WO2008036954A1

WO2008036954A1 - Use of n- [5- [ [ [5- (1, 1-dimethylethyl) -2-oxazoyl] methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide

Info

Publication number: WO2008036954A1
Application number: PCT/US2007/079244
Authority: WO
Inventors: Daniel C. Adelman; Ute Hoch; Arthur P. Decillis; Jeffrey A. Silverman; Duncan Walker; Robert Martell
Original assignee: Bristol Myers Squibb Co; Sunesis Pharmaceuticals Inc
Current assignee: Bristol Myers Squibb Co; Viracta Therapeutics Inc
Priority date: 2006-09-21
Filing date: 2007-09-21
Publication date: 2008-03-27
Anticipated expiration: 2009-03-21

Abstract

The use of N- [5- [ [ [5- (1, 1- dimethylethyl) -2- oxazolyl] methyl] thio] -2-thiazolyl] -4-piperidinecarboxamide for the treatment of cancer is disclosed. Also provided is the use of the compound in combination with other therapies for treating cancer. Also provided are pharmaceutical compositions and single unit dosage forms that can be used for treating cancer.

Description

USE OF

N- [5- [ [ [5- (1 , 1-DIMETHYLETHYL) -2-OXAZOYL] METHYL] THIO] -2-THIAZOLYL] -4-PIPERIDINECA

RBOXAMIDE

1. FIELD

The present invention relates to N-[5-[[[5-(l,l-dimethylethyl)-2- 5 oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, compositions thereof, and methods for its use to treat cancer.

2. BACKGROUND

N-[5-[[[5-(l,l-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide is referred to herein as "Compound I". Compound I, salts of

10 Compound I, and processes to prepare Compound I and salts are disclosed in U.S. Patent 6,515,004 Bl, which is assigned to the present assignee and is incorporated herein by reference in its entirety. U.S. Patents 6,040,321, 6,214,852 Bl, 6,262,096 Bl, 6,392,053 B2, 6,414,156 B2, 6,515,004 Bl, 6,521,759, 6,613,911 B2, 6,639,074 B2, and 6,897,321 B2, which are assigned to the present assignee and relate to the

15 invention, are also incorporated herein by reference in their entirety. Compound I is suitable as an inhibitor of protein kinases such as the cyclin dependent kinases (cdks), for example, cdc2 (cdkl), cdk2, cdk3, cdk4, cdk5, cdk6, cdk7, cdk8, and cdk9. Compound I may be expected to be useful for treating cancer. Other proliferative diseases that Compound I may be useful to treat include inflammation, arthritis,

20 Alzheimer's disease, and cardiovascular disease.

Two of the principal hallmarks of cancer are uncontrolled proliferation and the avoidance of cell death. Molecules that directly control cell-cycle progression and apoptosis can be altered during tumorigenesis enabling tumor cells to survive and proliferate uncontrollably, independent of normal mitogenic and antigrowth signals. 25 The CDK family of protein serine/threonine kinases includes key drivers of cell-cycle progression and transcriptional control. The inappropriate activation of both cell- cycle and transcriptional-regulatory CDKs in cancers can lead to unregulated proliferation and avoidance of apoptosis, suggesting that these kinases may be important targets for cancer therapeutics.

30 Flavopiridol, the first nonselective CDK inhibitor to enter clinical trials, has had disappointing activity against solid tumors in part due to unacceptable toxicity and poor PK properties. Other CDK inhibitors with improved tolerability profiles and pharmaceutical properties have the potential to meet a large unmet medical need. Compound I is a potent and selective inhibitor of CDKs, in particular CDK2, CDK7, and CDK9. CDK2 is a cell cycle-regulated kinase that controls the entry into and normal progression through DNA synthesis. Inappropriate activation of CDK2 occurs in many human cancers and is associated with a poorer prognosis for patients. Activation of CDK2 in several cancer types including breast, NSCLC, and ovarian cancers is mediated through either overexpression of the associated activating subunit (cyclin E) or underexpression of the CDK2-inhibitor, p27. In melanoma, CDK2 protein is directly upregulated, and its overexpression correlates with sensitivity to CDK inhibitors.

CDK7 and CDK9 are not cell cycle regulated kinases, but are required for transcriptional control, particularly of short half-life mRNAs, many of which encode antiapoptotic and growth regulatory genes. The deregulation of CDK7 or 9 in cancers has not been widely studied to date. However, an inhibitor of CDKs 2, 7 and 9 in tumor cells may be expected to cause cell cycle arrest and induce apoptosis in tumors both as a single agent and in combination with chemotherapy.

3. SUMMARY

Provided herein are methods of treating cancer comprising administering to a mammal in need thereof a dose of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, referred to herein as Compound I, of about 1 mg/m² - 150 mg/m². In certain embodiments, the dose is given on a daily schedule. In other embodiments, Compound I is dosed on a once daily for 5 days every three weeks schedule. In other embodiments Compound I is dosed on a once every three weeks schedule.

Also provided herein are combinations for use with the 1 mg/m²- 150 mg/m² dose of Compound I. The combinations comprise use of the dose Compound I and another cancer therapy such as, for example, surgery or radiation. In another embodiment, the combinations comprise Compound I and a second active agent. In certain embodiments of the combinations, the second active agents are anticancer cytoxics such as cisplatin or carboplatin. In certain embodiments of the combinations, Compound I and the second active agent are each administered on a weekly schedule. Further provided are pharmaceutical compositions comprising 1 mg -300 mg dosage forms of Compound I. In certain embodiments, the pharmaceutical dosage forms comprise N- [5 - [ [ [5 -( 1 , 1 -dimethyl ethyl)-2-oxazolyl]methyl] thio] -2-thiazo IyI] -4- piperidinecarboxamide hemi-L-tartrate, also referred to herein as "Compound I API". 4. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 illustrates the structures of Compound I (top) and Compound I API (bottom). Figure 2 illustrates the effect of combining Compound I with carboplatin on tumor growth volume over time in the A2780 mouse xenograft model. Shown are vehicle (squares); 75 mg/kg IV carboplatin on a q4d ^χ2 schedule (circles); 60 mg/kg IP Compound I on a q4d ^χ2 schedule (triangles); 30 mg/kg IP Compound I on a qd ^χ8 schedule (inverted triangles); and a combination of 75 mg/kg IV carboplatin on a q4d x 2 schedule with 60 mg/kg IP Compound I (diamonds) on a q4d ^χ2 schedule administered 24 hours after the respective carboplatin doses. Figure 3 illustrates the effect of combining Compound I with cisplatin on tumor growth volume over time in the A2780 mouse xenograft model. Shown are vehicle (squares); 5 mg/kg IV cisplatin on a q4d ^χ2 schedule (circles); 30 mg/kg IP Compound I on a q4d ^χ2 schedule (triangles); and a combination of 5 mg/kg IV carboplatin on a q4d ^χ2 schedule with 30 mg/kg IP Compound I (diamonds) on a q4d ^χ2 schedule administered 24 hours after the respective cisplatin doses. 5. DESCRIPTION

In one aspect of the present invention, methods for using Compound I comprise administering Compound I in a dose of about 1 mg/m² - 150 mg/m².

In another aspect of the present invention, methods for using Compound I comprise daily administration of Compound I for at least 2 days. In other embodiments, Compound I is administered daily for at least 3 days. In other embodiments, Compound I is administered daily for at least 4 days. In other embodiments, Compound I is administered daily for at least 5 days. In still other embodiments, Compound I is administered daily for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days. In another aspect of the present invention, methods of using Compound I comprise administering Compound I as a 1 -hour infusion. In other embodiments, Compound I is administered as a 3-hour infusion. In other embodiments, Compound I is administered as a 6-hour infusion. In other embodiments, Compound I is administered as an 8 -hour infusion. In still other embodiments, Compound I is administered as a 24-hour infusion.

In another aspect of the present invention, methods of treating cancer are provided. In one embodiment, the method of treating cancer comprises administering a daily dose of Compound I of 10-50 mg/m² as a 1-hour infusion for five days every three weeks. In one embodiment, the daily dose of Compound I is 10-20 mg/m². In another embodiment, the daily dose of Compound I is 15-25 mg/m². In another embodiment, the daily dose is 20-30 mg/m². In another embodiment, the daily dose of Compound I is 25-35 mg/m². In another embodiment, the daily dose of Compound I is 30-40 mg/m². In another embodiment, the daily dose of Compound I is 35-45 mg/m². In another embodiment, the daily dose of Compound I is 40-50 mg/m².

In another aspect of the present application, a method of treating cancer is provided, the method of treating cancer comprising administering to a mammal a dose of Compound I of about 40 mg/m²- 150 mg/m² every three weeks, wherein the mammal receives at least two doses of Compound I. In one embodiment, Compound I is adminstered as a 1 -hour infusion. In another embodiment, Compound I is administered as a 24-hour infusion.

In another aspect of the present application, a method of treating cancer is provided, the method of treating cancer comprising administering to a mammal a dose of

Compound I of about 40 mg/m²-90 mg/m² every three weeks, wherein the mammal receives at least two doses of Compound I. In one embodiment, Compound I is administered as a 1 -hour infusion. In another embodiment, Compound I is administered as a 24-hour infusion. In another aspect of the present application, a method of treating cancer is provided, the method of treating cancer comprising administering to a mammal a dose of Compound I of about 75 mg/m²- 150 mg/m² every three weeks, wherein the mammal receives at least two doses of Compound I. In one embodiment, Compound I is administered as a 1 -hour infusion. In another embodiment, Compound I is administered as a 24-hour infusion.

In another embodiment, the dose is 75-85 mg/m² and Compound I is administered as a 1 -hour infusion once every three weeks, wherein the mammal receives at least two doses of Compound I. In another embodiment, the dose is 80-90 mg/m² and Compound I is administered as a 1 -hour infusion once every three weeks. In another embodiment, the dose is 85-95 mg/m² and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment, the dose is 90-100 mg/m² and Compound I is administered as a 1 -hour infusion once every three weeks.

