WO2017201156A1

WO2017201156A1 - Method of treating kras wild-type metastatic colorectal cell carcinoma using cabozantinib plus panitumumab

Info

Publication number: WO2017201156A1
Application number: PCT/US2017/033085
Authority: WO
Inventors: John STRICKLER
Original assignee: Duke University
Current assignee: Duke University
Priority date: 2016-05-18
Filing date: 2017-05-17
Publication date: 2017-11-23
Anticipated expiration: 2018-11-18

Abstract

The present disclosure relates to a method of treating method of treating KRAS Wild Type metastic colorectal cancer, comprising administering to a patient in need of such treatment cabozantinib plus panitumumab.

Description

Method of Treating KRAS Wild-Type Metastatic Colorectal Cell Carcinoma Using

Cabozantinib Plus Panitumumab

CROSS-REFERENCE APPLICATIONS

[0001] The present disclosure claims priority to U.S. Provisional Application 62/338,236 filed May 18, 2016 entitled "Method of Treating KRAS Wild-Type Metastatic Colorectal Cell Carcinoma Using Cabozantinib Plus Panitumumab," the contents of which is incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The present disclosure relates to a method of treating KRAS wild-type metastatic colorectal cancer in human patients using cabozantinib plus panitumumab.

BACKGROUND

[0003] Patients with chemotherapy-refractory metastatic colorectal cancer (CRC) have modest survival benefit from standard of care therapies. Grothey, A., et al., Regorafenib monotherapy or previously treated metastatic colorectal cancer (CORRECT) : an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet, 2013. 381(9863): p. 303-12. Mayer, R.J., et al., Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med, 2015. 372(20): p. 1909-19. Price, T.J., et al., Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol, 2014. 15(6): p. 569-79. Although new therapies such as Panitumumab, an FDA-approved anti-EGFR monoclonal antibody are available for the treatment of KRAS and NRAS (RAS) wild-type (WT) metastatic CRC, resistance to anti-EGFR therapies due to MET amplification remains an issue. Bardelli, A., et al., Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov, 2013. 3(6): p. 658-73.

[0004] As a result, a need remains for therapies that overcome treatment resistance due to MET amplification in KRAS wild-type metastatic colorectal cancer. SUMMARY

[0005] These and other needs are met by the present invention, which is directed to a method of treating KRAS wild-type metastatic colorectal cancer in human patients using cabozantinib plus panitumumab.

[0006] Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGF receptors, and AXL. CABOMETYX is the (<S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (^-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4- yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-l, l-dicarboxamide, (2,S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5 C4H6O5, and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is depicted below.

Cabozantinib as a capsule formulation has been approved for the treatment of medullary thyroid cancer. Cabozantinib as a tablet formulation has been approved for the treatment of advanced renal cell carcinoma who have received prior anti angiogenic therapy.

[0007] The tablet formulation (CABOMETYX) achieved a 19% increase in the Cmax compared to the capsule formulation (COMETRIQ^®) following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations.

[0008] In one aspect, a method of treating KRAS Wild Type metastatic colorectal cancer is provided. The method comprises administering to a patient in need of such treatment an effective amount of the combination of cabozantinib or a pharmaceutically acceptable salt thereof and panitumumab.

[0009] In another aspect, a method of treating a patient with KRAS wildtype metastatic colorectal cancer which is resistant to anti-EGFR therapies is provided. The method comprising

(a) determining the patient has metastatic colorectal cancer that is at least partially resistant to anti-EFGR therapy, and (b) administering an effective amount of the combination of cabozantinib or a pharmaceutically acceptable salt thereof and panitumumab, wherein the metastatic colorectal cancer is treated.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 depicts the best response to cabozantinib plus panitumumab therapy (% change in RECIST lesions).

[0011] FIG. 2 depicts the total target lesion size over time.

[0012] FIG. 3 depicts radiographic images from a 57 year old male with metastatic rectal cancer and baseline and during cabozantinib plus panitumumab treatment.

