCI Common Terminology Criteria for Adverse Events (CTCAE v4.03). A Safety Monitoring Committee comprised of the Medical Monitor, Principal

Investigators and Sponsor representatives will be convened to review safety information and to decide upon dose escalation and further subject enrollment.

The antitumor activity of study treatment will be assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST vl . l, e.g. , US NCI Cancer Therapy Evaluation Program Protocol Development template—

http://ctep.cancer.gov/protocolDevelopment/docs/recist_measurement_of_effect.doc) or by the rWG revised response criteria for malignant lymphoma.

Biomarkers of the compound of Formula (I) will include examinations of pre-treatment tumor biopsies (archival and/or study specific in consenting subjects with accessible tumors only) and post-treatment tumor biopsies in consenting subjects with accessible tumors only as well as an assessment of the compound of Formula (I) target proteins in platelet rich plasma in all subjects. Pharmacokinetic samples will be collected over 48 hours starting on Cycle 1 Day 1 and over 24 hours starting on Cycle 1 Day 17. A subset of the pharmacokinetic samples collected may also be assessed for biomarker response in plasma. A single saliva sample will be collected on Cycle 1 Day 1 to assess the genetic risk factors for mTOR inhibitor-associated stomatitis (mlAS).

Dose Escalation Procedure

Subject enrollment will proceed according to a standard 3+3 design. The starting dose of the compound of Formula (I) will be 5 mg administered once daily on Day 1, 3, 5, 8, 10, 12, 15, 17, and 19 in each 21 days cycle {e.g., Monday, Wednesday, and Friday). In the absence of DLT, subsequent dose levels will increase sequentially according to a modified Fibonacci approach with increments of 100%, 67%, 50%, and 40%, followed by 33% for all subsequent dose levels, adjusted to accommodate available pill strengths.

In the 3+3 design, each cohort will consist of a minimum of 3 subjects. All subjects within a cohort must complete 1 cycle (21 days) of dosing without DLT prior to escalation to the next dose in a new cohort. Three subjects will be treated at each dose level until the first instance of DLT, after which up to 6 subjects will be treated at that dose levels. If a second DLT is observed in up to 6 subjects, the DLT dose level will have been reached. The MTD is defined as the highest dose level studied at which <1 subject out of 3 or <2 subjects out of 6 experience a DLT.

The standard 3+3 dose escalation procedure is described below:

• If 0 of 3 subjects in a cohort experiences a DLT, then the next higher dose-level cohort may be enrolled. • If 1 of 3 subjects in a cohort experiences a DLT, then enrollment into that cohort will be expanded to a total of 6 subjects.

• If 1 of 6 subjects in an expanded cohort experiences a DLT, then the next higher dose-level cohort may be enrolled.

• If >1 of 3-6 subjects in a cohort experiences a DLT, then the MTD has been exceeded and further enrollment into that cohort will cease. Using the same criteria, lower-dose cohorts may then be explored until the MTD has been determined.

Dosing Information

Treatment assignment for eligible subjects will be completed according to a process defined by the Sponsor. The starting dose of the compound of Formula (I) will be 5 mg administered orally, once daily, on Days 1, 3, 5, 8, 10, 12, 15, 17, and 19 (e.g., Monday,

Wednesday, and Friday) of each 21 day cycle. In the absence of MTD, subsequent dose levels will increase sequentially according to a modified Fibonacci approach with increments of 100%, 67%, 50%, and 40%, followed by 33% for all subsequent dose levels, adjusted to accommodate available pill strengths.

The following instructions should be reviewed with the subject and a written copy of the instructions provided to the subject:

• Take capsule(s) of the compound of Formula (I) by mouth at approximately the same time once daily on Days 1, 3, 5, 8, 10, 12, 15, 17, and 19 (e.g., Monday, Wednesday, Friday) of each 21 -day cycle. Capsules should be taken on an empty stomach (approximately 1 hour prior or 2 hours after a meal). Take the capsule(s) with a full glass of water

(approximately 8 ounces). Swallow the capsule(s) whole. • If a scheduled dose of study drug is missed for a particular day, do not take the missed dose. Wait and take the next regularly scheduled dose.

• Each day record date and time the capsule(s) were taken on the dosing diary. If a dose is missed, include the reason the dose was not taken.

• Return the dosing diary to your study doctor at each visit.

• Return opened and unopened bottles in which the capsules were dispensed.

• You cannot consume grapefruit containing products while you are on the study.

Adherence with the study treatment regiment must be assessed at each visit by checking the returned drug supply and review the dosing diary.

Definitions

A DLT is defined as any of the following toxicities related to the compound of Formula (I), defined as at least possibly related to study drug therapy) occurring in the first cycle (21 days) of study treatment:

• Grade 4 neutropenia

• Grade > 3 febrile neutropenia

• Neutropenic infection

• Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding

• Grade 4 anemia

• Grade > 3 prolonged QTc interval (QTc > 500 ms), in the absence of electrolyte

abnormalities, as judged by a qualified reader that has been confirmed on a subsequent ECG

• Symptomatic grade 4 hyperglycemia • Symptomatic grade 3 or asymptomatic grade 4 hyperglycemia that does not resolve to < grade 3 within 48 hours with optimal supportive measures

• Any other Grade >3 non-hematologic toxicity with the following exception s: alopecia, grade > 3 nausea, vomiting, diarrhea, or skin rash that persists for < 3 days with optimal medical intervention.

• Grade > 3 increase of AST, ALT, total bilirubin, and serum creatinine

• Any other increase in lab values will be noted and if clinically relevant will be evaluated for DLT by the medical monitor and investigator

• Any treatment-related toxicities that result in failure to receive all of the planned dose during Cycle 1

• Delay of starting cycle 2 dosing by > 2 weeks due to drug related toxicities.