In another embodiment the dose is 75 mg/m², and Compound I is administered as a 1- hour infusion once every three weeks, wherein the mammal receives at least two doses of Compound I. In another embodiment the dose is 80 mg/m², and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 85 mg/m², and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 90 mg/m², and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 95 mg/m², and Compound I is administered as a 1 -hour infusion once every three weeks. In another embodiment the dose is 100 mg/m , and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 1 10 mg/m², and Compound I is administered as a 1 -hour infusion once every three weeks. In another embodiment the dose is 120 mg/m², and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 130 mg/m², and Compound I is administered as a 1-hour infusion once every three weeks. In another embodiment the dose is 140 mg/m², and Compound I is administered as a 1 -hour infusion once every three weeks. In another embodiment the dose is 150 mg/m², and Compound I is administered as a 1-hour infusion once every three weeks.

In another embodiment, the dose is 90-130 mg/m², and Compound I is administered as a 24-hour infusion once every three weeks, wherein the mammal receives at least two doses of Compound I. In another embodiment, the dose is 90-100 mg/m², and Compound I is administered as a 24-hour infusion once every three weeks. In another embodiment, the dose is 100- 110 mg/m², and Compound I is administered as a 24- hour infusion once every three weeks. In another embodiment, the dose is 1 10-120 mg/m² and Compound I is administered as a 24-hour infusion once every three weeks. In another embodiment, the dose is 120-130 mg/m² and Compound I is administered as a 24-hour infusion once every three weeks. In another aspect of the present application, a method of treating cancer is provided, the method of treating cancer comprising administering to a mammal a dose of Compound I of about 1 mg/m²-150 mg/m² once a week as a 1-hour infusion, wherein the mammal receives at least two doses of Compound I. In one embodiment, the cancer is a solid tumor.

The types of cancers that can be treated, prevented or managed using methods provided herein include, but are not limited to solid tumors and blood borne tumors. In certain embodiments, cancer can be disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, uterus and hematologic malignancies, such as leukemias, lymphomas and myelomas. In certain embodiments, the myeloma is multiple myeloma. In certain embodiments, the lymphoma is Non-Hodgkin's Lymphoma, B-cell lymphoma, mantle cell lymphoma, and Hodgkin's disease (also called Hodgkin's Lymphoma). In certain embodiments, the leukemia is chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myelogenous leukemia and acute myeloblastic leukemia (AML). In certain embodiments, the cancer comprises solid tumor. In certain embodiments, the cancer comprises blood borne tumor cells released from a primary tumor. In certain embodiments, the cancer comprises a hematological maligancy. In certain embodiments, the cancer can be relapsed, refractory or resistant to conventional therapy.

Forms of Compound I that can be used in the compositions and methods provided herein include, but are not limited to the following salts: hydrochloride, dihydrochloride, sulfate, trifluoroacetate, mixture of trifluoroacetate and hydrochloride, tartrate, fumarate, succinate, maleate, citrate, methanesulfonate, bromate and iodate salts. These salts include racemic forms as well as enantiomers and diastereomers (such as, for example, D-tartrate and L-tartrate salts). In a preferred embodiment, the salt of Compound l is a hemi-L-tartrate salt. In one embodiment, Compound I is formulated for intravenous (IV) administration, which is currently under development for the treatment of cancer. Its chemical structure is shown in Figure 1 (top). The active pharmaceutical ingredient (API) of Compound I is a 2: 1 salt of Compound I as a free base with L-tartaric acid (Compound I API), and is manufactured under Good Manufacturing Practice (GMP) controls. The molecular formula of Compound I API is Ci₇H₂₄N₄O₂S₂^(C₄H₆O₆)Iz₂ and its molecular weight is 455.5 Daltons. The structure of Compound I API is also shown in Figure 1 (bottom).

Compound I API is a white non-hygroscopic powder with lumps and melts between 233 ⁰C and 240 ⁰C. By USP definition, Compound I API is slightly soluble in water, propylene glycol and methanol, very slightly soluble in ethanol and polyethylene glycol 400 (PEG 400), and practically insoluble in acetone and acetonitrile. The apparent 1 -octanol/water partition coefficient (P₀/_w) of the free base of Compound I API is 4.9 (log P_0/w = 0.69) at pH 7.4. The pH of a saturated solution of Compound I API in water at 25⁰C is 5.1. Based on the pH-solubility profile at 25⁰C, the Compound I API pKa values are estimated to be 8.4 and 11.

Dosage amounts used in the compositions and methods provided herein are based on the molecular weight of Compound I API (i.e. 455.5 Da). It is routine for one of skill in the art to calculate molecular weights of other salts of Compound I in order to determine corresponding amounts of the salt necessary for use in the methods provided herein, or for use for the pharmaceutical compositions provided herein.

Compound I may be used as a single agent according to methods of the invention, or alternatively other therapies, chemotherapeutic agents or other anti-cancer agents may be used in combination with Compound I to treat proliferative diseases and cancer. Thus in one embodiment, the invention is directed to a method of treating cancer comprising administering to a mammal in need thereof a dose of Compound I of about 1 mg/m²-150 mg/m and a second active agent.

As used herein "in combination with" does not necessarily indicate that Compound I is physically combined with the second active agent prior to administration; in fact, whether it is possible to physically combine Compound I and the second active agent will depend on the identity of the second active agent. Unless it is known that the second active agent will be compatible with Compound I in the particular formulation to be used, it is preferred that Compound I is not physically combined with the second active agent prior to administration. Where the administration of Compound I and of the second active agent is intravenous, the intravenous administration may be in the same IV line, or in separate IV lines. In one embodiment of the method using Compound I in combination with a second active agent, the 1 mg/m²-150 mg/m² dose of Compound I is administered once every four days. In another embodiment of the method using Compound I in combination with a second active agent, the 1 mg/m²- 150 mg/m² dose of Compound I is administered once a week. In another embodiment of the method , the method using Compound I in combination with a second active agent, the 1 mg/m²- 150 mg/m² dose of Compound I is administered once every two weeks. In another embodiment, the method using Compound I in combination with a second active agent, the 1 mg/m²- 150 mg/m² dose of Compound I is administered once every three weeks. In another embodiment of the method using Compound I in combination with a second active agent, the 1 mg/m²- 150 mg/m² , the dose of Compound I is administered once every four weeks.

The second active agent may be administered at a different frequency than the 1 mg/m²- 150 mg/m² dose of Compound I, or it may be administered at the same frequency as the 1 mg/m²- 150 mg/m² dose of Compound I. In one embodiment, the second active agent is administered at the same frequency as Compound I, but on a staggered schedule as compared with Compound I. As used herein, a staggered schedule refers to a waiting period between the end of administration of the second active agent or Compound I and the start of administration of Compound I or the second active agent, respectively. Specifically, the second active agent may be administered prior to the start of administration of Compound I, subsequently to the completion of the administration of Compound I, concurrently with Compound I, or simultaneously with Compound I. In one embodiment, the administration of the second active agent is completed 24 hours prior to administration of Compound I. In another embodiment, the administration of the second active agent is completed 48 hours prior to administration of Compound I. In another embodiment, the administration of the second active agent is completed 72 hours prior to administration of Compound I. In another embodiment, both Compound I and the second active agent are present at the same time in the subject. In another embodiment, the second active agent is administered on the same day as (i.e. within 24 hours of) the 1 mg/m²-150 mg/m² dose of Compound I. In another embodiment, the second active agent is administered immediately prior to Compound I. In another embodiment, the second active agent is administered immediately after Compound I. In one example where Compound I is given as a 1-hour infusion, the infusion of Compound I would start immediately after administration of the second active agent is complete.

In another embodiment, the second active agent administered in combination with Compound I is an anticancer cytotoxic agent. In another embodiment, Compound I is administered on a staggered schedule with respect to the anticancer cytotoxic agent. In another embodiment, Compound I is admininistered 24 hours after the end of the administration of the anticancer cytotoxic agent.

The second active agent may be administered using a different length infusion than is used for Compound I. In one embodiment, the second active agent is administered in a 10- 15 minute intravenous infusion. In another embodiment, the second active agent is administered as a 1-hour infusion. In another embodiment, the second active agent is administered as a 24-hour infusion.

In another embodiment, the second active agent administered in combination with Compound I is a DNA-damaging agent. In another embodiment, the second active agent administered in combination with Compound I is cisplatin. In another embodiment, the second active agent administered in combination with Compound I is carboplatin.

In another aspect, the invention is directed to a method of treating cancer comprising administering to a mammal in need thereof a dose of Compound I of 1 mg/m²- 150 mg/m² once a week, and a dose of a second active agent given at least once every four weeks. In one embodiment, the second active agent given at least once every four weeks is cisplatin. In another embodiment, the second active agent given at least once every four weeks is carboplatin.

In one embodiment, the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m²- 150 mg/m² once a week, and a dose of cisplatin of 1 mg/m -30 mg/m² administered once a week. In another embodiment, the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 10 mg/m -120 mg/m once a week, and a dose of cisplatin of 1 mg/m²-30 mg/m² administered once a week. In another embodiment of the method, Compound I and cisplatin are administered once a week for two weeks. In another embodiment, Compound I and cisplatin are administered once a week for three weeks. In another embodiment, Compound I and cisplatin are administered once a week for four weeks. In another embodiment, Compound I and cisplatin are administered once a week for five weeks. In another embodiment, Compound I and cisplatin are administered once a week for six weeks.

In another embodiment of the method, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-40 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 40 mg/m²-50 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²- 30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 50 mg/m²-60 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 60 mg/m²-70 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 70 mg/m -80 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 80 mg/m²-90 mg/m administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m administered once a week.

In another embodiment of the method, the dose of Compound I is 30 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 40 mg/m administered once a week, and the dose of cisplatin is 1 mg/m -30 mg/m administered once a week. In another embodiment, the dose of Compound I is 50 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 60 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 70 mg/m administered once a week, and the dose of cisplatin is 1 mg/m -30 mg/m administered once a week. In another embodiment, the dose of Compound I is 80 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week. In another embodiment, the dose of Compound I is 90 mg/m² administered once a week, and the dose of cisplatin is 1 mg/m²-30 mg/m² administered once a week.