DETAILED DESCRIPTION

[0013] The present invention provides methods of treating KRAS Wild Type metastatic colorectal cancer. The method comprises, consist essentially of or consists of administering to a patient in need of such treatment an effective amount of the combination of cabozantinib or a pharmaceutically acceptable salt thereof and panitumumab. The administration of the combination increases the reduction or inhibition of cancer cell growth, reduction and/or inhibition of metastasis, or reduction in invasiveness of the cancer cells or metastasis as compared to treatment with panitumumab alone. In some instances, cancer cell growth or tumor volume is decreased by at least 10% in the patient treated with the combination, alternatively at least 20%, alternatively at least 30%, alternatively at least 40%, alternatively at least 50%, alternatively at least 60%, alternatively at least 80% reduction in tumor cell volume or tumor cell growth. The reduction or inhibition of cancer cell growth may also be assessed by no change or no increase in tumor volume/size over time, and/or reduction in the size and/or number of metastatic tumors.

[0014] In some embodiments, the reduction in tumor cells or tumor volume is determined by

RECIST guidelines version 1.1, which can be found in "New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)" by E. A. Eisenhouer et al., European Journal of Cancer, 45 (2009) 228-247, which is incorporated by reference in its entirety. Suitably, treatment may consist of a reduction in tumor burden by RECIST of at least 10%, alternatively at least 20%), alternatively at least 25%, alternatively at least 30%, alternatively at least 40%, alternatively at least 50%, alternatively at least 60%, alternatively at least 70%, alternatively at least 80%) change in RECIST lesions.

[0015] The terms "subject" and "patient" are used interchangeably and refer to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject. A suitable subject is a patient who has chemotherapy-refractory metastatic colorectal cancer. In some embodiments, the subject is a patient that is characterized by colorectal cancer that is resistant and/or is less responsive to anti-EGFR treatment alone.

[0016] For example, in some instances the subject is a patient that has previously been administered and anti-EGFR treatment and found to be resistant to anti-EFGR therapies due to MET amplification. The increase in MET amplification may be detected by increased detection of MET in the bloodstream and/or an increase expression of MET on cancer cells. c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR) is encoded by the MET gene.

[0017] In other instances, the patient is a patient that has not been previously administered anti- EGFR therapies.

[0018] The combination of cabozantinub and panitumumab are administered separately as cabozanitunub is administered orally and panitumumab is administered intraveneously in an effective amount to treat the cancer.

[0019] The terms "effective amount" or "therapeutically effective amount" refer to an amount sufficient to effect beneficial or desirable biological and/or clinical results.

[0020] For oral administration, the cabozantinib or pharmaceutical salt thereof may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, pills, powders, granules or other suitable oral dosage forms. For example, the active agent may be combined with at least one excipient such as fillers, binders, humectants, disintegrating agents, solution retarders, absorption accelerators, wetting agents absorbents or lubricating agents. Suitable forms of cabozanitinib are CABOMETYX® and COMETRIQ®.

[0021] The pharmaceutical composition is preferably in unit dosage form. In such form the preparation is divided into unit doses containing appropriate quantities of the active component.

The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Suitable dosages of cabozanitinib include, but are not limited to, for example, 20 mg to 200 mg, preferably 20 mg to about 140 mg, alternatively 20 mg to about 60 mg, alternatively about 20 mg, about 40 mg, about 60 mg, 80mg, lOOmg, 140mg, daily and include amounts and ranges inbetween. In a preferred embodiment, the patient is administered about 20 mg to about 140 mg once a day, more preferably about 60 mg once daily.

[0022] Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR), and can be found manufactured by Amgen as VECTIBIX®.

[0023] Suitably, panitumumab is administered intraveneously by IV infusion, suitably it is administered in an amount of about 5.5 mg/kg body weight to about 6.5 mg/kg body weight, preferably about 6 mg/kg body weight over a time period of about 30-90 minutes (suitably over 60 minutes) every 14 days with a physiologically acceptable salt solution. For example, the panitumumab can be dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Preferably, the dilution should not exceed a final concentration of 10 mg/mL.

[0024] The terms "tumor cell growth" or "tumor cell proliferation" are used herein interchangeably to refer to the increase in number of tumor cells.

[0025] The term "metastasis" or "secondary tumor" refers to cancer cells that have spread to a secondary site, e.g., outside of the colon or rectal tissue. Secondary sites include, but are not limited to, the lymphatic system, skin, distant organs (e.g., liver, stomach, pancreas, brain, etc.) and the like.

