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WO2025101623A1 - Méthodes de traitement du cancer - Google Patents

Méthodes de traitement du cancer Download PDF

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WO2025101623A1
WO2025101623A1 PCT/US2024/054745 US2024054745W WO2025101623A1 WO 2025101623 A1 WO2025101623 A1 WO 2025101623A1 US 2024054745 W US2024054745 W US 2024054745W WO 2025101623 A1 WO2025101623 A1 WO 2025101623A1
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cancer
patient
sotorasib
administered
intravenously
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Emily CHAN
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Amgen Inc
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Amgen Inc
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the rat sarcoma (RAS) proto-oncogene has been identified as an oncogenic driver of tumorigenesis in cancers, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • the RAS family consists of 3 closely related genes that express guanosine triphosphate (GTP)-ases responsible for regulating cellular proliferation and survival (Simanshu et al, 2017).
  • the RAS proteins, Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), and neuroblastoma RAS viral oncogene homolog (NRAS) can be mutationally activated at codons 12, 13, or 61, leading to human cancers.
  • KRAS Kirsten rat sarcoma viral oncogene homolog
  • HRAS Harvey rat sarcoma viral oncogene homolog
  • NRAS neuroblastoma RAS viral oncogene homolog
  • KRAS Kirsten rat sarcoma viral oncogene homolog
  • HRAS Harvey rat sarcoma viral oncogene homolog
  • NRAS neuroblastoma RAS viral oncogene homolog
  • the EGFR antibody is an EGFR antagonist.
  • the EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.
  • the EGFR antibody comprises the heavy chain variable region sequence of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 9.
  • the EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10.
  • the EGFR antibody is panitumumab.
  • the drug regimen under Item (c) above is a FOLFOX regimen.
  • the cancer is a solid tumor.
  • the cancer is colorectal cancer.
  • the cancer is metastatic colorectal cancer.
  • the cancer is non-small cell lung cancer, and in some cases, the cancer is metastatic or locally advanced non-small cell lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof comprising administering to the patient (a) a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of an EGFR antibody, and (c) (1) a therapeutically effective amount of oxaliplatin, (2) a therapeutically effective amount of leucovorin or a therapeutically effective amount of levoleucovorin, and (3) a therapeutically effective amount of 5-fluorouracil (5-FU).
  • sotorasib or a pharmaceutically acceptable salt thereof comprising administering to the patient (a) a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of an EGFR antibody, and (c) (1) a therapeutically effective amount of oxaliplatin, (2) a therapeutically effective amount of leucovorin or a therapeutically effective amount of levoleucovorin, and (3) a therapeutically effective amount of 5-fluorouraci
  • sotorasib at 960 mg QD was shown to be safe and effective under study conditions under Study 20170543 (https://clinicaltrials.gov/ct2/show/NCT03600883; CodeBreaK100). Since resistance to sotorasib may be mediated by upregulation of signaling through epidermal growth factor receptor (EGFR) pathway, adding an EGFR antagonist to sotorasib therapy may block bypass activation of the mitogen activated kinase (MAPK) signaling and lead to improved anti-tumor activity.
  • EGFR epidermal growth factor receptor
  • FOLFIRI and FOLFOX are the recommended chemotherapy backbone regimens for metastatic ORC (National Comprehensive Cancer Network [NOON] Colon Cancer Guidelines, version 2, 2023; NCCN Rectal Cancer Guidelines, version 3, 2023, and the European Society for Medical Oncology [ESMO] mCRC Guidelines, Cervantes A, et al. ESMO Guidelines Committee, 2023). Both FOLFIRI and FOLFOX have been combined successfully with panitumumab in phase 3 studies of metastatic colorectal cancer (Peeters et al, 2010; Douillard et al., 2010).
  • panitumumab to both FOLFIRI and FOLFOX regimens was restricted to the KRAS wildtype population.
  • studies evaluating EGFR antibody in combination with FOLFOX have demonstrated lower progression free survival (PFS) and overall survival (OS), however, the mechanism for this effect is unknown (Maughan et al, 2011; Bokemeyer et al, 2011; Douillard et al, 2010).
  • the methods of treatment disclosed herein include concomitant administration of the therapeutics (e.g., within 1 hour, within 45 minutes, within 30 minutes, within 15 minutes, or within 10 minutes of each other), and sequential administration (e.g., administration separated by at least 1 hour, or at least two hours, or at least four hours, or at least six hours, or at least eight hours, or at least twelve hours, or at least 24 hours, or at least 2 days, or at least 3 days).
  • combination therapy as discussed herein include both concomitant and sequential administration.
  • Sotorasib is a small molecule that irreversibly inhibits the KRAS G12C mutant protein. Sotorasib is also referred to as AMG 510 or 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4- [(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidin-2(1/-/)-one and has the following structure:
  • Sotorasib binds to the P2 pocket of KRAS adjacent to the mutant cysteine at position 12 and the nucleotide-binding pocket.
  • the inhibitor contains a thiol reactive portion which covalently modifies the cysteine residue and locks KRAS G12C in an inactive, guanosine diphosphate (GDP) bound conformation.
  • GDP guanosine diphosphate
  • KRAS Inactivation of KRAS through a small molecule inhibitor has previously demonstrated an inhibition of cell growth and induction of apoptosis in tumor cell lines and xenografts harboring KRAS mutations (including the KRAS G12C mutation) (Janes et al., 2018; Xie et al., 2017; Ostrem and Shokat, 2016; Patricelli et al., 2016). Studies with sotorasib have confirmed these in vitro findings and have likewise demonstrated inhibition of growth and regression of cells and tumors harboring KRAS G12C mutations (Canon et al., 2019).
  • the methods disclosed herein comprise administering 960 mg sotorasib once daily to the patient. In some embodiments, the methods disclosed herein comprise administering 480 mg sotorasib once daily to the patient. In some embodiments, the methods disclosed herein comprise administering 240 mg sotorasib once daily to the patient.
  • sotorasib is administered as a free base. In some embodiments, sotorasib is administered as a pharmaceutically acceptable salt.
  • sotorasib refers to the free base of sotorasib unless otherwise noted. Any method described herein referencing sotorasib can also be practiced using a pharmaceutically acceptable salt of sotorasib.