In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of cisplatin is 5 mg/m²-25 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of cisplatin is 10 mg/m²-20 mg/m² administered once a week.

In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of cisplatin is 5 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m² administered once a week, and the dose of cisplatin is 10 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of cisplatin is 15 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of cisplatin is 20 mg/m administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m² administered once a week, and the dose of cisplatin is 25 mg/m² administered once a week.

In another embodiment, the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m²- 150 mg/m² once a week, and a dose of cisplatin of 5 mg/m²-60 mg/m² every 2 weeks. In another embodiment comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m²- 150 mg/m² once a week, and a dose of cisplatin of 10 mg/m²- 100 mg/m² every 3 weeks. In one embodiment, the method comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m²- 150 mg/m once a week, and a dose of cisplatin of 15 mg/m²- 120 mg/m² every 4 weeks.

In another aspect, the present application is directed to a method for treating cancer comprising administering to a mammal in need thereof a dose of Compound I of 1 mg/m²- 150 mg/m² once a week, and a dose of carboplatin of 60 mg/m²-225 mg/m² administered once a week. In another embodiment, the method for treating cancer comprising administering to a mammal in need thereof a dose of Compound I of 10 mg/m²-120 mg/m² once a week, and a dose of carboplatin of 60 mg/m²-225 mg/m² administered once a week. In another embodiment of the method, Compound I and carboplatin are administered once a week for two weeks. In another embodiment, Compound I and carboplatin are administered once a week for three weeks. In another embodiment, Compound I and carboplatin are administered once a week for four weeks. In another embodiment, Compound I and carboplatin are administered once a week for five weeks. In another embodiment, Compound I and carboplatin are administered once a week for six weeks. In another embodiment of the method, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²-225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-40 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²- 225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 40 mg/m²-50 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²-225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 50 mg/m²-60 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m -225 mg/m administered once a week. In another embodiment, the dose of Compound I is 60 mg/m -70 mg/m administered once a week, and the dose of carboplatin is 60 mg/m²-225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 70 mg/m²-80 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²-225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 80 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²- 225 mg/m² administered once a week.

In another embodiment of the method, the dose of Compound I is 30 mg/m administered once a week, and the dose of carboplatin is 60 mg/m -225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 40 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²-225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 50 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²-225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 60 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²-225 mg/m² administered once a week. In another embodiment, the dose of Compound I is 70 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m -225 mg/m administered once a week. In another embodiment, the dose of Compound I is 80 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m -225 mg/m administered once a week. In another embodiment, the dose of Compound I is 90 mg/m² administered once a week, and the dose of carboplatin is 60 mg/m²-225 mg/m² administered once a week.

In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 65 mg/m²-200 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 70 mg/m²- 175 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 75 mg/m²- 150 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m administered once a week, and the dose of carboplatin is 80 mg/m²- 125 mg/m² administered once a week.

In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 75 mg/m administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m administered once a week, and the dose of carboplatin is 85 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 95 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m² administered once a week, and the dose of carboplatin is 105 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 115 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 125 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m -90 mg/m administered once a week, and the dose of carboplatin is 135 mg/m² administered once a week. In another embodiment, the dose of Compound I is 30 mg/m²-90 mg/m² administered once a week, and the dose of carboplatin is 145 mg/m² administered once a week. In another embodiment, the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m²-150 mg/m² once a week, and a dose of carboplatin of 125 mg/m²-250 mg/m² every 2 weeks. In another embodiment comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m -150 mg/m² once a week, and a dose of carboplatin of 175 mg/m²-375 mg/m² every 3 weeks. In one embodiment, the method comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m²- 150 mg/m² once a week, and a dose of carboplatin of 250 mg/m²-500 mg/m² every 4 weeks. In another embodiment, the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 1 mg/m²- 150 mg/m² once a week and an amount of carboplatin sufficient to achieve an AUC of 4 mg/mL x min - 7 mg/mL x min, wherein the amount of carboplatin is administered once a week. In another embodiment, the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 10 mg/m²- 120 mg/m² once a week and an amount of carboplatin sufficient to achieve an AUC of 4 mg/mL x min - 7 mg/mL x min, wherein the amount of carboplatin is administered once a week. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 4 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 5 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 6 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 7 mg/mL x min.

In another embodiment, the method for treating cancer comprises administering to a mammal in need thereof a dose of Compound I of 30 mg/m²-90 mg/m² once a week and an amount of carboplatin sufficient to achieve an area under the concentration vs time curve (AUC) of 4 mg/mL x min - 7 mg/mL x min, wherein the amount of carboplatin is administered once a week. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 4 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 5 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 6 mg/mL x min. In another embodiment of the method, the amount of carboplatin is sufficient to achieve an AUC of about 7 mg/mL x min.

The amount of carboplatin necessary to achieve a desired AUC can be calculated using the Calvert formula for carboplatin dosing: Total dose (mg) = [target area under the concentration vs time curve (AUC in mg/mL x min)] X [Glomerular filtration rate (GFR in mL/in) + 25].

Other therapies or anticancer agents may be used in combination with Compound I, or in combination with Compound I and a second active agent. Non-limiting examples of such therapies include surgery, radiotherapy (in but a few examples, gamma- radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g. , antiemetics), and other approved chemotherapeutic drugs. Examples of chemotherapeutic drugs that may be used as a second active agent in combination with Compound I include, but are not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine antagonists and pyrimidine antagonists (6- Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes (Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and Megestrol), Gleevec™, adriamycin, dexamethasone, and cyclophosphamide. Some specific anticancer agents that can be used in combination with Compound I include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; capecitabline; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; erlotinib; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gefitinib; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pemetrexed; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanidine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride. Other anti-cancer drugs that can be used in combination with Compound I include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1 ; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta- alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec^®); imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim;Erbitux, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense ); O⁶-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl ; ruboxyl; safingol; saintopin;

SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to, rituximab, oblimersen (Genasense ), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron ), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa^®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil^®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt^®), sulindac, and etoposide. For a more comprehensive discussion of updated cancer therapies see, The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (CNI) website and the Food and Drug Administration (FDA) website for a list of the FDA approved oncology drugs.

In other embodiments, the second active agent is a supportive care agent. An example of supportive care agent is an antiemetic. Specific antiemetic agents include, but are not limited to, phenothiazines, butyrophenones, benzodiazapines, corticosteroids, serotonin antagonists, cannabinoids, and NKi receptor antagonists. Examples of phenothiazine antiemetics include, but are not limited to, prochlorperazine and trimethobenzamide. Examples of butyophenone antiemetic include, but are not limited to, haloperidol. Examples of benzodiazapine antiemetic include, but are not limited to, lorazepam. Examples of corticosteroid antiemetic include, but are not limited to, dexamethasone. Examples of serotonin antagonist antiemetic include, but are not limited to, ondansetron, granisetron, and dolasetron. Examples of cannabinoid antiemetic include, but are not limited to, dronabinol. Examples of NKi receptor antagonists include, but are not limited to, aprepitant. Doses and dosing regimens of antiemetic agents should depend on the specific indication being treated, age and condition of a patient, and severity of adverse effects, and may be adjusted accordingly by those of skill in the art. Examples of doses and dosing regimens can be found, for example, in The Physician 's Desk Reference.

The methods provided herein use pharmaceutical compositions containing Compound I and pharmaceutically acceptable carriers, such as diluents or adjuvants, or in combination with other active ingredient, such as another anti-cancer agent. In clinical practice Compound I may be administered by any conventional route, including but not limited to orally, parenterally, or rectally. In one embodiment, Compound I is administered by an IV injection.

The compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, or injectable organic esters, for example ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium. Pharmaceutical compositions can be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms comprise Compound I and one or more excipients.

Pharmaceutical compositions and dosage forms can also comprise one or more additional active ingredients. Examples of optional second, or additional, active ingredients are disclosed herein.

In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of Compound I, and typically one or more pharmaceutically acceptable carriers or excipients. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils. In certain embodiments, water is a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy, 21^st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005), the contents of which are hereby incorporated by reference in their entirety. Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

Further provided herein are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

The pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, powders and the like. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject. The formulation should suit the mode of administration. In one embodiment, the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, such as a mammalian subject, such an animal subject, or in particular a human subject.

A pharmaceutical composition provided herein is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, topical, transmucosal, intra- tumoral, intra-synovial and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, intranasal or topical administration to human beings. In one embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.

Examples of dosage forms include, but are not limited to: liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

The composition, shape, and type of dosage forms provided herein will typically vary depending on their use. For example, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed herein will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21^st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005), the contents of which are hereby incorporated by reference in their entirety.

Generally, the ingredients of compositions provided herein are supplied either separately or mixed together in unit dosage form. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

In another aspect the invention is directed to a dosage forms comprising Compound I within the range of about 1 mg to about 300 mg per vial. Particular dosage forms provided herein have about 1, 3, 6, 9, 10, 12, 13.5, 15, 18, 19, 21, 24, 25, 27, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120, 125, 130, 135, 140, 145 150 mg of Compound I per vial. Other dosage forms have about 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of Compound I per vial.

In another aspect, the application is directed to a pharmaceutical composition comprising a 1 mg-300 mg dose of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide hemi-L-tartrate. In another embodiment, the pharmaceutical composition comprises a 20 mg-100 mg dose of N- [5 - [ [[5 -( 1 , 1 -dimethylethyl)-2-oxazolyl]methy 1] thio] -2-thiazolyl] -4- piperidinecarboxamide hemi-L-tartrate. In another embodiment, the pharmaceutical composition comprises a 60 mg -180 mg dose of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide hemi-L-tartrate. In another embodiment, the pharmaceutical composition comprises a 150 mg-300 mg dose ofN-[5-[[[5-(l,l-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide hemi-L-tartrate.

Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles such as, but not limited to, vegetable oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms. For example, cyclodextrin and its derivatives can be used to increase the solubility of active ingredients. See, e.g., U.S. Patent No. 5,134,127, which is incorporated herein by reference.