[0026] In some aspects, the method of treating KRAS wild-type metastatic colorectal cancer comprises administering the combination of cabozantinib and panitumumab.

[0027] In some aspects, methods of reducing, inhibiting or preventing colorectal cancer cell growth in a patient are provided. The method comprises administering an effective amount of the combination provided here, including, for example, a combination comprising cabozantinib or a pharmaceutical salt thereof and panitumumab, wherein the combination is administered in an effective amount to reduce, inhibit or prevent colorectal cancer cell growth. [0028] In some aspects, reducing, inhibiting or preventing colorectal cancer cell growth comprises inhibiting, reducing or preventing colorectal cancer cell proliferation, invasiveness of colorectal cancer cells, or colorectal cancer cell metastasis in a patient.

[0029] In some aspects, methods of reducing therapeutically resistant residual tumor cells in a patient suffering from colorectal cancer are described. The method comprises administering an effective amount of the combination of cabozantinib and panitumumab.

[0030] This disclosure provides kits. The kits can be suitable for use in the methods described herein. Suitable kits include a kit for treating colorectal cancer comprising a combination comprising cabozantinib or a pharmaceutically acceptable salt thereof and panitumumab. In some aspects, instructions on how to administer the combination and/ or active agents.

[0031] In some embodiment, a method of treating a patient with KRAS wildtype metastatic colorectal cancer which is resistant to anti-EGFR therapies are provided. The method comprises (a) determining the patient has metastatic colorectal cancer that is at least partially resistant to anti-EFGR therapy, (b) administering an effective amount of the combination of cabozantinib or a pharmaceutically acceptable salt thereof and panitumumab, wherein the metastatic colorectal cancer is treated. In some embodiments, the method further comprises determining if the patient is characterized by the amplification of MET. Amplification of MET may be detected in a blood sample or tissue sample (e.g. tumor biopsy) from the patient. Suitable methods of detection are known in the art, including, ELISA, flow cytometry, PCR, RT-PCR, RT-qPCR (including realtime fluorescent quantitative PCR) and the like. In some aspects, the effective amount comprises about 20 mg to about 140 mg cabozantinib administered once a day orally and about 5.5-6.5 mg/kg body weight panitumumab administered once every 14 days by intravenous injection.

[0032] Cabozantinib is available as a tablet formulation under the name CABOMETYX. CABOMETYX is the (^-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)- malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide, (2,S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5 C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:

Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.

[0033] CABOMETYX (cabozantinib) tablets are supplied as film-coated tablets containing 20 mg, 40 mg, or 60 mg of cabozantinib, which is equivalent to 25 mg, 51 mg, or 76 mg of cabozantinib (^-malate, respectively. CABOMETYX also contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate as indicated below.

[0034] The film coating contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow.

Clinical Pharmacology

Mechanism of Action [0035] In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYR03, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Pharmacodynamics

[0036] The exposure-response or -safety relationship for cabozantinib is unknown.

Cardiac Electrophysiology

[0037] The effect of orally administered cabozantinib on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with medullary thyroid cancer administered a dose of 140 mg. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating cabozantinib. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No cabozantinib-treated patients in this study had a confirmed QTcF > 500 ms nor did any cabozantinib-treated patients in the RCC study (at a dose of 60 mg).

Pharmacokinetics

[0038] Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC (area under the curve)) compared to a single dose administration; steady state was achieved by Day 15.

Absorption

[0039] Following oral administration of cabozantinib, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 3 hours post-dose.

[0040] A 19% increase in the Cmax of the tablet formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ^®) was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations.

[0041] Cabozantinib Cmax and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140 mg oral dose of an investigational cabozantinib capsule formulation. Distribution

[0042] The oral volume of distribution

of cabozantinib is approximately 319 L. Cabozantinib is highly protein bound in human plasma

Elimination

[0043] The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady-state is estimated to be 2.2 L/hr.

Metabolism

[0044] Cabozantinib is a substrate of CYP3A4 in vitro.

Excretion

[0045] Approximately 81% of the total administered radioactivity was recovered within a 48- day collection period following a single 140 mg dose of an investigational ¹⁴C-cabozantinib formulation in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72 hour collection.