  • sotorasib can be administered as a hydrochloride, phosphate, or mesylate. In some embodiments, sotorasib can be administered as a hydrochloride. In some embodiments, sotorasib can be administered as a phosphate. In some embodiments, sotorasib can be administered as a mesylate.
  • a method provided herein recites, e.g., the administration of 960 mg of sotorasib or a pharmaceutically acceptable salt thereof to a subject
  • the method calls for the administration 960 mg of the free base of sotorasib or the amount of a pharmaceutically acceptable salt that corresponds to the administration of 960 mg of free base of sotorasib.
  • pharmaceutically acceptable refers to a species or component that is generally safe, nontoxic, and neither biologically nor otherwise undesirable for use in a subject, such as a human.
  • pharmaceutically acceptable salt refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use.
  • Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid).
  • inorganic acids e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, ni
  • Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound either is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or associates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine).
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • an organic base e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine.
  • the salts of the compounds described herein can exist in either hydrated or anhydrous form or as solvates with other solvent molecules.
  • the methods further comprise administering an EGFR antibody to the patient.
  • the EGFR antibody is an antagonist.
  • the EGFR antibody comprises the heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.
  • the EGFR antibody comprises the heavy chain variable region sequence of SEQ ID NO: 4 and the light chain variable region of SEQ ID NO: 9.
  • the EGFR antibody comprises the heavy chain sequence of SEQ ID NO: 5 and the light chain sequence of SEQ ID NO: 10.
  • the EGFR antibody is panitumumab.
  • Panitumumab is a fully human immunoglobulin (lg)G2 monoclonal antibody to the epidermal growth factor receptor (EGFR). Panitumumab binds to the extracellular domain of EGFR, thus preventing its activation and intracellular signaling.
  • EGFR epidermal growth factor receptor
  • panitumumab Retrospective subset analyses of metastatic CRC trials did not show a treatment benefit for panitumumab in subjects whose tumors contained a KRAS mutation in codon 12 or 13 and use of panitumumab was thus not recommended for treatment of CRC with a KRAS mutation in codon 12 or 13.
  • the recommended dose is 6 mg/kg, administered as an IV infusion over 60 minutes ( ⁇ 1000 mg) or 90 minutes (> 1000 mg), every 14 days (Q2W). See also, VECTIBIX® US Prescribing Information, Amgen Inc., Thousand Oaks, California, 91320 (revision 8/2021), which is herein incorporated by reference in its entirety.
  • the methods described herein further comprise administering a modified FOLFOX regimen comprising oxaliplatin, leucovorin (or levoleucovorin), and 5-fluorouracil (5-FU) to the patient.
  • a modified FOLFOX regimen comprising oxaliplatin, leucovorin (or levoleucovorin), and 5-fluorouracil (5-FU)
  • the FOLFOX regimen is a modified FOLFOX6 (mFOLFOX6), which consists of oxaliplatin 85 mg/m 2 IV on day 1, leucovorin 400 mg/m 2 IV on day 1, and 5-fluorouracil 400 mg/m 2 IV bolus on day 1 and 2400 mg/m 2 IV continuous infusion (I VCI) over 46 to 48 hours beginning on day 1 given every two weeks (Q2W) (National Comprehensive Cancer Network (NCCN) Colon Cancer Guidelines version 2.2023; NCCN Rectal Cancer Guidelines version 3.2023; and Cervantes et al., EMSO mCRC Guidelines 2023).
  • NCCN National Comprehensive Cancer Network
  • Oxaliplatin e.g., ELOXATIN® US Prescribing Information, Sanofi-aventis U.S. LLC, Bridgewater, New Jersey 08807 (revision 4/2020), which is herein incorporated by reference in its entirety
  • infusional 5-FU e.g., US Prescribing Information, Gland Pharma Limited, India (revision 9/2022), which is herein incorporated by reference in its entirety
  • leucovorin e.g., US Prescribing Information, Bedford Laboratories, Bedford, Ohio 44146 (revision 11/2011), which is herein incorporated by reference in its entirety
  • infusional 5-FU e.g., US Prescribing Information, Gland Pharma Limited, India (revision 9/2022), which is herein incorporated by reference in its entirety
  • leucovorin e.g., US Prescribing Information, Bedford Laboratories, Bedford, Ohio 44146 (revision 11/2011), which is herein incorporated by reference in its entirety
  • levoleucovorin at 200 mg/m 2 can be used instead of 400 mg/m 2 leucovorin. See, e.g., Levoleucovorin Injection, US Prescribing Information, Sandoz, Inc., Princeton, New Jersey 08540, USA (revision 11/2013), which is herein incorporated by reference in its entirety.
  • the modified FOLFOX regimen is FOLFOX4 (FOLFOX4, NOON Clinical Practice Guidelines in Oncology: Colon Cancer Version 4/2020), which consists of oxaliplatin 85 mg/m 2 on day 1 , leucovorin 200 mg/m 2 on day 1, and 5-fluorouracil 400 mg/m 2 IV bolus on day 1, and 600 mg/m 2 IV continuous infusion (IVCI) over 22 hours, then leucovorin 200 mg/m 2 on day 2, and 5-fluorouracil 400 mg/m 2 IV bolus on day 2, and 600 mg/m 2 IV continuous infusion (IVCI) over 22 hours, given every two weeks.
  • FOLFOX4 FOLFOX4, NOON Clinical Practice Guidelines in Oncology: Colon Cancer Version 4/2020
  • the methods comprise administering therapeutic agents (e.g., sotorasib, panitumumab, oxaliplatin, leucovorin or levoleucovorin, 5-fluorouracil, and combinations thereof) in doses at particular time points as part of a dosing regimen.
  • therapeutic agents e.g., sotorasib, panitumumab, oxaliplatin, leucovorin or levoleucovorin, 5-fluorouracil, and combinations thereof
  • the methods comprise administering sotorasib in an amount ranging from 240 mg to 960 mg. In some embodiments, the methods comprise administering 960 mg sotorasib to the patient once daily. In some embodiments, the methods comprise administering 480 to the patient once daily. In some embodiments, the methods comprise administering 240 mg to the patient once daily. In some embodiments, sotorasib is administered as a solid dosage form. In some embodiments, the solid dosage form is a tablet. In some embodiments, sotorasib is administered orally.