In one embodiment, the methods of treating, preventing or managing cancers provided herein comprise administering to a patient Compound I, alone or in combination with a second active agent, on the basis of body surface area. Body surface area calculations can be calculated for example, with the Mosteller formula wherein:

B8A(m²)=square root of [(height(cm) x weight(kg)/3600]. In one embodiment, Compound I can be administered orally or intravenously and in single or divided daily doses in an amount of about 1 to about 150 mg/m². Certain exemplary doses per day include about 1, 3, 6, 9, 10, 12, 13.5, 15, 18, 19, 21, 24, 25, 27, 30, 38, 45, 50, 60, 63, 75, 80, 85, 90, 95, 100, 105, 1 10, 115, 120, 125, 130, 135, 140, 145 or 150 mg/m².

In another embodiment the dose of Compound I is about 20 mg/m² -30 mg/m². In another embodiment the dose is about 25 mg/m²-35 mg/m². In another embodiment the dose is about 40 mg/m²-50 mg/m². In another embodiment the dose is about 45 mg/m²-55 mg/m². In another embodiment the dose is about 50 mg/m²-60 mg/m². In another embodiment the dose is about 55 mg/m²-65 mg/m². In another embodiment the dose is about 60 mg/m²-70 mg/m². In another embodiment the dose is about 65 mg/m -75 mg/m . In another embodiment the dose is about 70 mg/m -80 mg/m . In another embodiment the dose is about 75 mg/m²-85 mg/m². In another embodiment the dose is about 80 mg/m²-90 mg/m². In another embodiment the dose is about 85 mg/m²-95 mg/m². In another embodiment the dose is about 90 mg/ni²-100 mg/m². In another embodiment the dose is about 100 mg/m²-l 10 mg/m². In another embodiment the dose is about 1 10 mg/m²- 120 mg/m². In another embodiment the dose is about 120 mg/m²-130 mg/m². In another embodiment the dose is about 130 mg/m²- 140 mg/m². In another embodiment the dose is about 140 mg/m²- 150 mg/m .

In another embodiment, the dose is 1 mg/m², 2 mg/m², 3 mg/m², 4 mg/m², 5 mg/m², 6 mg/m , 7 mg/m , 8 mg/m , 9 mg/m , 10 mg/m , 1 1 mg/m , 12 mg/m , 13 mg/m , 14 mg/m², 15 mg/m², 16 mg/m², 17 mg/m², 18 mg/m², 19 mg/m², 20 mg/m², 21 mg/m², 22 mg/m², 23 mg/m², 24 mg/m², 25 mg/m², 26 mg/m², 27 mg/m² , 28 mg/m², 29 mg/m², 30 mg/m², 31 mg/m², 32 mg/m², 33 mg/m², 34 mg/m², 35 mg/m², 36 mg/m², 37 mg/m², 38 mg/m², 39 mg/m², 40 mg/m², 41 mg/m², 42 mg/m², 43 mg/m², 44 mg/m², 45 mg/m², 46 mg/m², 47 mg/m², 48 mg/m², 49 mg/m², or 50 mg/m².

In another embodiment, the dose is 51 mg/m², 52 mg/m², 53 mg/m², 54 mg/m², 55 mg/m², 56 mg/m , 57 mg/m², 58 mg/m², 59 mg/m , 60 mg/m², 61 mg/m², 62 mg/m², 63 mg/m², 64 mg/m², 65 mg/m², 66 mg/m², 67 mg/m², 68 mg/m², 69 mg/m², 70 mg/m², 71 mg/m , 72 mg/m , 73 mg/m², 74 mg/m , 75 mg/m², 76 mg/m², 77 mg/m² , 78 mg/m², 79 mg/m², 80 mg/m², 81 mg/m², 82 mg/m², 83 mg/m², 84 mg/m², 85 mg/m², 86 mg/m², 87 mg/m², 88 mg/m², 89 mg/m², 90 mg/m², 91 mg/m², 92 mg/m², 93 mg/m², 94 mg/m², 95 mg/m², 96 mg/m², 97 mg/m², 98 mg/m², 99 mg/m², or 100 mg/m². The administered dose of Compound I can be delivered as a single dose (e.g. a single bolus IV injection) or over a 24-hour period (e.g., continuous infusion over time or divided bolus doses over time) and is repeated until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by methods known in the art, such as evaluation of patient symptoms, physical examination and other commonly accepted evaluation modalities.

The administered dose of Compound I can be expressed in units other than as mg/m . For example, doses can be expressed as mg/kg. One of ordinary skill in the art would know how to convert doses from mg/m to mg/kg to given either the height or weight of a subject or both (see, e.g, www.fda.gov/cder/cancer/animalframe.htm).

In certain embodiments, Compound I is cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.

The invention is further described by the following examples. The examples are for illustrative purposes and are non-limiting. 6. EXAMPLES

Example 1

In Vitro Activity Studies

Compound I demonstrated in vitro antiproliferative activity against a panel of human tumor cell lines covering the major solid tumor types. Compound I induced a cellular phenotype consistent with CDK-2, and CDK7/9 inhibition, based on alteration of cell cycle distribution, induction of apoptosis, and inhibition of DNA synthesis. In addition to demonstrating in vitro cytotoxic activity, Compound I showed antitumor activity in five tumor models.

Sensitivity to Compound I was neither dependent on tumor type nor cellular p53 status, but was mediated by overexpression of the multidrug resistance protein- 1 (MDRl) mRNA. Transport of Compound I by P-glycoprotein (P-gp) was further substantiated in permeability studies using Caco-2 monolayers. The permeability coefficient (Pc) of Compound I in the apical to basolateral direction was 14 to 42 nm/sec while in the basolateral to apical direction it was 161 nm/sec. This large difference in the bidirectional transport suggests Compound I may be a P-gp substrate.

Treatment with Compound I results in abrupt inhibition of cell cycle progression followed by an apoptotic response. Clonogenic assays indicate that as little as 8 hours of drug exposure is sufficient to elicit a maximal antiproliferative response in vitro. Compound I also has been tested in vitro in combination with several anticancer cytotoxics. In particular, Compound I shows schedule-dependent synergy with both cisplatin and carboplatin and additivity with doxorubicin and paclitaxel.

Example 2

In Vivo Activity Studies Compound I exhibited broad-spectrum antitumor activity, showing stasis or regression in multiple murine and human tumor models in vivo. These include the P388 mouse leukemia, cyclin E transgenic mouse breast carcinoma, A2780 human ovarian carcinoma, Colo205 human colorectal carcinoma, and A431 human squamous cell carcinoma. Compound I demonstrated curative efficacy at multiple dose levels in the A2780 human tumor xenograft when dosed IV on a qd x 8 schedule. Activity is dose and schedule dependent. In dose and scheduling studies, daily dosing schedules of 8 or 14 days showed equivalent and potent antitumor activity (greater than 1 log cell kill) in the A2780 ovarian carcinoma xenograft model. In contrast, less frequent dosing (q2d x 5, q4d ^χ 3) schedules showed significantly less activity (less than 1 log cell kill). These data suggest that Compound I has the greatest antitumor potential when dosed on a daily schedule as compared with intermittent schedules (i.e., weekly or every 3 weeks).

Example 3 Formulation of Compound I API The formulation for intravenous administration (Compound I Injection) is a clear, colorless to light-yellow aqueous solution (50 mg/vial (5 mg/mL) free base). It is supplied in 10 mL Type I glass vials. A 6% fill overage is included for vial-needle- syringe (VNS) withdrawal loss. Each vial contains 53.0 mg of Compound I active free base, 95.4 mg sodium chloride (tonicity agent), 3.39 mg L-tartaric acid (buffer, pH 4.0), and water. The vials of Compound I Injection should be stored under refrigeration (2 ⁰C to 8 ⁰C) and protected from light. The diluted solution can be stored refrigerated or at room temperature, but must be used within 26 hours of dilution. Compound I Injection is diluted with 0.9% Sodium Chloride Injection (Normal Saline) to the desired concentrations prior to administration (Compound I API can be diluted between 0.1 and 1.0 mg/mL).

For the studies described in the subsequent Examples, Compound I API was used, and is referred to in these Examples as "Compound I".

Example 4 Human Studies

A total of 135 patients with metastatic refractory solid tumors were treated with Compound I in three previous phase 1 studies (CA 174001, CAl 74002, and CAl 74006). The patient's ages ranged from 26 to 82 years with a median age of 60 years. A total of 464 cycles were administered to all patients treated in these three studies.

These studies, which had different dose schedules and/or routes of administration, are summarized in Table 1.

Table 1. Summary of Phase 1 Studies of COMPOUND I for the Treatment of Cancer

Study

CA174001 CA174002 CA174006 Number

Patients

64 51 20 Treated (N)

Dose (me/m ) 9.6, 13.0, 14.4, 17.5, 19.2, 4.8, 7.2, 9.6, 12.8, 17.0, 4.0, 6.7, 10.0, 13.0,

21.0, 25.0, 30.0, 37.5, 22.7, 30.3, 38, 47, 59, 74, and 16.0

47.0, 59.0, 71.0, 85.0, and 93, and 1 16

95.0

Cycle Length 21 days 21 days 21 days

Dosing 1-hour FV infusion 24-hour IV infusion 1-hour rv infusion

Schedule every 21 days every 21 days q7d x 3 doses.

On Cycle 2 Day 1 only

Compound I was given

PO, not IV

Endpoints Safety, PD, and PK Establish MTD and DLT, Establish MTD and DLT, and Safety, PD, and PK and Safety, PD, and PK

Safety Results Most frequent DLT was DLTs of elevated One patient at 13 mg/m² neutropenia transaminases and had an SAE of acute renal

At 95 mg/m², one DLT of hyperbilirubinemia failure occurred during chest pressure and one At 1 16 mg/m², one patient Cycle 2 syncopal episode had DLTs of hypotension, occurred^a syncope, dyspnea, and

The MTD was deemed acute renal failure. The

85 mg/m². MTD was not determined.