Specific Populations

[0046] The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m² as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with worse than moderate renal impairment (eGFR less than 29 mL/min/1.73m²) as estimated by MDRD equation or renal impairment requiring dialysis.

Hepatic Impairment

[0047] Cabozantinib exposure (AUCo-inf) increased by 81% and 63%, respectively, in patients with mild (C-P A) and moderate (C-P B) hepatic impairment. Patients with severe hepatic impairment have not been studied.

Pediatric Population

[0048] The pharmacokinetics of cabozantinib has not been studied in the pediatric population.

Drug Interactions

[0049] CYP3A4 Inhibition on Cabozantinib: Administration of a strong CYP3A4 inhibitor, ketoconazole, (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUCo-inf) by 38%. [0050] CYP3A4 Induction on Cabozantinib: Administration of a strong CYP3A4 inducer, rifampin, (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUCo-inf) by 77%.

[0051] Cabozantinib on CYP2C8 substrates: No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) was observed when coadministered with cabozantinib at steady-state plasma concentrations (> 100 mg/day daily for a minimum of 21 days) in patients with solid tumors.

[0052] Gastric pH modifying agents on Cabozantinib: No clinically-significant effect on plasma cabozantinib exposure (AUC) was observed following co-administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers.

In vitro Studies

Metabolic Pathways

[0053] Inhibition of CYP3A4 reduced the formation of the oxidative metabolite by > 80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.

[0054] Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYPl A2 and CYP2D6 isozymes in vitro.

[0055] Cabozantinib is an inducer of CYPlAl mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.

Drug Transporter Systems

[0056] Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase plasma concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown. Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. The clinical relevance of this finding is unknown.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

[0057] Cabozantinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 transgenic mice. Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay. Based on nonclinical findings, male and female fertility may be impaired by treatment with CABOMETYX. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately 13-fold of human AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (5-fold of human AUC at the recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and post-implantation losses.

[0058] Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at plasma exposures (AUC) approximately 0.5-fold (males) and <0.1-fold (females) of those expected in humans at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately 9-fold of human AUC at the recommended dose) exhibited ovarian necrosis.

[0059] The following non-limiting examples are included for purposes of illustration only, and are not intended to limit the scope of the range of techniques and protocols in which the compositions and methods of the present invention may find utility, as will be appreciated by one of skill in the art and can be readily implemented.

Example 1

[0060] Phase lb study of cabozantinib plus panitumumab in KRAS wild-type (WT) metastatic colorectal cancer (mCRC).

[0061] Background: Patients with chemotherapy-refractory metastatic colorectal cancer (CRC) have modest survival benefit from standard of care therapies. Grothey, A., et al., Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet, 2013. 381(9863): p. 303-12. Mayer, R.J., et al., Randomized trial ofTAS-102 for refractory metastatic colorectal cancer. N Engl J Med, 2015. 372(20): p. 1909-19. Price, T.J., et al., Panitumumab versus cetuximab in patients with chemotherapy- refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol, 2014. 15(6): p. 569-79. Although new therapies such as Panitumumab, an FDA-approved anti-EGFR monoclonal antibody are available for the treatment of KRAS and NRAS (RAS) wild-type (WT) metastatic CRC, resistance to anti-EGFR therapies due to MET amplification remains an issue. Bardelli, A., et al., Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov, 2013. 3(6): p. 658-73. Cabozantinib is a potent inhibitor of multiple receptor tyrosine kinases, incuding VEGFR2, AXL, and c-MET. Yakes, F.M., et al, Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular cancer therapeutics, 2011. 10(12): p. 2298-308. We hypothesize that cabozantinib will enhance the activity of panitumumab, and be particularly active against MET amplified tumors.

[0062] Objectives. The primary objective was to define the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) of cabozantinib + panitumumab. The secondary objectives were to (i) describe the dose limiting and non-dose limiting toxicities of cabozantinib + panitumumab; (ii) describe the clinical activity (objective response rate [ORR], progression free survival [PFS], and overall survival [OS]) for cabozantinib + panitumumab; and (iii) explore the relationship between tissue and blood-based biomarkers and clinical outcomes.