The MTD is defined as the highest dose level studied at which < 1 subject out of 3 or < 2 subjects out of 6 experience a DLT.

The Recommended Phase 2 Dose (RP2D) and schedule will be determined in discussion among the Sponsor, Medical monitor and Investigators. Observations related to pharmacokinetics, pharmacodynamics, and any toxicities related to a compound of Formula (I) may be included in the rationale supporting the RP2D.

Claims

CLAIMS What is claimed is:

1. A method of treating a human subject having cancer, the method comprising administering to the subject a course of treatment comprising three administrations of a compound of Formula (I) over a seven day period, wherein the compound is administered on days 1, 3, and 5 of the seven day period, thereby treating the subject.

2. The method of claim 1, wherein the administrations are delivered orally (e.g., one oral administration daily).

3. The method of claim 1 or 2, comprising a plurality of courses of treatment.

4. The method of one of claims 1-3, wherein the method comprises two courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, and 12).

5. The method of one of claims 1-3, wherein the method comprises three courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, 12, 15, 17, and 19).

6. The method of one of claims 1-3, wherein the method comprises six courses of treatment (e.g. , on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33, 36, 38, and 40).

7. A method of treating a human subject having cancer, the method comprising administering to the subject a course of treatment comprising five administrations of a compound of Formula (I) over a seven day period, wherein the compound is administered on days 1, 2, 3, 4, and 5 of the seven day period, thereby treating the subject.

8. The method of claim 7, wherein the administrations are delivered orally.

9. The method of claim 7 or 8, comprising a plurality of courses of treatment.

10. The method of one of claims 7-9, wherein the method comprises two courses of treatment (e.g., administrations on days 1, 2, 3, 4, 5, 8, 9, 10, 11, and 12).

11. The method of one of claims 7-9, wherein the method comprises three courses of treatment (e.g., administrations on days 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 22, 23, 24, 25 and 26).

12. The method of claim 1 or 7, wherein the cancer is an advanced non-hematologic malignancy or lymphoma (e.g. , malignant lymphoma, FDG-avid lymphoma, FDG-avidity unknown, diffuse large B-cell lymphoma [DLBCL], Hodgkin' s lymphoma, follicular lymphoma, mantle-cell lymphoma; large-cell lymphoma, small neoplastic B cell lymphoma, pulmonary lymphoma).

13. The method of claim 1 or 7, wherein the oral dosage form is a capsule (e.g. , a 5 mg, 10 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 100 mg, 200 mg or more capsule).

14. The method of claim 1 or 7, wherein the oral dosage form comprises about 5 to 70%, about 10 to 50%, or about 10 to 40% by weight of the compound of Formula (I) or a

pharmaceutically acceptable salt thereof.

15. The method of claim 1 or 7, wherein the subject is administered at least 1, 2.5, 5, 10, or

20 mg of compound daily (e.g., once daily).

16. The method of claim 1 or 7, wherein the duration of the course of treatment is at least

21 days.

17. The method of claim 1 or 7, wherein each administration occurs as in a single dose.

18. The method of claim 1 or 7, wherein the subject has failed (e.g. , relapsed from, insensitive to, received no or little benefit from) conventional or standard cancer treatment (e.g. , surgery, first-line therapy for cancer).

19. The method of claim 1 or 7, wherein the subject has failed (e.g. , relapsed from, insensitive to, received no or little benefit from) first-line treatment (e.g. , first-line therapy for cancer).

20. The method of claim 1 or 7, further comprising administration of an additional agent (e.g. , therapeutic agent, drug).

21. The method of claim 20, wherein the additional agent is selected from a chemotherapeutic agent, an anti-inflammatory agent, an immunotherapy, an analgesic agent, a FAK inhibitor, a targeted therapy, or an antiemetic agent.

22. The method of claim 21, wherein the additional agent is a FAK inhibitor (e.g., a FAK inhibitor described herein).

23. The method of claim 21, wherein the additional agent is a first or second line therapy for cancer.

24. The method of claim 20, wherein the course of treatment is administered (e.g. , about 5, 15, 30, 60 minutes; about 1, 2, 3, 5, 6, 8, 10, 12, 15, 18, 20 hours; about 1, 2, 3, 4, 5, 6 days; about 1, 2, 3, 4 weeks) before the administration of the additional agent.

25. The method of claim 20, wherein the course of treatment is administered (e.g. , about 5, 15, 30, 60 minutes; about 1, 2, 3, 5, 6, 8, 10, 12, 15, 18, 20 hours; about 1, 2, 3, 4, 5, 6 days; about 1, 2, 3, 4 weeks) after the administration of the oral dosage form comprising a compound of Formula (I).

26. The method of claim 23, wherein the first or second line therapy comprises

administering multiple therapeutic agents (e.g. , a combination of therapeutic agents).

27. The method of claim 1 or 7, wherein the duration of the method is at least 4, 5, 6 weeks; 1, 2, 3, 4, 5, 6 months (e.g. , 6 weeks).

28. The method of claim 1 or 7, further comprising an additional course of treatment (e.g., administrations on days 1, 3, and 5).

29. The method of claim 1 or 7, further comprising an additional two courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, and 12).

30. The method of claim 1 or 7, further comprising an additional three courses of treatment (e.g., administrations on days 1, 3, 5, 8, 10, 12, 15, 17, and 19).

31. The method of claim 28, wherein the administration is performed by self-administration (e.g., outside of the clinic).