Abbreviations: DLT = dose-limiting toxicity; IV = intravenously; MTD = maximum tolerated dose;

PD = pharmacodynamics; PK = pharmacokinetics; PO = orally. aThe syncopal episode occurred during Cycle 2, but was considered in determining the MTD.

CA 174001

Study CA 174001 was a open label dose-escalation study in which Compound I was administered as a 1-hour IV infusion once every 21 days. Cohorts of at least three patients were treated at each dose level, starting at 9.6 mg/m² of Compound I. The dose was escalated following a modified Fibonacci scheme. Intrapatient dose escalation was allowed only after a patient had received at least two cycles. If a patient had an acceptable toxicity profile, the dose could be increased by one dose level for the next cycle, but only if all 3 patients at the next highest dose level had already completed Cycle 1 without having a DLT.

Objective tumor response was to be evaluated in all patients with measurable disease using a modified form of the WHO criteria incorporating the use of target/nontarget lesions used in the Response evaluation criteria in solid tumors (RECIST) response criteria. The assessments were to be made every two cycles (six weeks) or more frequently if medically indicated. A response was considered confirmed if it was noted on two assessments at least four weeks apart.

A total of 65 patients were enrolled and 64 were treated. All 64 treated patients had received prior cancer therapy, predominantly chemotherapy with or without radiotherapy (45% and 23%, respectively). The patients had the following tumor types: NSCLC (N=I 8), colon (N=8), breast (N=3), prostate (N=2), gastric (N=I), melanoma (N=I), and other (N=31). Of the 37 men and 27 women treated, 59 were white, 2 black, and 3 other, with ages ranging from 26 to 82 years with a median age of 60 years.

The 64 treated patients received a combined total of 254 Compound I treatment cycles. The dose levels, the number of patients by assigned dose cohort, and the number of treatment cycles administered to each dose cohort are summarized in Table 2.

Table 2. Number of Patients Receiving Treatment Cycles by Dosing Cohort in Study CA174001

Dose Cohort Subsequent Reduced Escalated

First Cycle Total Cycles (mg/m²) Cycles Cycles Cycles

9.6 3 12 0 0 15

13.0 0 1 1 0 1

14.4 3 10 0 3 13

17.5 6 15 0 5 21

19.2 1 0 0 0 1

21.0 4 19 0 5 23

25.0 3 9 0 4 12

30.0 3 14 0 7 17

37.5 4 6 0 4 10

47.0 6 6 0 0 12

59.0 3 8 1 2 1 1

71.0 1 1 56 2 23 67

85.0 13 29 2 0 42

95.0 4 5 0 0 9

Total 64 190 6 53 254

Of the 64 patients treated in this study, 53 patients completed 2 or more treatment cycles. The reasons why 11 patients did not receive at least 2 treatment cycles are as follows: 8 for disease progression/relapse, and 1 each for deterioration without progression, subject request, and other.

Serial ECGs were recorded for patients at dose levels ranging from 9.6 to 95.0 mg/m². There were no incidences of QTc by Bazett's correction greater than 500 msec. Ten patients experienced QTcB > 450 msec during Cycle 1, and in each case the QTc corrected by Friderica's method was < 450 msec. One of these patients (CA174001- 1-121) had a change in QTc from a baseline of > 60 msec. Two patients had a QTc > 450 in Cycles 2 and later. There was no apparent dose-related trend in QTc increase.

Clinical AEs were reported for all 64 (100%) patients who received treatment. The severity of each AE was evaluated using the National Cancer Institute Common Toxicity Criteria, version 2.0 (NCI CTC v2.0) scale. The most common AEs (regardless of relationship) reported were fatigue (89%), nausea (52%), dyspnea (47%), anorexia (39%), cough (39%), diarrhea (39%), arthralgia (31%), constipation (31%), infection without neutropenia (31%), and pain other (31%). Treatment-related AEs occurred in 54 (84%) patients. The most common treatment- related AEs were fatigue (41%) and nausea (39%). Table 3 lists treatment-related AEs reported in > 10% of patients.

Table 3. Summary of Treatment Related Adverse Events Reported in ≥ 10% of Patients in Study CA174001

Event No. (Percent)

Fatigue 26 (41)

Nausea 25 (39)

Diarrhea 18 (28)

Vomiting 13 (20)

Anorexia 10 (16)

Sinus Tachycardia 7 (H)

Myalgia 7 (11)

Abbreviation: No. = number of patients.

Serious adverse events were reported in 15 of 64 patients (23.4%) treated in this study. Six of the 15 patients had 8 SAEs assessed as related to Compound I (Table 4). Table 4. Summary Serious Adverse Events Reported as Related to Compound I for Patients in CA174001

Relationship

Dose

Patient Event Grade to Compound Outcome

(mg/m²)

I

0001-001 10 13 Increased LFTs 3 Possible Resolved

0001-00140 95 Syncopal Episode^*1 3 Possible Resolved Sinus Bradycardia⁸ 4 Possible Resolved Seizure 3 Possible Resolved

0002-00215 85 Neutropenia 4 Probably Resolved

0002-00216 85 Febrile Neutropenia 3 Probably Resolved

0002-00218 71 Neutropenia w/o fever^b 4 Probably Resolved

0002-00225 95 Neutropenia 4 Certain Resolved ^aBecause of this event, Compound 1 treatment was discontinued. bBecause of this event, the patient received a reduced Compound I dose for subsequent doses.

There were no patient deaths attributed to Compound I, all deaths were related to disease.

Four patients were treated at the maximum administered dose (MAD), 95.0 mg/m². Table 5 summarizes the reported DLTs by dose level. The MTD was defined as the dose level just below the MAD, providing DLT was observed in less than two of six treated patients (or fewer than one-third if more than six treated patients) at that dose level. In the 85.0 mg/m² Compound I dose cohort, DLTs were observed in 3 of 13 patients (23%). Therefore, the MTD for Compound I administered IV on Day 1 of each 21 -day treatment cycle was deemed 85 mg/m². Fifty-seven of 64 patients (89.1%) had measurable disease at baseline. The best clinical response was stable disease in 23 of 57 patients.

Table 5. Incidence of Dose-Limiting Toxicities by Dose Cohort in Study CA174001

No. of Patients with

Dose

DLT / No of Cohort DLT

Treated Patients

(mg/m²) (%)

9 6 0/3 (0%) —

13 0 0/1 (0) —

14 4 0/3 (0) —

17 5 1/6 (16 7) Grade 2 AST and ALT elevation

19 2 0/1 (0) —

21 0 0/4 (0) —

25 0 0/3 (0) —

30 0 0/3 (0) —

37 5 0/4 (0) —

47 0 1/6 (16 7) Grade 3 AST elevation

59 0 0/3 (0) —

71 0 1/1 1 (9 0) Grade 4 neutropenia

85 0 3/13 (23 1 ) Grade 4 neutropenia

Grade 4 neutropenia

Grade 3 febrile neutropenia⁸

95 0 2/4 (50%) Grade 3 syncopal episode⁶

Grade 3 chest pressure

Total 8/64 (12 5%)

Abbreviations DLT = dose-limiting toxicity, No = number of patients

"Study drug was interrupted on Cycle 1 Day 1 due to a hypersensitivity reaction The patient presented the next day with febrile neutropenia and was admitted to the hospital No fevers were noted prior to this event bSyncopal episode occurred in Cycle 2, thus it is not a Cycle 1 DLT per protocol, but was taken into consideration for MTD determination

CA 174002

Study CA 174002 was an open label, dose-escalation study in which Compound I was administered as a 24-hour infusion on Day 1 of each 21 -day treatment cycle. The starting dose was 4.8 mg/m and the dose was increased by 50% after the first cohort, then increased by 33% after the next 6 dose levels, after which the dose was increased by only 25%. Intrapatient dose escalation was allowed only after a patient had received at least two cycles and had an acceptable toxicity profile. For these patients, the dose could be increased by one dose level for the next cycle, but only if all 3 patients at that next highest dose level had already completed Cycle 1 without having a DLT. Tumor assessments were as previously described for Study CAl 4001.

Fifty-five patients enrolled into the study, and 51 were treated. All 51 treated patients had received prior cancer therapy, predominantly chemotherapy with radiotherapy (43%) and chemotherapy without radiotherapy (35%).

The 51 treated patients had the following tumor types: colon (N=I 1), NSCLC (N=6), gastric (N=2), pancreas (N=2), breast (N=I), melanoma (N=I), ovary (N=I), prostate (N=I), other (N=25), and unknown (N=I). Of the 28 men and 23 women treated, 48 were white and 3 black, with ages ranging from 27 to 82 years and median age was 60 years.

A total of 51 treated patients received a combined total of 171 Compound I treatment cycles. The Compound I dose levels, the number of patients by assigned dose cohort, and the number of treatment cycles administered to each dose cohort are summarized in Table 6.

Table 6. Number of Patients Receiving Treatment Cycles by Dosing Cohort Protocol CAl 74002

Dose Cohort First Cycle s Suubosseeqquueennt. u Essccaaⁱlaaⁱteeαd _{Total Cycles}

CCyycclleess CCyycclleess

(mg/m ) (N) (N)

(N) (N)

4.8 1 3 0 4

7.2 3 1 0 4

9.6 7 6 0 13

12.8 3 6 0 9

17.0 3 7 1 10

22.7 6 1 1 4 17

30.3 6 16 2 22

38 3 9 6 12

47 6 1 1 2 17

59 3 1 1 6 14

74 3 13 6 16

93 6 26 13 32

1 16 1 0 0 1

Total 51 120 40 171

Of the 51 patients treated in this study, 37 patients completed at least 2 treatment cycles. The reasons 14 patients did not receive at least two treatment cycles are as follows: 8 for deterioration without progression, 3 for disease progression and 3 for study drug toxicity (patient 0001-00113 QTc abnormalities, patient 0002-00213 increased LFTs, and patient 0002-00225 multi-organ system failure).