[0063] Methods. Eligible pts with chemotherapy refractory KRAS WT mCRC were enrolled in a 3+3 dose finding cohort (Dose Find) to identify the recommended phase II dose (RPTD). Prior anti-EGFR therapy was permitted. Cycle length was 28 days. Pts were then enrolled in a single-arm expansion cohort (EXP) and treated at the RPTD. The EXP cohort included a 2-week C monotherapy lead-in. The objectives of the EXP cohort were to better describe the safety, tolerability, and efficacy of C+P. Response assessment occurred every 2 months (mos) using RECIST version 1.1. Peripheral blood was sequenced for >54 gene mutations and focal amps, including MET (Guardant Health, Inc.).

[0064] Key Inclusion Criteria:

• KRAS WT adenocarcinoma of the colon or rectum that is metastatic and/or unresectable • Prior treatment with 5-FU, oxaliplatin, irinotecan, and anti-VEGF monoclonal antibody

• Prior cetuximab or panitumumab permitted

• Adequate organ and bone marrow function

[0065] Key Exclusion Criteria:

• Prior tyrosine kinase inhibitor within 2 weeks, cytotoxic chemotherapy within 3 weeks, or any other investigational treatment within 4 weeks of study treatment

• Hypertension (BP> 140/90)

• Concomitant therapeutic doses of anticoagulants (warfarin, factor Xa inhibitors, etc.) [0066] Trial Design:

• Dose Finding: 3+3 design to determine the MTD and RPTD of cabozantinib + panitumumab

• Dose Expansion: To define the safety, tolerability, and activity of the RPTD

[0067] Table 1 summarizes the dose and schedule of cabozantinib and panitumumab. Cycle length: cycle 1 of the Expansion cohort 6 weeks; all other cycles 4 weeks.

[0068] Assessments:

• Adverse events (AEs) graded according to NCI CTCAE, version 4.0

• Dose-limiting toxicity (DLT) assessment window: 28 days

• Tumor assessments: Dose Finding- CT or MRI every 8 weeks (Q2 cycles); Expansion- CT or MRI after week 10 (end of cycle 2), then Q8 weeks (Q2 cycles)

• Tumors evaluated using RECIST criteria (version 1.1) [0069] Biomarkers:

• Blood collection: Baseline, cycle 1 day 15 of Expansion cohort only, and each restaging until progression

• Plasma-EDTA cell free DNA (cfDNA) retrospectively sequenced for >54 gene mutations and focal amplifications (Guardant Health, Inc.)

• Archived paraffin-embedded tumor tissue collected from all eligible subjects

• Genomic amplification tested in tumor tissue using commercially available NGS or FISH

[0070] Results: As of 11/24/2015, 16 pts were evaluable for toxicity (6 Dose Find; 10 EXP), and 14 pts were evaluable for response (6 Dose Find; 8 EXP). 13 pts had received prior anti- EGFR therapy. There were no dose limiting toxicity events in the Dose Find cohort (0/6). The RPTD was C 60mg PO daily and P 6 mg/kg IV Q2 weeks. In the Dose Find and EXP cohorts, there were no grade 4 or 5 treatment related adverse events (TRAEs). The most frequently reported (all grades > 30%) TRAEs were (n, %) acneiform rash (10, 63%), oral mucositis (9, 56%), diarrhea (8, 50%), increased AST (7, 44%), paronychia (6, 38%), increased ALT (5, 31%), and fatigue (5, 31%). Median PFS was 3.7 mos (95% C.I., 2.3-7.4 mos). Median OS was 7.5 mos (95% C.I., 6.4-12.1 mos). 2 pts (14%) had a confirmed partial response, and 5 pts had PFS > 6 months.

[0071] Treatment Summary:

• 18 patients enrolled and dosed

• 18 subjects evaluable for toxicity, PFS, OS

• 16 subjects evaluable for response

• 17 subjects completed at least 1 cycle

• 14 of 18 pts have discontinued treatment: 11 for disease progression, 3 for toxicity

• 4 patients remain on active treatment as of cut-off date

[0072] Patient Characteristics are summarized in Table 2.

[0073] Safety: Table 3 summarizes treatment-related adverse events. There were no treatment related grade 4/5 adverse events.

[0074] Determination of MTD/RPTD

• No DLTs in Dose Finding Cohort (0/6)

• MTD/RPTD: cabozantinib 60mg p.o. daily + panitumumab 6mg/kg I.V. Q2 weeks

[0075] The efficacy of Cabozantinib + paniumumab is summarized in Table 4.