  • sotorasib when given to patients with difficulties swallowing, may be given as a dispersion of one or more tablets comprising a therapeutically effective amount of sotorasib in 120 mL (4 ounces) of non-carbonated, room-temperature water without crushing.
  • the dispersion is prepared by stirring the one or more tablets in water in a container until the tablets are dispersed into small pieces. The dispersion should be administered to the patient immediately or within 2 hours. Subsequently, the container is rinsed with an additional 120 mL (4 ounces) of water and the water used for rinsing is administered to the patient.
  • sotorasib is administered with food. In some embodiments, sotorasib is administered without food.
  • the methods comprise administering panitumumab to the patient once every two weeks (Q2W).
  • the methods comprise administering an EGFR antibody (e.g., panitumumab) in an amount ranging from 3.0 mg/kg to 6 mg/kg ⁇ e.g., 3.0 mg/kg, 3.1 mg/kg, 3.2 mg/kg, 3.3 mg/kg, 3.4 mg/kg, 3.5 mg/kg, 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/kg, 4.0 mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg, 4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg, 5 mg/kg, 5.1 mg.
  • an EGFR antibody e.g., panitumumab
  • the methods comprise administering 6 mg/kg panitumumab. In some embodiments, the methods comprise administering 4.8 mg/kg panitumumab. In some embodiments, the methods comprise administering 3.6 mg/kg panitumumab. In some embodiments, panitumumab will be administered as an IV infusion over 60 min (equal or less than 1000 mg) or 90 minutes (more than 1000 mg) Q2W.
  • panitumumab is administered intravenously using a low-protein binding 0.2 pm or 0.22 m in-line filter. In some embodiments, panitumumab may be administered over 30 to 60 minutes for doses of 1000 mg or less.
  • the methods further comprise administering 85 mg/m 2 oxaliplatin to the patient every two weeks.
  • oxaliplatin is administered to the patient intravenously in 500 mL D5W (5% dextrose in water) over 90 minutes every two weeks.
  • the methods further comprise administering leucovorin to the patient.
  • the methods comprise administering 400 mg/m 2 leucovorin to the patient every two weeks.
  • the methods further comprise administering levoleucovorin to the patient.
  • the methods comprise administering 200 mg/m 2 levoleucovorin to the patient every two weeks.
  • the leucovorin or levoleucovorin is administered to the patient intravenously.
  • the leucovorin or levoleucovorin is administered to the patient in 500 mL D5W (5% dextrose in water) over 120 minutes every two weeks concurrently with oxaliplatin.
  • Oxaliplatin and leucovorin (or levoleucovorin) can be infused at the same time, e.g., in separate bags using a Y-site connector.
  • the methods further comprise administering 2800 mg/m 2 5-FU to the patient every two weeks.
  • the methods comprise administering 2800 mg/m 2 5-FU are administered in two separate doses of 400 mg/m 2 5-FU and 2400 mg/m 2 5-FU.
  • the 5-FU is administered to the patient intravenously.
  • the 5-FU is administered to the patient in a bolus intravenous push over 5 minutes (e.g., 400 mg/m 2 5-FU of the 2800 mg/m 2 total 5-FU dose), after the patient was administered oxaliplatin and leucovorin (or levoleucovorin).
  • the 5-FU is administered to the patient in an intravenous continuous infusion (I VCI) in 500 mL D5W (5% dextrose in water) over 46 to 48 hours (e.g., the 2400 mg/m 2 5-FU of the 2800 mg/m 2 total 5-FU dose), via a suitable means, such as an ambulatory infusion device after the patient was administered the 5-FU bolus dose.
  • I VCI intravenous continuous infusion
  • the methods described herein comprise administering to the patient (a) 960 mg sotorasib daily; (b) 6 mg/kg panitumumab via IV administration on day 1 of every two week cycle; and (c) (1) on day 1 of every two week cycle of 85 mg/m 2 oxaliplatin IV, (2) 400 mg/m 2 leucovorin or 200 mg/m 2 levoleucovorin, and (3) 400 mg/m 2 5-FU IV bolus on day 1 of every two week cycle and 2400 mg/m 2 5-FU IV continuous infusion over 46-48 hours beginning on day 1 of every two week cycle.
  • the methods described herein comprise administering to the patient (a) 480 mg sotorasib daily; (b) 6 mg/kg panitumumab via IV administration on day 1 of every two week cycle; and (c) (1) on day 1 of every two week cycle of 85 mg/m 2 oxaliplatin IV, (2) 400 mg/m 2 leucovorin or 200 mg/m 2 levoleucovorin, and (3) 400 mg/m 2 5-FU IV bolus on day 1 of every two week cycle and 2400 mg/m 2 5-FU IV continuous infusion over 46-48 hours beginning on day 1 of every two week cycle.
  • the methods described herein comprise administering to the patient (a) 240 mg sotorasib daily; (b) 6 mg/kg panitumumab via IV administration on day 1 of every two week cycle; and (c) (1) on day 1 of every two week cycle of 85 mg/m 2 oxaliplatin IV, (2) 400 mg/m 2 leucovorin or 200 mg/m 2 levoleucovorin, and (3) 400 mg/m 2 5-FU IV bolus on day 1 of every two week cycle and 2400 mg/m 2 5-FU IV continuous infusion over 46-48 hours beginning on day 1 of every two week cycle.
  • the patient is in further need of treatment with an acid-reducing agent.
  • Acidreducing agents include, but are not limited to, a proton pump inhibitor (PPI), a H2 receptor antagonist (H2RA), and a locally acting antacid.
  • PPI proton pump inhibitor
  • H2RA H2 receptor antagonist
  • the patient, who is in further need of treatment with an acidreducing agent is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib.
  • Exemplary PPIs include, but are not limited to, omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole.
  • Exemplary H2RAs include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine, roxatidine and lafutidine.
  • Exemplary locally acting antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide.
  • the patient who is in further need of treatment with an acid-reducing agent, is not administered a proton pump inhibitor or a H2 receptor antagonist in combination with sotorasib, but is administered a locally acting antacid in combination with sotorasib.
  • sotorasib is administered about 4 hours before or about 10 hours after a locally acting antacid.
  • the patient is not administered a strong CYP3A4 inducer in combination with sotorasib.
  • strong CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates- inhibitors-and-inducers, accessed May 2021.
  • strong CYP3A4 inhibitors include, but are not limited to ombitasvir and paritaprevir and ritonavir and dasabuvir, indinavir and ritonavir, tipranavir and ritonavir, ritonavir, cobicistat, ketoconazole, troleandomycin, telaprevir, danoprevir and ritonavir, elvitegravir and ritonavir, saquinavir and ritonavir, lopinavir and ritonavir, itraconazole, indinavir, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, lonafarnib, posaconazole, telithromycin, grapefruit juice DS3, conivaptan, tucatinib, nefazodone, ceritinib, nelfin
  • the patient is not administered a CYP3A4 substrate in combination with sotorasib.
  • CYP3A4 substrates include, but are not limited to, abemaciclib, abiraterone, acalabrutinib, alectinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, avanafil, axitinib, boceprevir, bosutinib, brexpiprazole, brigatinib, buspirone, cafergot, caffeine, carbamazepine, cariprazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, c
  • the patient is not administered a P-gp substrate in combination with sotorasib.
  • P-gp substrates include, but are not limited to dabigatran etexilate, digoxin, fexofenadine, everolimus, cyclosporine, sirolimus, and vincristine. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers, accessed May 2021.
  • the patient is not administered a P-gp substrate in combination with sotorasib, wherein the P-gp substrate is a P-gp substrate with a narrow therapeutic window.
  • P-gp substrates with a narrow therapeutic window include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, and vincristine.
  • the patient is in further need of treatment with a QT prolonging medication.
  • the patient is not administered a QT prolonging medication.
  • Medications known to prolong QT include, but are not limited to, amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, and vandetanib.
  • the patient has a cancer that was determined to have one or more cells expressing the KRAS G12C mutant protein prior to administration of sotorasib as disclosed herein. Determination of KRAS G12C mutant protein can be assessed as described elsewhere in this disclosure. In some embodiments, the patient does not have KRAS exon 2, exon 3, or exon 4 mutations or NRAS exon 2, exon 3, or exon 4 mutations. [0040] In some embodiments, the patient has not received treatment with a KRAS G12C inhibitor prior to start of a sotorasib/EGFR therapy/FOLFOX therapy as disclosed herein.
  • KRAS G12C inhibitor is sotorasib, adagrasib, divarasib (GDC-6036), garsoarsib (D-1553), opnurasib (JDQ443), glecirasib (JAB-21822), fulzerasib (IBI351, GFH925), RMC-6291, LY3484356, BI1823911, GH35, ZG1077, ASP2453, AZD4747, AZD4625, or APG-1842.
  • the KRAS G12C inhibitor is sotorasib.
  • the KRAS G12C inhibitor is adagrasib.
  • the therapy is monotherapy.
  • the therapy with a KRAS G12C inhibitor is sotorasib monotherapy.
  • the therapy with a KRAS G12C inhibitor is adagrasib monotherapy.
  • the patient has had at least one prior therapy for metastatic disease prior to start of a sotorasib/EGFR therapy/FOLFOX therapy as disclosed herein.
  • Prior therapies for metastatic disease include, but are not limited to, chemotherapies and immunotherapies.
  • Specific contemplated prior systemic cancer therapies include, but are not limited to, fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, ramucirumab, aflibercept, pembrolizumab, nivolumab, ipilimumab, trifluridine and tipiracil, and regorafenib, or any combination the foregoing.
  • the patient exhibits an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 (see, e.g., Zubrod et al., 1960).
  • ECOG PS Eastern Cooperative Oncology Group
  • the patient exhibits an ECOG PS of ⁇ 1 .
  • the patient exhibits an ECOG PS score of 0 or 1 .
  • a PS of 0 indicates fully active and able to carry on all pre-disease performance without restriction.
  • PS of 1 indicates restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
  • PS of 2 indicates ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours.
  • PS of 3 indicates capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
  • PS of 4 indicates completely disabled, cannot carry on any selfcare and totally confined to bed or chair.
  • PS of 5 indicates death.
  • the methods comprise administering a reduced total daily dose of sotorasib when the patient experiences an adverse event to the initial total daily dose.
  • the initial daily dose is 960 mg sotorasib and the reduced total daily dose is 480 mg sotorasib.
  • the initial daily dose is 480 mg sotorasib and the reduced total daily dose is 240 mg sotorasib.
  • the methods further comprise administering a second reduced total daily dose of sotorasib when the patient experiences an adverse event to the reduced total daily dose.
  • AE reverse event
  • the adverse event is hepatotoxicity ⁇ e.g., elevation of liver enzymes), interstitial lung disease (ILD)/pneumonitis, diarrhea, and/or nausea/vomiting.
  • hepatotoxicity e.g., elevation of liver enzymes
  • ILD interstitial lung disease
  • pneumonitis e.g., diarrhea, and/or nausea/vomiting.
  • nausea/vomiting e.g., nausea/vomiting.
  • the adverse event is hepatotoxicity.
  • hepatotoxicity refers to a patient having abnormal laboratory values of liver biomarkers (e.g., alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine aminotransferase (ALT), and/or total bilirubin (TBL)), when the patient had baseline levels of the liver biomarker(s) prior to sotorasib administration that were not abnormal laboratory values or were lower than those measured after administration of sotorasib.
  • ALP alkaline phosphatase
  • AST aspartate amino transferase
  • ALT alanine aminotransferase
  • TBL total bilirubin
  • ALT Alanine transaminase
  • SGPT serum glutamic pyruvate transaminase
  • ALAT alanine aminotransferase
  • AST Aspartate transaminase
  • SGOT serum glutamic oxaloacetic transaminase
  • ASAT aspartate aminotransferase
  • AST can increase in response to liver damage. Elevated AST also can result from damage to other sources, including red blood cells, cardiac muscle, skeletal muscle, kidney tissue, and brain tissue. The ratio of AST to ALT can be used as a biomarker of liver damage.
  • Bilirubin is a catabolite of heme that is cleared from the body by the liver. Conjugation of bilirubin to glucuronic acid by hepatocytes produces direct bilirubin, a water-soluble product that is readily cleared from the body. Indirect bilirubin is unconjugated, and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin can be indicative of liver impairment.
  • Alkaline phosphatase hydrolyzes phosphate groups from various molecules and is present in the cells lining the biliary ducts of the liver. ALP levels in plasma can rise in response to liver damage and are higher in growing children and elderly patients with Paget's disease. However, elevated ALP levels usually reflect biliary tree disease.
  • the patient is not suffering from a disorder that results in elevated liver biomarkers.
  • Disorders associated with elevated liver biomarkers include, but are not limited to, hepatobiliary tract disease; viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; heritable disorders causing impaired glucuronidation (e.g, Gilbert's syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g, indinavir, atazanavir); alpha-one antitry
  • hepatobiliary tract disease e.g., hepati
  • the baseline liver function of the patient can be assessed by various means known in the art, such as blood chemistry tests measuring biomarkers of liver function.
  • the methods described herein comprise monitoring liver biomarkers in the patient and withholding sotorasib administration in patients having > Grade 2 abnormal liver function, as assessed by levels of AST and/or ALT.
  • sotorasib administration is paused until the AST and/or ALT levels in the patient improve(s) to Grade 1 or better (baseline).
  • Adverse effect Grades for abnormal liver function are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 1. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.
  • CTC Common Toxicity Criteria
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • ULN upper limit of normal
  • WNL within normal limits
  • Grade 0 levels are characterized by biomarker levels within normal limits (WNL).
  • Normal refers to Grade 0 adverse effects.
  • Abnormal liver function, as used herein, refers to Grade 1 and above adverse effects.
  • Grade 1 liver function abnormalities include elevations in ALT or AST greater than the ULN and less than or equal to 3-times the ULN if baseline was normal; 1 .5 - 3.0 x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of bilirubin levels greater than the ULN and less than or equal to 1 ,5-times the ULN if baseline was normal; > 1 .0 - 1 .5 x baseline if baseline was abnormal. Grade 1 liver function abnormalities also include elevations of ALP greater than the ULN and less than or equal to 2.5-times the ULN if baseline was normal; > 2.0 - 2.5 x baseline if baseline was abnormal.
  • Grade 2 liver function abnormalities include elevations in ALT or AST greater than 3-times and less than or equal to 5-times the upper limit of normal (ULN) if baseline was normal; >3.0 - 5.0 x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of bilirubin levels greater than 1 ,5- times and less than or equal to 3-times the ULN if baseline was normal; > 1 .5 - 3.0 x baseline if baseline was abnormal. Grade 2 liver function abnormalities also include elevations of ALP greater than 2.5-times and less than or equal to 5-times the ULN if baseline was normal; > 2.5 - 5.0 x baseline if baseline was abnormal.
  • Grade 3 liver function abnormalities include elevations in ALT, AST, or ALP greater than 5-times and less than or equal to 20-times the ULN if baseline was normal; >5.0 - 20.0 x baseline if baseline was abnormal. Grade 3 liver function abnormalities also include elevations of bilirubin levels greater than 3-times and less than or equal to 10-times the ULN if baseline was normal; > 3.0 - 10 x baseline if baseline was abnormal.
  • Grade 4 liver function abnormalities include elevations in ALT, AST, or ALP greater than 20-times the ULN if baseline was normal; > 20 x baseline if baseline was abnormal. Grade 4 liver function abnormalities also include elevations of bilirubin levels greater than 10 times the ULN if baseline was normal; > 10.0 x baseline if baseline was abnormal.
  • the ULN for various indicators of liver function depends on the assay used, the patient population, and each laboratory's normal range of values for the specified biomarker, but can readily be determined by the skilled practitioner. Exemplary values for normal ranges for a healthy adult population are set forth in Table 2 below. See Cecil Textbook of Medicine, pp. 2317-2341, W.B. Saunders & Co. (1985). [0063] Table 2. - Upper Limit of Normal (ULN) Values
  • the total daily dose of sotorasib is reduced ⁇ e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the AST and/or ALT level (s) in the patient is/are elevated, e.g. to a Grade 2 or Grade 3 level, where the baseline AST and/or ALT levels of the patient were below Grade 2 or Grade 3 levels.
  • the total daily dose of sotorasib is reduced ⁇ e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg), when the AST and/or ALT level(s) in the patient is/are elevated is to a Grade 1 level, wherein the baseline AST and/or ALT levels of the patient were below Grade 1 levels.
  • the total daily dose of sotorasib is reduced ⁇ e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when (1) AST and bilirubin levels in the patient are elevated, or (2) when AST or ALP levels in the patient are elevated, or (3) when ALT and bilirubin levels in the patient are elevated, or (4) when ALT and ALP levels in the patient are elevated, or (5) when bilirubin and ALP levels in the patient are elevated, e.g., to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline AST, bilirubin, ALP, and/or ALT levels of the patient were below Grade 1 , Grade 2, Grade 3 or Grade 4 levels, respectively.
  • three biomarkers of liver function may be elevated in the patient ⁇ e.g, ALT and AST and bilirubin, or ALT and AST and ALP) to a Grade 1, Grade 2, Grade 3 or Grade 4 level, wherein the baseline biomarker levels of the patient were below Grade 1 , Grade 2, Grade 3 or Grade 4 levels, respectively.
  • the total daily dose of sotorasib is reduced ⁇ e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 3 times compared to the upper limit of normal (ULN).
  • the abnormal level of ALT and/or AST is greater than about 3- to about 5-fold increase compared to the upper limit of normal (ULN), i.e. a "Grade 2 abnormality".
  • the Grade 2 abnormality is an abnormal level of ALT and/or AST greater than about 3-fold to about 5-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 2.5- to about 5-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality".
  • the Grade 2 abnormality is an abnormal level of ALP greater than about 2.5-fold to about 5-fold increase compared to baseline.
  • the abnormal level of bilirubin is greater than about 1.5- to about 3-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 2 abnormality”.
  • the Grade 2 abnormality is an abnormal level of bilirubin greater than about 1.5-fold to about 3-fold increase compared to baseline.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 5 times compared to the upper limit of normal (ULN).
  • the total daily dose is reduced when the level of ALT, AST, or ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e. a "Grade 3 abnormality".
  • the Grade 3 abnormality is an abnormal level of ALT and/or AST greater than about 5-fold to about 20-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 5- to about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality".
  • the Grade 3 abnormality is an abnormal level of ALP greater than about 5-fold to about 20- fold increase compared to baseline.
  • the total daily dose is reduced when the level of bilirubin is greater than about 3- to about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 3 abnormality".
  • the Grade 3 abnormality is an abnormal level of bilirubin greater than about 3-fold to about 10-fold increase compared to baseline.
  • the total daily dose of sotorasib is reduced (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) when the level of ALT and/or AST is greater than about 20 times compared to the upper limit of normal (ULN) (i.e., a "Grade 4 abnormality”).
  • the Grade 4 abnormality is an abnormal level of ALT and/or AST greater than about 20-fold increase compared to baseline.
  • the abnormal level of ALP is greater than about 20-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality".
  • the Grade 4 abnormality is an abnormal level of ALP greater than about 20- fold increase compared to baseline.
  • the total daily dose is reduced when the level of bilirubin is greater than about 10-fold increase compared to the upper limit of normal (ULN), i.e., a "Grade 4 abnormality".
  • the Grade 4 abnormality is an abnormal level of bilirubin greater than about 10-fold increase compared to baseline.
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g, from 240 mg to 480mg, or from 480 mg to 960 mg) when liver biomarker(s) in the patient has improved to a Grade 1 or better (e.g, baseline).
  • sotorasib e.g, from 240 mg to 480mg, or from 480 mg to 960 mg
  • the adverse event is nausea or vomiting.
  • the nausea/vomiting is present despite appropriate supportive care (e.g, anti-emetic therapy).
  • “Nausea” as used herein refers to a disorder characterized by a queasy sensation and/or the urge to vomit.
  • Adverse effect Grades for nausea and vomiting are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 3. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.
  • the methods described herein comprise withholding sotorasib administration in a patient having > Grade 3 nausea until the patient has improved to ⁇ Grade 1 or baseline. In some embodiments, once the patient has improved to ⁇ Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
  • a reduced total daily dose of sotorasib e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg
  • the methods described herein comprise withholding sotorasib administration in a patient having > Grade 3 vomiting until the vomiting improves to ⁇ Grade 1 or baseline.
  • the methods comprise administering a reduced total daily dose of sotorasib (e.g., from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g., from 240 mg to 480mg, or from 480 mg to 960 mg) when nausea in the patient has improved to a Grade 1 or better (e.g., baseline).
  • sotorasib e.g., from 240 mg to 480mg, or from 480 mg to 960 mg
  • the adverse event is diarrhea.
  • the diarrhea is present despite appropriate supportive care (e.g., anti-diarrheal therapy).
  • Adverse effect Grades for diarrhea are defined herein by the modified Common Toxicity Criteria (CTC) provided in Table 4. See the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE) published Nov. 27, 2017 by the National Cancer Institute, incorporated herein by reference in its entirety.
  • the methods described herein comprise withholding sotorasib administration in a patient having > Grade 3 diarrhea until the patient has improved to ⁇ Grade 1 or baseline. In some embodiments, once the patient has improved to ⁇ Grade 1 or baseline, the methods comprise administering a reduced total daily dose of sotorasib (e.g, from 960 mg to 480 mg, or from 480 mg to 240 mg) to the patient.
  • a reduced total daily dose of sotorasib e.g, from 960 mg to 480 mg, or from 480 mg to 240 mg
  • the methods described herein further comprise increasing the total dose of sotorasib (e.g, from 240 mg to 480mg, or from 480 mg to 960 mg) when diarrhea in the patient has improved to a Grade 1 or better (e.g., baseline).
  • sotorasib e.g., from 240 mg to 480mg, or from 480 mg to 960 mg
  • the adverse event is interstitial lung disease (ILD) or pneumonitis.
  • ILD interstitial lung disease
  • pneumonitis In cases where ILD or pneumonitis is suspected at any grade level, sotorasib is withheld. In cases where ILD or pneumonitis is confirmed, and no other causes of the ILD or pneumonitis is identified, sotorasib is permanently discontinued.
  • Response rates or results for patients administered the therapeutics in the methods disclosed herein can be measured in a number of ways, after the patient has been taking the therapy for a suitable length of time.
  • response is measured after a patient is administered the therapy for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, e.g., for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months.
  • response is measured after the patient is administered the therapy for at least 1 month.
  • response is measured after the patient is administered the therapy for at least 3 months.
  • response is measured after the patient is administered
  • the patient can respond to the therapy as measured by at least a stable disease (SD), as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 protocol (Eisenhauer, et al., 2009).
  • SD stable disease
  • the stable disease is neither sufficient shrinkage to qualify for partial response (PR) nor sufficient increase to qualify for progressive disease (PD).
  • Response can be measured by one or more of decrease in tumor size, suppression or decrease of tumor growth, decrease in target or tumor lesions, delayed time to progression, no new tumor or lesion, a decrease in new tumor formation, an increase in survival or progression-free survival (PFS), and no metastases.
  • the progression of a patient's disease can be assessed by measuring tumor size, tumor lesions, or formation of new tumors or lesions, by assessing the patient using a computerized tomography (CT) scan, a positron emission tomography (PET) scan, a magnetic resonance imaging (MRI) scan, an X-ray, ultrasound, or some combination thereof.
  • CT computerized tomography
  • PET positron emission tomography
  • MRI magnetic resonance imaging
  • Progression free survival can be assessed as described in the RECIST 1.1 protocol.
  • the patient exhibits a PFS of at least 1 month.
  • the patient exhibits a PFS of at least 3 months.
  • the patient exhibits a PFS of at least 6 months.
  • sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C (Hong et al., 2020). Hong et al. report that “ [p] reclinical studies showed that [sotorasib] inhibited nearly all detectable phosphorylation of extracellular signal- regulated kinase (ERK), a key down-stream effector of KRAS, leading to durable complete tumor regression in mice bearing KRAS p.G12C tumors.” (id., see also Canon et al., 2019, and Lanman et al., 2020).
  • ERK extracellular signal- regulated kinase
  • Sotorasib was evaluated in a Phase 1 dose escalation and expansion trial with 129 patients having histologically confirmed, locally advanced or metastatic cancer with the KRAS p.G12C mutation identified by local molecular testing on tumor tissues, including 59 patients with non-small cell lung cancer, 42 patients with colorectal cancer, and 28 patients with other tumor types (Hong et al., 2020, at page 1208-1209). Hong et al. report a disease control rate (95% Cl) of 88.1% for non-small cell lung cancer, 73.8% for colorectal cancer and 75.0% for other tumor types (Hong et al., 2020, at page 1213, Table 3).
  • the cancer types showing either stable disease (SD) or partial response (PR) as reported by Hong et al. were non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma (Hong et al., 2020, at page 1212 ( Figure A), and Supplementary Appendix (page 59 ( Figure S5) and page 63 ( Figure S6)).
  • SD stable disease
  • PR partial response
  • KRAS G12C mutations occur with the alteration frequencies shown in the table below (Gerami et al., 2012; Gao et al., 2013). For example, the table shows that 11.6% of patients with non-small cell lung cancer have a cancer, wherein one or more cells express KRAS G12C mutant protein. Accordingly, sotorasib, which specifically and irreversibly bind to KRAS G12C is useful for treatment of patients having a cancer, including, but not limited to the cancers listed in Table 5 below.
  • the cancer is a solid tumor.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is small bowel cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non-small cell lung cancer, and in some specific embodiments, metastatic or locally advanced non-small cell lung cancer.
  • the cancer is colorectal cancer.
  • the cancer is metastatic colorectal cancer.
  • the cancer is pancreatic cancer.
  • a method of treating cancer comprising a KRAS G12C mutation in a patient in need of treatment comprising administering to the patient (a) a therapeutically effective amount of sotorasib or a pharmaceutically acceptable salt thereof, (b) a therapeutically effective amount of an epidermal growth factor receptor (EGFR) antibody and (c) (1) a therapeutically effective amount of oxaliplatin, (2) a therapeutically effective amount of leucovorin or a therapeutically effective amount of levoleucovorin, and (3) a therapeutically effective amount of 5-fluorouraci I (5-FU).
  • EGFR epidermal growth factor receptor
  • the EGFR antibody comprises a heavy chain HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, a light chain LCDR1 of SEQ ID NO: 6, LCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8.
  • step (a) is executed 2 hours before step (b) on the first day of the first two week period.
  • step (c) oxaliplatin and (2) leucovorin or levoleucovorin are administered, concurrently or subsequently, and then (3) 5-FU is administered.
  • cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, endometrial cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • ALT alanine aminotransferase
  • the QT prolonging medication is amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, or vandetanib.
  • [00161] 65 The method of any one of embodiments 1-64, wherein the patient exhibits at least a stable disease (SD) after 1, 3, or 6 months of sotorasib, panitumumab, oxaliplatin, leucovorin or levoleucovorin, and 5- FU administration, as measured by RECIST 1.1 protocol.
  • SD stable disease
  • [00162] 66 The method of any one of embodiments 1-64, wherein the patient exhibits at least a partial response (PR) after 1, 3, or 6 months of sotorasib, panitumumab, oxaliplatin, leucovorin or levoleucovorin, and 5- FU administration, as measured by RECIST 1.1 protocol.
  • PR partial response
  • subject is used throughout the disclosure interchangeably with “patient”, who is in need of treatment with one or more methods described herein.
  • patient who is in need of treatment with one or more methods described herein.
  • subject and patient refer to a human subject and a human patient, respectively.
  • Example 1 Sotorasib in combination with panitumumab and mFOLFOX6
  • sotorasib in combination with panitumumab and FOLFOX will not be administered to subjects enrolled in Part 1 Cohort C and Part 2 Cohort J with known mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4, other than the KRAS G12C mutation.
  • a phase 1b multicenter, open label study is set up to evaluate the safety, tolerability, pharmacokinetic (PK) behavior, pharmacodynamic (PD) behavior, and efficacy of sotorasib in combination with panitumumab and mFOLFOX6 in subjects with KRAS G12C mutant metastatic colorectal cancer.
  • sotorasib On days when PK samples are drawn in cycle 1, and after any dose hold of sotorasib, the treatments will be administered in the following sequence: sotorasib, panitumumab, and mFOLFOX6. Sotorasib will be administered orally once daily (QD). Alternatively, twice daily dosing may be used but the total daily dose will be the same. Panitumumab 6 mg/kg will be administered as 60-minute ( ⁇ 1000 mg) or 90-minute (> 1000 mg) intravenous (IV) infusion every 2 weeks (Q2W).
  • the mFOLFOX6 regimen consists of oxaliplatin 85 mg/m 2 IV on day 1, leucovorin 400 mg/m 2 IV on day 1 and 5-fluorouracil 400 mg/m 2 IV bolus on day 1 and 2400 mg/m 2 IV continuous infusion (I VCI) over 46 to 48 hours beginning on day 1 given Q2W (National Comprehensive Cancer Network [NCCN] Colon Cancer Guidelines version 2. 2023 and NCCN Rectal Cancer Guidelines version 3. 2023).
  • Levoleucovorin at 200 mg/m 2 may be used instead of leucovorin.
  • panitumumab The first dose of panitumumab will be administered 2 hours after sotorasib administration. Subsequent panitumumab doses may be administered before or immediately following sotorasib administration. In Part 1, Cohort C and Part 2 Cohort J mFOLFOX6 will be administered after panitumumab.
  • Part 1 Cohort C will consist of dose exploration of sotorasib, panitumumab, and mFOLFOX6.
  • the dose expansion in Part 2 Cohort J is based on the dose identified as recommended phase 2 dose (RP2D) in Part 1 Cohort C.
  • Dose level 1 sotorasib 960 mg orally total daily dose + 6 mg/kg panitumumab IV on day 1 Q2W + oxaliplatin 85 mg/m 2 IV on day 1, leucovorin 400 mg/m 2 IV on day 1 and 5-FU 400 mg/m 2 IV bolus on day 1 and 2400 mg/m 2 IV continuous infusion (IVCI) over 46 to 48 hours beginning on day 1 given Q2W.
  • the levoleucovorin dose will be 200 mg/m 2 .
  • Dose level -1 sotorasib 480 mg orally total daily dose + 6 mg/kg panitumumab IV on day 1 Q2W + oxaliplatin 85 mg/m 2 IV on day 1, leucovorin 400 mg/m 2 IV on day 1 and 5-FU 400 mg/m 2 IV bolus on day 1 and 2400 mg/m 2 IV continuous infusion (IVCI) over 46 to 48 hours beginning on day 1 given Q2W.
  • the levoleucovorin dose will be 200 mg/m 2 .