Serial ECGs were recorded for patients at dose levels ranging from 4.8 to 93.0 mg/m². There were no incidences of QTc by Bazett's correction (QTcB) greater than 500 msec. Seven patients experienced QTcB > 450 msec during Cycle 1, and in each case the QTc corrected by Friderica's method was < 450 msec. An additional 3 patients had QTcB > 450 msec with QTc by Friderica's method < 450 msec in subsequent cycles. There were no increases from baseline QTcB > 60 msec. There was no apparent dose related trend in QTc increase. Clinical AEs were reported for all 51 (100%) patients who received treatment. The most common AEs reported were fatigue (86%), constipation (49%), abdominal pain or cramping (43%), anorexia (43%), nausea (41%), dyspnea (35%), and diarrhea

(33%).

Treatment-related AEs were reported for 39 (76%) patients. The most common treatment-related AE was fatigue (39%). Table 7 lists treatment-related AEs reported in > 10% of patients.

Table 7. Summary of Treatment Related Adverse Events Reported in > 10% of Patients in Study CA 174002

Event No. (%)

Fatigue 20 (39)

Allergy/Immunology - Other 14 (27)

Nausea 10 (20)

Diarrhea 10 (20)

Vomiting 5 (10)

Injection Site Reaction 5 (10)

Abbreviation: No. = number of patients

Serious adverse events were reported in 22 of 51 (43.1%) treated patients. Seven patients had 18 SAEs assessed as related to Compound I (Table 8). Patient 0001- 00102 (dosed at 9.6 mg/m²) had SAEs of Grade 3 elevated SPGT (ALT) and bilirubin and Grade 4 jaundice that the Investigator initially assessed as "probably related" to Compound I; thus requiring expansion of the cohort. Based on supplemental information subsequently received after the dose cohort was expanded, the Investigator amended his assessments to "not related." Patient 0002-00223 had an SAE of Grade 3 increased abdominal pain that the Investigator initially assessed as "possibly related" to study drug. The abdominal pain was later determined to be due to disease progression and was re-assessed as "not related" to Compound I.

Table 8. Summary Serious Adverse Events Reported as at least Possibly Compound I Related in Study CAl 74002

Relationship

Patient Dose

Event Grade to Compound Outcome ID # (mg/m²) I

0001 -001 13 22.7 QTc Prolonged Interval 1 Certain Resolved"

0001 -001 19 38 Fever 2 Possible Resolved^b

0001-00124 59 Hypertension 3 Possible Resolved^b

0002-00208 17 Phlebitis 2 Probable Resolved

0002-00213 22.7 Elevated AIk Phosphatase 3 Possible⁰ Resolved" Elevated AST 3 Possible⁰ Resolved"^* Elevated ALT 3 Possible⁰ Resolved" Elevated Bilirubin 3 Possible⁰ Resolved"

0002-00218 47 Elevated AST 3 Probable Resolved

0002-00225 1 16 Acute Renal Failure 3 Probable Resolved" Neutropenia 4 Certain Resolved Syncope 3 Probable Resolved" Fever 1 Possible Resolved Hypotension 5 Probable Resolved¹¹ Dyspnea 3 Probable Ongoing¹* Elevated AST 1 Probable Ongoing^d Elevated Creatinine 2 Probable Ongoing^d Sinus Tachycardia 1 Possible Ongoing^d

"Because of this event, Compound I treatment was discontinued. bBecause of this event, Compound I treatment was interrupted.

°These events were originally assessed as "related" to disease progression. After 3 patients were treated at the next dose, these events were recategorized as "possibly related" Compound I. dThese SAEs were ongoing at the time of the patient's death.

There were 18 (35.3%) reported deaths, none of which were considered Compound I related.

Six patients were treated at 22.7 mg/m . Initially, one of these patients had a DLT of Grade 1 QT prolongation. A second patient had AEs related to disease progression, which were subsequently considered possibly related to study drug and, thus, categorized as DLTs after 3 patients had been enrolled at the next dose level (30.3 mg/m²). No DLTs were noted in the first 3 patients at 30.3 mg/m² or in an additional 3 patients enrolled as an extra precaution at that dose level. Dose escalation continued for an additional 6 dose levels. Table 9 summarizes the DLTs by cohort. Table 9. Incidence of Dose-Limiting Toxicity by Dose Cohort in Study CAl 74002

Compound I No. with DLT /

DLT No. Treated (%)

(mg/m²)

4 8 0/1 (0)

7 2 0/3 (0)

9 6 0/7 (0) Grade 3 elevated AST, Grade 4 jaundice, hyperbilirubinemia and hepatic-other^a, Grade 3 elevated bilirubin (patient CA174002-l-102)^b

12 8 0/3 (0)

17 0 0/3 (0)

22 7 2/6 (33 3) Grade 1 prolonged QTc interval- discontinued (patient CA 174002-1-

1 13)

Grade 3 elevated transaminases and bilirubin discontinued drug (patient

CA 174002-2-213)°

30 3 0/6 (0) —

38 0/3 (0) -

47 1/6 (16 7) Grade 3 AST elevation (patient CA 174002-2-218)

59 0/3 (0) -

74 0/3 (0) ~

93 0/6 (0) Grade 3 Increased Abdominal Pain and increased LFTs (patient CA 174002-2-

223)^d

1 16 1/1 (100) Grade 3 hypotension, syncope, dyspnea, and acute renal failure - discontinued drug (patient CA 174002- 2-225)

Total 4 of 51 (7.8%) -

Abbreviations DLT = dose-limiting toxicity, No = number of patients

"Hepatic-other = CTC term for hepatic replacement by tumor bThe Investigator initially assessed these events as related to study drug, requiring expansion of the cohort Based on supplemental information subsequently received after the dose cohort was expanded, the Investigator amended his assessment to "not related " Thus, the adverse events no longer counted toward the DLT total cThese events were originally assessed as "related" to disease progression

After 3 patients were treated at the next dose, these events were recategoπzed as "possibly related" to Compound I dThe Investigator initially assessed abdominal pain as "possibly related" to study drug The abdominal pam was later determined to be due to disease progression and was re-assessed as "not related" to Compound I Thus, it no longer counts toward the DLT total Compound I was safe and well tolerated at doses up to 93.0 mg/m², where 6 patients were treated without DLTs. The MTD was not formally established as only 1 patient was treated at the 1 16 mg/m² dose level. At or below 93.0 mg/m², the most prominent DLTs were elevated transaminases and hyperbilirubinemia. Forty-nine (96.1%) of 51 treated patients had measurable disease at baseline. The best clinical response was stable disease in 8 of 49 (16.3%) patients.

CA 174006

This was an open-label, phase 1 dose-escalation study of Compound I administered once weekly as a 1-hour IV infusion. A cycle was defined as a 21 -day period with 3 weekly Compound I administrations (ie, on Days 1, 8, and 15). On Cycle 2 Day 1 only, patients were to receive Compound I PO (orally, fasting) instead of IV. The strength of the PO dose was to be equivalent to the IV dose that the patient had been receiving. For oral administration, vials of Compound I Injection (described in Example 3 herein) were used. The appropriate doses were withdrawn directly from the vial into a syringe from which the solution was dispensed directly to the patient's motuth. This administration was followed with 8 oundes of water. Patients fasted for at least 8 hours prior to and 2 hours after oral administration. Concomitant medications were held for two hours after oral dosing.

Cohorts of at least 3 patients were to be given at least 2 Compound I treatment cycles. Pending safety results and tumor response, patients could continue treatment as long as clinical benefit was observed. The starting dose for this once-weekly dosing schedule was 4 mg/m², and dose escalations were made according to a modified Fibonacci scheme.

If a DLT was observed during Cycle 1 in 1 of 3 treated patients, then up to 3 additional patients could be treated at the same dose level. Dose escalation continued until a Cycle 1 DLT was observed in at least 2 of 6 patients (> 1/3 of the patients) treated at that dose level, or until the Investigator and Sponsor agreed the MTD had been reached. Intrapatient dose escalation was allowed only after a patient had received at least two cycles. If a patient had no > Grade 2 toxicity, the dose was increased by one dose level for the next cycle, but only if all 3 patients at that next highest dose level had already completed Cycle 1 without having a DLT. Patients were evaluated for tumor response using the new RECIST criteria. The assessments were to be made every two cycles (six weeks) or more frequently if medically indicated. A response was considered confirmed if it was noted on two assessments at least four weeks apart. A total of 21 patients were enrolled, 20 of whom were treated. All 20 patients had received prior cancer therapy, predominantly chemotherapy alone (50%) or in combination with either radiotherapy and hormonal therapy (25%), or radiotherapy alone (20%).

The 20 treated patients had the following tumor types: colon (N=6), NSCLC (N=S), other (N=4), pancreas (N=3), breast (N=I), prostate (N=I), unknown (N=I). Of the 9 males and 1 1 females treated in study CA714006, 18 were white and 2 black, with ages ranging from 42 to 78 years and a median age of 57 years.

The 20 treated patients received a combined total of 39 Compound I treatment cycles. The Compound I dose levels, the number of patients by assigned dose cohort, and the number of treatment cycles administered to each dose cohort are summarized in Table 10.

Table 10. Number of Patients Receiving Treatment Cycles by Dosing Cohort in Study CA174006

Dose Cohort First Cycle Subsequent Total Cycles

(mg/m²) (N) ^C ₍ ^y^^eS (N)

4.0 4 3 7

6.7 3 2 5

10.0 3 6 9

13.0 6 5 1 1

16.0 4 3 7

Total 20 19 39

Of the 20 treated patients, 16 received two or more treatment cycles. The reasons 4 patients did not receive at least 2 treatment cycles are as follows: one each for disease progression, deterioration without progression, AE, and subject request.

Serial ECGs were recorded for patients at dose levels ranging from 4.0 to 16.0 mg/m². There were no incidences of QTc by Bazett's correction > 450 msec, nor were there any increases from baseline in the QTc > 60 msec. Clinical AEs were reported for all 20 treated patients (100%). The most common AEs reported were fatigue (90%), abdominal pain or cramping (45%), pain other (45%), constipation (35%), nausea (35%), anorexia (30%), cough (30%), diarrhea (30%) and sensory neuropathy (30%). Treatment-related AEs occurred in 13 patients (65%). The most common treatment-related AEs were fatigue (25%) and nausea (20%). No clear pattern of treatment-related AEs could be attributed to Cycle 2 Day 1 PO Compound I. Table 11 summarizes the treatment-related AEs.