[0076] FIG. 1 depicts the best response to cabozantinib plus panitumumab therapy (% change in RECIST lesions).

[0077] FIG. 2 depicts the total target lesion size over time.

[0078] FIG. 3 depicts baseline and post cabozantinib plus panitumumab treatment radiographic images from a case report of a 57 year old male with metastatic rectal cancer who had showed disease progression on 6 prior lines of therapy. MET amplification was detected in the patient's blood, not tissue.

[0079] Table 5 summarizes cfDNA profiles and treatment response.

[0080] Conclusions: The combination of cabozantinib + panitumumab demonstrated an acceptable safety profile. Blood-based cfDNA profiling may reveal sub-populations that are sensitive to cabozantinib + panitumumab. Enrollment to the Dose Expansion cohort will be increased to better describe the safety and activity of the combination

Other Embodiments

[0081] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. A method of treating KRAS Wild Type metastatic colorectal cancer, comprising administering to a patient in need of such treatment an effective amount of the combination of cabozantinib or a pharmaceutically acceptable salt thereof and panitumumab.

2. The method of claim 1, wherein the treating is characterized by reducing, inhibiting or preventing the growth of cancer cells or reducing, inhibiting or preventing metastasis of the cancer cells or invasiveness of the cancer cells or metastasis in the patient.

3. The method of any one of the preceding claims, wherein the administration of the combination increases the reduction or inhibition of cancer cell growth, reduction and inhibition of metastasis, or invasiveness of the cancer cells or metastasis as compared to treatment with panitumumab alone.

4. The method of any one of the preceding claims, wherein the patient has chemotherapy- refractory metastatic colorectal cancer.

5. The method of any one of the preceding claims, wherein the combination of cabozantinub and panitumumab are administered separately.

6. The method of any one of the preceding claims, wherein cabozanitunub is administered orally at least once a day at a dosage from about 20 mg to about 140 mg.

7. The method of claim 6, wherein cabozantinib is administered at least once a day at a dosage of about 20 mg to about 100 mg.

8. The method of claim 6 or 7, wherein cabozantinib is administered in a dosage of about 40 mg to about 60 mg per day.

9. The method of any one of the preceding claims, wherein the panitumumab is administered intraveneously in an amount of about 5 mg/kg body weight to about 7 mg/kg body weight at an interval of about once every 14 days.

10. The method of claim 9, wherein cabozantinib is administered to the patient at an oral dose of 60mg p.o. daily and panitumumab is administered to the patient at 6mg/kg IV. Q2 weeks.

11. The method of any one of the preceding claims, wherein the combination is administered for at least 4 weeks.

12. The method of claim 11, wherein the combination is administered for at least six week.

13. The method of claim 12, wherein the combination is administered for at least 10 weeks.

14. The method of any one of the preceding claims, wherein the combination is administered for at least 24 weeks.

15. The method of any one of the preceding claims, wherein the patient has colorectal cancer is characterized by increased MET amplification.

16. The method of any one of the preceding claims, wherein the cancer is resistant to anti- EFGR therapy alone.

17. The method of any one of the preceding claim, wherein the treating is characterized by a reduction in the tumor volume by at least 50%.

18. A method of treating a patient with KRAS wildtype metastatic colorectal cancer which is resistant to anti-EGFR therapies, the method comprising

(a) determining the patient has metastatic colorectal cancer that is at least partially resistant to anti-EFGR therapy, (b) administering an effective amount of the combination of cabozantinib or a pharmaceutically acceptable salt thereof and panitumumab, wherein the metastatic colorectal cancer is treated.

19. The method of claim 17, wherein the treating is characterized by reducing, inhibiting or preventing the growth of cancer cells or reducing, inhibiting or preventing metastasis of the cancer cells in the patient.

20. The method of claim 17 or 18, wherein the effective amount comprises about 20 mg to about 140 mg cabozantinib administered once a day orally and about 5.5-6.5 mg/kg body weight panitumumab administered once every 14 days by intraveneous injection.

21. The method of any of the preceding claims, wherein the cabozantinib is cabozantinib (S)- malate of the formula: