WO2017201156A1 - Méthode de traitement du cancer colorectal métastatique kras sauvage au moyen de cabozantinib et de panitumumab - Google Patents

Méthode de traitement du cancer colorectal métastatique kras sauvage au moyen de cabozantinib et de panitumumab Download PDF

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WO2017201156A1
WO2017201156A1 PCT/US2017/033085 US2017033085W WO2017201156A1 WO 2017201156 A1 WO2017201156 A1 WO 2017201156A1 US 2017033085 W US2017033085 W US 2017033085W WO 2017201156 A1 WO2017201156 A1 WO 2017201156A1
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cabozantinib
administered
panitumumab
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combination
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John STRICKLER
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Duke University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators

Definitions

  • the present disclosure relates to a method of treating KRAS wild-type metastatic colorectal cancer in human patients using cabozantinib plus panitumumab.
  • 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.
  • 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.
  • a method of treating KRAS Wild Type metastatic colorectal cancer 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.
  • a method of treating a patient with KRAS wildtype metastatic colorectal cancer which is resistant to anti-EGFR therapies comprising
  • FIG. 1 depicts the best response to cabozantinib plus panitumumab therapy (% change in RECIST lesions).
  • FIG. 2 depicts the total target lesion size over time.
  • FIG. 3 depicts radiographic images from a 57 year old male with metastatic rectal cancer and baseline and during cabozantinib plus panitumumab treatment.
  • 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.
  • 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.
  • the reduction in tumor cells or tumor volume is determined by
  • 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.
  • 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.
  • animal e.g., a mammal
  • 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.
  • the subject is a patient that is characterized by colorectal cancer that is resistant and/or is less responsive to anti-EGFR treatment alone.
  • 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.
  • the patient is a patient that has not been previously administered anti- EGFR therapies.
  • cabozantinub and panitumumab are administered separately as cabozanitunub is administered orally and panitumumab is administered intraveneously in an effective amount to treat the cancer.
  • an effective amount or “therapeutically effective amount” refer to an amount sufficient to effect beneficial or desirable biological and/or clinical results.
  • 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.
  • 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.
  • 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®.
  • 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.
  • the patient is administered about 20 mg to about 140 mg once a day, more preferably about 60 mg once daily.
  • Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR), and can be found manufactured by Amgen as VECTIBIX®.
  • 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.
  • 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.
  • tumor cell growth or “tumor cell proliferation” are used herein interchangeably to refer to the increase in number of tumor cells.
  • 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.
  • the method of treating KRAS wild-type metastatic colorectal cancer comprises administering the combination of cabozantinib and panitumumab.
  • methods of reducing, inhibiting or preventing colorectal cancer cell growth in a patient comprise 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.
  • 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.
  • methods of reducing therapeutically resistant residual tumor cells in a patient suffering from colorectal cancer comprise administering an effective amount of the combination of cabozantinib and panitumumab.
  • 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.
  • instructions on how to administer the combination and/ or active agents are provided.
  • a method of treating a patient with KRAS wildtype metastatic colorectal cancer which is resistant to anti-EGFR therapies 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the film coating contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow.
  • 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.
  • 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.
  • Tmax median time to peak cabozantinib plasma concentrations
  • 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.
  • cabozantinib The oral volume of distribution of cabozantinib is approximately 319 L. Cabozantinib is highly protein bound in human plasma
  • 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.
  • Cabozantinib is a substrate of CYP3A4 in vitro.
  • Cabozantinib exposure 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.
  • 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%.
  • 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%.
  • 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.
  • 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.
  • 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.
  • other less sensitive substrates of pathways affected by cabozantinib in vitro i.e., CYP2C9, CYP2C19, and CYP3A4
  • Cabozantinib does not inhibit CYPl A2 and CYP2D6 isozymes in vitro.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.).
  • 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
  • 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.
  • Plasma-EDTA cell free DNA (cfDNA) retrospectively sequenced for >54 gene mutations and focal amplifications (Guardant Health, Inc.)
  • 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.
  • FIG. 1 depicts the best response to cabozantinib plus panitumumab therapy (% change in RECIST lesions).
  • FIG. 2 depicts the total target lesion size over time.
  • 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.
  • Table 5 summarizes cfDNA profiles and treatment response.

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Abstract

La présente invention concerne une méthode de traitement du cancer colorectal métastique KRAS sauvage, qui consiste à administrer à un patient nécessitant un tel traitement du cabozantinib et du panitumumab.
PCT/US2017/033085 2016-05-18 2017-05-17 Méthode de traitement du cancer colorectal métastatique kras sauvage au moyen de cabozantinib et de panitumumab Ceased WO2017201156A1 (fr)

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