Table 11. Summary of Treatment Related Adverse Events Reported in ≥ 10% of CAl 74006

Event No. (%)

Fatigue 5 (25)

Nausea 4 (20)

Diarrhea 2 (10)

Abbreviation: No. = number of patients.

Serious adverse events were reported in 6 (30%) patients in this study. Two patients had 4 SAEs assessed as at least possibly related to Compound I. Table 12 summarizes the SAEs assessed as related to Compound I.

Table 12. Summary Serious Adverse Events Reported as Related to Compound I for Patients in Study CA174006

„ .. . _r. Relationship

Patient Dose _r. ^ ^ j _{± n *}. r_rv „ , , ₂^ Event Grade to Outcome

ID # (mg/m ) _, v^s ' Compoundl

0001-00101 16 Anemia 3 Possible Resolved Hemoglobin 3 Possible Resolved

0002-0021 1 13 Acute Renal Failure¹¹ 4 Possible Resolved^b Increased Creatinine 3 Possible Ongoing⁰

"The acute renal failure occurred during Cycle 2. bBecause of this event, Compound I treatment was discontinued. cBecause of this event, Compound I treatment was interrupted. This SAE was ongoing at the time of the patient's death.

Two deaths unrelated to Compound I occurred during the study follow-up period. An MTD could not be determined as the study was incomplete. The best clinical response was stable disease in 3 (15%) patients. Human Pharmacokinetics and Metabolism

The PK of Compound I was evaluated in three clinical trials (CA 174001 [1-hour infusion once every 3 weeks], CA 174002 [24-hour infusion once every 3 weeks], and

CAl 74006 [1-hour infusion once every week, except the Cycle 2 Day 1 dose was administered PO]). Preliminary PK data are available from 63 (CA 174001), 44 (CA 174002), and 20 (CA 174006) patients treated at doses ranging from 4 to 116 mg/m . A validated method using liquid chromatography in tandem with mass spectrometry (LC-MS/MS) detection was used to analyze plasma samples. CAl 74001 Pharmacokinetics

In study CA 174001, Compound I was administered once every 3 weeks as a 1-hour IV infusion. Pharmacokinetic parameters after Cycles 1 and 2 administration of 9.6 to 95 mg/m² Compound I are summarized in Table 13. Plasma concentrations declined in a biphasic manner, resulting in Ty₂ between 8 and 13 hours. Across this dose range, C_max and AUCo-inf increased relatively linearly with dose, ranging between 0.220 and 2.21 μg/mL, and 0.435 to 4.245 μg»hr/mL, respectively for the 9.6 to 95 mg/m² dose levels. The CL averaged 26 L/hr/m² (range: 18-33L/hr/m²) and V_ss averaged 204 L/m² (range: 111-278 L/m²). These values were dose independent and did not change from Cycle 1 to Cycle 2.

Table 13. Single-Dose Plasma Pharmacokinetics ofa 1-hour Infusion ofCompound I give to

Patients with Solid Tumors in Study CA174001

Cmpd I" Pharmacokinetic Parameter ± Standard Deviation¹¹

(mg/m²) n AUCo-.nf CL v_ss Tl/2

Cycle (μg/mL) (μg»hr/mL) (L/hr/m²) (L/m²) (hr)

9.6 0286±007

1 3 5 056710207 1918 111178 8+2

2 3 022±0028 043510121 2317 130124 8+1

14.4 0328±014

1 3 3 067310136 22+5 2221111 1314

03511006

3 4 086010231 1815 2431108 1315

17.5 0386±003

1 6 8 0755+0292 2517 155135 912

0333±004

5 6 061610220 3119 2781118 10+3

19.2

1 1 0358 0676 28 268 13

21 0344±005

1 4 8 069910111 3115 220143 911

0386±006

3 8 074410070 2813 253+56 1210

25 0527±005

1 3 4 0953+0510 31115 245184 11+1

Z 0627±007

3 3 120210435 2318 161128 1011

30 07181018

1 3 9 124310284 2516 161+55 913

Z 06731024

3 2 113710570 31113 2301103 1011

37.5 06441008

1 4 3 1205+0092 3112 240121 1212

Z 03581050

2 4 1057 35 274 11

47 10751015

1 6 7 204610532 2417 201168 11+2

Z, 08281017

4 5 153210418 3319 237130 1111

59

1 3 13161025 236310605 2616 193122 1112

Z 12141007

2 8 202010361 3015 219135 1110

71 1954+091

1 11 7 3631+1068 21+7 179173 1112

Z 18711081

10 7 360110806 2115 169151 1112

85 20611098

1 12 1 398611084 23±5 176+55 10+1

Δ 19671074

11 1 380911462 25+9 192150 nil

95 22101013

1 5 8 424511261 24+6 196138 1212 2.160±0.28

0 3.934±0.813 25±6 152±52 9±3

"Compound I ver 1 hour. Plasma samples obtained between 0.5 and 48 hours after Cycles 1 and 2 Day 1 doses. Samples stored frozen until analysis using a validated LC-MS/MS method.

CA 174002 Pharmacokinetics

In study CA 174002, Compound I was administered once every three weeks as 24-hour IV infusion. Table 14 summarizes the PK parameters after Cycle 1 Compound I doses of 4.8 to 93 mg/m². After the infusion was completed the plasma concentration declined in a biphasic manner, resulting in Ty₂ between 7 and 17 hours. Over this 20-fold dose range, C_max and AUCo-mf increased approximately linearly with dose, ranging between 0.011 and 0.252 μg/mL, and 0.145 to 5.225 μg»hr/mL, respectively. Clearance and Vss remained unchanged with increasing dose levels, averaging 28 L/hr/m² (range: 19-40 L/hr/m²) and 547 L/m² (range: 387-714 him²), respectively.

The AUC, CL, and Ty₂ were similar after 1-hour and 24-hour infusions, indicating that Compound I PK is independent of the infusion duration (see Table 13).

Table 14. Single-Dose Plasma Pharmacokinetics of a 24-hour Infusion of Compound I given to Patients with Solid Tumors in Study CA174002

Abbreviations: AUC₀._inf = area under the curve from time 0 to infinity; CL = clearance;

C_raax ⁼ maximum measured concentration; SD = standard deviation; T,_A = terminal half-life;

V_ss = volume of distribution at steady state. aCompound I given IV over 24 hours. Plasma samples were obtained between 2 and 74 hours after the Cycle 1 Day 1 administration. Samples were stored frozen until analysis was performed using a validated LC-MS/MS method. cThe patient treated at 1 16 mg/m² only had PK samples going out to 24 hours postdose.

CA 174006 Pharmacokinetics

Pharmacokinetic parameters after a single dose 1 -hour IV infusion of 4 to 16 mg/m² Compound I are summarized in Table 15. Plasma concentration declined in a biphasic manner, resulting in Ty₂ between 5 and 9 hours. The C_max and AUCo_-mf increased nearly linearly with dose, ranging between 0.067 and 0.287 μg/mL, and 0.103 to 0.553 μg»hr/mL, respectively. Clearance and V_ss remained unchanged with increasing dose levels, averaging 38 L/hr/m (range: 35-40 L/hr/m ) and 212 L/m²(range: 155-259 L/hr/m²), respectively.

Patients dosed at 13 and 16 mg/m² received their Cycle 2 Day 1 dose PO. Oral PK results are summarized in Table 16. In the 6 patients available for evaluation, the average bioavailability was 21%, indicating that PO administration may be possible in the future. (Two patients were excluded from this bioavailability calculation due to > 20% deviation from nominal sampling time or due to inadequate characterization of the terminal phase of the plasma AUC.)

Table 15. Single-Dose Plasma Pharmacokinetics of a 1-hour Infusion of Compound I given to Patients with Solid Tumors in Study CA174006

Mean Pharmacokinetic Parameter ± SD

Cmpd I"

(mg/m²) n ^-max AUCo-mf CL v_ss T./,

(μg/mL) (μg»hr/mL) (L/hr/m ²) (L/m2) (hr)

4 4 0 067±0013 0103±0021 4018 1551104 4 9134

6.7 3 0 11410018 019210082 40117 17618 6 4+11

10 J -_> 0 143±002 0279±0080 38+10 259119 9 4128

13 6 0 237±0075 039610116 35111 226180 9 8148

16 4 0 287±0081 0553+084 37122 2461176 9 1118

Abbreviations AUC_{0 inf} = area under the curve from time 0 to infinity, CL = clearance, C_maχ ⁼ maximum measured concentration, SD = standard deviation, T_Λ = terminal half-life, V_ss = volume of distribution at steady state aCompound I infusion was given IV over 1 hour Plasma samples were obtained between 0 5 and 48 hours after the Cycle 1 Day 1 administration Samples were stored frozen until analysis was performed using a validated LC-MS/MS method

Table 16. Single-Dose Plasma Pharmacokinetics of Compound I

Administered Orally in Patients with Solid Tumors in Study CAl 74006

Abbreviations AUCo__mf = area under the curve from time 0 to infinity,

C_max ⁼ maximum measured concentration, SD = standard deviation, Ty₂ = terminal half-life, F = bioavailability aCompound I infusion was given orally on Cycle 2 Day 1 Plasma samples were obtained between 0 5 and 48 hours after the Cycle 2 Day 1 administration

Samples were stored frozen until analysis was performed using a validated

LC-MS/MS method

Data Summary

Compound I is a generally well tolerated cytotoxic drug. Over a hundred patients with advanced solid tumors have been treated with Compound I. Patient ages ranged from 26 to 82 years. The most frequent AEs include fatigue, nausea, vomiting, and diarrhea. There appears to be some schedule and dose-dependent toxicities, including neutropenia and elevation of liver enzymes, primarily in patients with GI and liver metastasis. Example 5

In Vivo Activity Studies in Combination With Anticancer Cytotoxics

The activity of Compound I was studied in combination with cisplatin or in combination with carboplatin in the A2780 human tumor xenograft model. For each study, animals were randomized by tumor volume and distributed into groups often animals each. Treatments were initiated when tumors averaged about 200 mm³ in volume. End points for each group were determined based on body weight nadir, adverse clinical observations, or tumor volumes exceeding maximum threshold of 2000 mm³. Responses were assessed by tumor growth inhibition (TGI) and tumor growth delay (TGD). TGI and TGD in the combination group was evaluated against the vehicle control group and comparable doses of single agent monotherapy.

In the carboplatin study, Compound I was administered intraperitoneally (IP) once every four days for 2 times (q4d ^χ2) at a dose of 60 mg/kg or at 30 mg/kg IP daily for 8 days (qd *8). Carboplatin was administered intravenously (IV) at a dose of 75 mg/kg q4d *2. In the combination group, animals were treated with carboplatin at 75 mg/kg IV and Compound I at 60 mg/kg IP on a q4d x2 schedule with staggered dosing of Compound I 24 hours after carboplatin administration. Tumor Growth Inhibition (TGI) was determined by examining the tumor volume graph and calculating the percent of inhibition from the vehicle control group on the last day the control contained at least 75% of the animals. TGI is then calculated with the following formula:

(control TV_, - control TV₁) - (treatment TV _t. - treatment TV₁) x 100 (control TVj - control TV₁) where TV _t is the average tumor volume on the last day the control contained at least 75% of the animals and TV₁ is the initial average tumor volume. ANOVA was performed to calculate statistical significance, defined as p<0.05. Time To Endpoint (TTE) was calculated for each individual animal to reach the predetermined study end point where the tumor volume becomes 1200 mm³ or 10% of body weight or a greater than 20% body weight loss for two sequential measurements. The TTE is calculated and the median value is recorded for the group. Tumor Growth Delay (TGD) is then calculated with the following formula: median TTEt_reatment - median TTE_controi Percent Tumor Growth Delay (%TGD) is calculated with the following formula: median TTE_treat_ment - median TTE_COntroi x 100 median TTE_controi A Log Rank test was performed to calculate statistical significance, defined as p<0.05.

The change in tumor volume over time is shown in Figure 2. Carboplatin dosed q4d ^χ2 did not have significant single agent activity as compared to the vehicle group. Compound I dosed at 30mg/kg as a single agent on a q4d ^χ2 and qd ^χ8 schedule showed efficacy compared to the vehicle group. The combination of Compound I dosed q4d ^χ2 at 60mg/kg 24hr after carboplatin at 75 mg/kg showed additional antitumor activity from the vehicle group and also from the activity of single agents alone. The combination of Compound I dosed q4d ^χ2 at 60mg/kg 24hr after carboplatin at 75 mg/kg significantly delayed tumor growth compared to the vehicle. Percent TGI and p-values and TGD(Days) and p-values are shown in Table 17.

Table 17. Tumor Inhibition by Compound I, Carboplatin, and Combinations in Mouse A2780 Xenograft Model

Dosing Group % TGI TGD(Days)

(p-value) (p-value)

Vehicle - -

Carboplatin 75 mg/kg q4d x2 49.2 6

(0.0026) (0.0094)

Compound I 60 mg/kg q4d x2 69 6

(0.0001) (0.0019)

Compound I 30 mg/kg qd x8 90.9 11.5

(O.OOOl) (0.0002)

Carboplatin 75 mg/kg + 100.16 21.5

Compound I 60 mg/kg q4d x2 (0.0001) (0.0001)

In the cisplatin study, Compound I was administered intraperitoneally (IP) once every four days for 2 times (q4d ^χ2) at a dose of 30 mg/kg. Cisplatin was administered intravenously (IV) q4d ^χ2 at a dose of 5 mg/kg. In the combination group, animals were treated with cisplatin at 5 mg/kg IV and Compound I IP at 30 mg/kg on a q4d ^χ2 schedule with staggered dosing of Compound I 24 hours after cisplatin administration. The change in tumor volume over time is shown in Figure 3. Compound I dosed as a single agent q4d ^χ2 at 30 mg/kg did not have significant single agent activity as compared to the vehicle group. Cisplatin dosed at 5 mg/kg IV q4d *2 showed efficacy compared to the vehicle group. The combination of Compound I dosed q4d ^χ2 at 30 mg/kg 24hr after cisplatin dosed at 5 mg/kg showed additional anti-tumor activity from the vehicle group and also from the activity of single agent Compound I alone. The combination of Compound I dosed q4d ^χ2 at 30 mg/kg 24hr after cisplatin dosed at 5 mg/kg significantly delayed the tumor growth compared to the vehicle. Percent TGI and p-values and TGD(Days) and p-values are shown in Table 18.

Table 18. Tumor Inhibition by Compound I, Cisplatin, and Combinations in Mouse A2780 Xenograft Model

Dosing Group % TGI TGD(Days)

(p-value) (p-value)

Vehicle - -

Cisplatin 5 mg/kg q4d x2 65 10

(0.0025) (0.0534)

Compound I 30 mg/kg q4d x2 22.9 2

(0.3163) (0.4871)

Cisplatin 5 mg/kg + 93.2 15

Compound I 30 mg/kg q4d x2 (<0.0001) (0.01 1 1)

Claims

What is Claimed Is:

1. A method of treating cancer comprising administering to a mammal in need thereof a dose of Compound I of about 1 mg/m² - 150 mg/m².

2. The method of claim 1 wherein the mammal is administered a daily dose of

Compound I for at least two days.

3. The method of claim 1 wherein the mammal is administered a daily dose of Compound I for three days.

4. The method of claim 1 wherein the mammal is administered a daily dose of Compound I for four days.

5. The method of claim 1 wherein the mammal is administered a daily dose of Compound I for five days.

6. The method of claim 1 wherein the mammal is administered a daily dose of Compound I for six days.

7. The method of claim 1 wherein the mammal is administered a daily dose of

Compound I for seven days.

8. The method of claim 1 wherein the mammal is administered a daily dose of

Compound I for eight days.

9. The method of claim 1 wherein the mammal is administered a daily dose of

Compound I for nine days.

10. The method of claim 1 wherein the mammal is administered a daily dose of Compound I for ten days.

11. The method of claim 1 wherein the cancer is a solid tumor.

12. The method of claim 1 wherein the cancer is a blood borne tumor.

13. The method of claim 1 wherein the cancer is a cancer of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, or uterus.

14. A method of cancer treatment comprising administering to a mammal in need thereof a daily dose of Compound I of 10-50 mg/m² as a 1-hour infusion for five days every three weeks.

15. The method of claim 14 wherein the daily dose is 15-25 mg/m².

16. The method of claim 14 wherein the daily dose is 20-30 mg/m².

17. The method of claim 14 wherein the daily dose is 25-35 mg/m².

18. The method of claim 14 wherein the daily dose is 30-40 mg/m².

19. The method of claim 14 wherein the daily dose is 35-45 mg/m².

20. The method of claim 14 wherein the daily dose is 40-50 mg/m².

21. The method of claim 14 wherein the cancer is a solid tumor.

22. A method of treating cancer comprising administering to a mammal in need thereof a dose of Compound I of about 40 mg/m² - 150 mg/m² every three weeks and wherein the mammal receives at least two doses of Compound I.

23. The method of claim 22, wherein the dose is about 75 mg/m -150 mg/m

24. The method of claim 22 wherein the dose is about 80-90 mg/m² and Compound I is administered as a 1 -hour infusion.

25. The method of claim 22 wherein the dose is about 85 mg/m and Compound I is administered as a 1 -hour infusion.

26. The method of claim 22 wherein the dose is about 90-130 mg/m² and Compound I is administered as a 24-hour infusion.

27. The method of claim 22 wherein the dose is about 90-100 mg/m² and Compound I is administered as a 24-hour infusion.

28. The method of claim 22 wherein the dose is about 110-120 mg/m² and Compound I is administered as a 24-hour infusion.

29. The method of claim 1, wherein Compound I is used in combination with an anticancer cytotoxic agent.

30. The method of claim 29, wherein the anticancer cytotoxic is a DNA- damaging agent.

31. The method of claim 30, wherein the DNA-damaging agent is carboplatin.

32. The method of claim 31 , wherein Compound I is administered at a dose of 1 mg/m²-150 mg/m² once a week, and carboplatin is administered at a dose of 60 mg/m²-225 mg/m² once a week.

33. The method of claim 32, wherein Compound I is administered at a dose of 30 mg/m²-90 mg/m² once a week and carboplatin is administered at a dose of 60 mg/m²- 225 mg/m² once a week.

34. The method of claim 32, wherein Compound I is administered at a dose of 30 mg/m²-90 mg/m² once a week and carboplatin is administered at a dose of 65 mg/m²- 200 mg/m² once a week.

35. The method of claim 30, wherein the DNA-damaging agent is cisplatin.

36. The method of claim 35, wherein Compound I is administered at a dose of 1

9 9 ^*) mg/m -150 mg/m once a week, and cisplatin is administered at a dose of 1 mg/m -30 mg/m² once a week.

37. The method of claim 36, wherein Compound I is administered at a dose of 30 mg/m²-90 mg/m² once a week, and cisplatin is administered at a dose of 1 mg/m²- 30 mg/m once a week.

38. The method of claim 36, wherein Compound I is administered at a dose of

30 mg/m -90 mg/m² once a week, and cisplatin is administered at a dose of 5 mg/m²- 25 mg/m² once a week.

39. The method of claim 29, wherein Compound I is administered on a staggered schedule with respect to the anticancer cytotoxic agent.

40. The method of claim 39, wherein Compound I is administered 24 hours after the completion of administration of the anticancer cytotoxic agent.

41. The method of claim 29, wherein the mammal receives at least two doses of Compound I.

42. A pharmaceutical composition comprising a 1 mg-300 mg dose of N-[5-[[[5- (l,l-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide hemi-L-tartrate.