  • Dose level -2 sotorasib 240 mg orally total daily dose + 6 mg/kg panitumumab IV on day 1 Q2W + oxaliplatin 85 mg/m 2 IV on day 1, leucovorin 400 mg/m 2 IV on day 1 and 5-FU 400 mg/m 2 IV bolus on day 1 and 2400 mg/m 2 IV continuous infusion (IVCI) over 46 to 48 hours beginning on day 1 given Q2W.
  • the levoleucovorin dose will be 200 mg/m 2 .
  • Subjects must have been tested for KRAS and NRAS mutations through molecular testing according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory. Note: Subjects may not have known mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4, other than the KRAS G12C mutation.
  • Subjects must not have required dose reduction or been intolerant of a KRAS G12C inhibitor if they have received treatment with a KRAS G12C inhibitor in the past.
  • a minimum of 2 subjects must be KRAS G12C inhibitor naive per dose level.
  • Subjects tumor must have been tested for KRAS and NRAS mutations through molecular testing. In the United States, this test must be performed in a CLIA-certified laboratory. Subjects may not have known mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4, other than the KRAS G12C mutation.
  • Subjects may not have received treatment with a KRAS G12C inhibitor in the past.
  • Subjects must be willing to undergo pretreatment tumor biopsy and tumor biopsy on treatment, if clinically feasible. If a tumor biopsy prior to treatment is not medically feasible, or if the sample has insufficient tissue for testing, subjects must be willing to provide archived tumor tissue samples (formalin-fixed, paraffin- embedded [FFPE] sample) collected within the past 5 years, if available. Subjects with prior molecularly confirmed KRAS G12C mutation who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator and the Medical Monitor if a tumor biopsy is not clinically feasible.
  • FFPE paraffin- embedded
  • Adequate renal laboratory assessments include measured creatinine clearance or estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation > 60 mL/min/1.73 m 2 .
  • Adequate coagulation laboratory assessments are as follows:
  • PT Prothrombin time
  • aPTT activated partial thromboplastin time
  • PTT PTT ⁇ 1.5 x ULN
  • I NR International normalized ratio
  • Active brain metastases and/or carcinomatous meningitis from non-brain tumors refers to a cancer that has spread from the original (primary, non-brain) tumor to the brain. Active brain metastases can be assessed by the presence of intracranial lesions. It is to be understood that while “metastases” is plural, patients exhibiting only one intracranial lesion under the criteria noted below is a patient who has "active brain metastases.” In some embodiments, a patient having active brain metastases has at least one measurable intracranial lesion > 5 mm.
  • a patient having active brain metastases has at least one measurable intracranial lesion >5 mm but ⁇ 10 mm. In some embodiments, a patient having active brain metastases has at least one measurable intracranial lesion > 10 mm.
  • a patient is not considered a patient with active brain metastases if the patient has had brain metastases or have received radiation therapy ending at least 4 weeks prior to study day 1 and are eligible if they meet all of the following criteria: a) residual neurological symptoms grade ⁇ 2; b) on stable doses of dexamethasone, if applicable; and c) follow-up MRI performed within 28 days shows no new lesions appearing.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events v5.0
  • Gastrointestinal (Gl) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for IV alimentation, uncontrolled inflammatory Gl disease (e.g., Crohn's disease, ulcerative colitis).
  • HepBsAg Positive Hepatitis B Surface Antigen
  • Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. Detectable Hepatitis C virus RNA suggests chronic hepatitis C.
  • HIV human immunodeficiency virus
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Part 1 Cohort C and Part 2 Cohort J Known mutation in KRAS exon 2, 3, or 4 or NRAS exon 2, 3, or 4 other than KRAS G12C mutation.
  • Anti-tumor therapy chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with history of breast cancer receiving adjuvant hormonal therapy], or investigational agent except for sotorasib) within 28 days of study Day 1 ; targeted small molecule inhibitors, within 14 days of study Day 1 , unless at least 5 half-lives have passed.
  • exemplary medications known to prolong QT interval include, but are not limited to, amiodarone, anagrelide, arsenic trioxide, azithromycin, chloroquine, chlorpromazine, cilostazol, ciprofloxacin, citalopram, disopyramide, dofetilide, donepezil, dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, haloperidol, ibutilide, levofloxacin, methadone, moxifloxacin, ondansetron, pentamidine, pimozide, procainamide, propofol, quinidine, sevoflurane, sotalol, thioridazine, and vandetanib If concomitant use is required, approval of the principal investigator
  • cytochrome P450 (CYP) 3A4 sensitive substrates or P-glycoprotein (P-gp) substrates e.g., with a narrow therapeutic window
  • CYP3A4 or P-gp substrate or its major active metabolite whichever is longer, prior to start of therapy.
  • CYP3A4 sensitive substrates include abemaciclib, buspirone, isavuconazole, ridaforolimus, ABT-384, capravirine, itacitinib, saquinavir, acalabrutinib, casopitant, ivabradine, sildenafil, alfentanil, cobimetinib, ivacaftor, simeprevir, alisporivir, conivaptan, L-771,688, simvastatin, almorexant, danoprevir, levomethadyl (LAAM), sirolimus, alpha dihydroergocryptine, darifenacin, lomitapide, tacrolimus, aplaviroc, darunavir, lopinavir, terfenadine, aprepitant, dasatinib, lovastatin, ticagrelor, asunaprevir, dronedarone, lumefantrine, tilidine
  • P- gp substrates with a narrow therapeutic window include digoxin, everolimus, cyclosporine, tacrolimus, sirolimus, and vincristine.
  • P450 (CYP) 3A4 sensitive substrates with a narrow therapeutic window include alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, tacrolimus, and sirolimus.
  • Strong inducers of CYP3A4 include ombitasvir and paritaprevir and ritonavir and dasabuvir, indinavir and ritonavir, tipranavir and ritonavir, ritonavir, cobicistat, ketoconazole, troleandomycin, telaprevir, danoprevir and ritonavir, elvitegravir and ritonavir, saquinavir and ritonavir, lopinavir and ritonavir, itraconazole, indinavir, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, josamycin, lonafarnib, posaconazole
  • Subject has known sensitivity to any of the products or components to be administered during dosing.
  • panitumumab -2 months after the last dose of panitumumab
  • panitumumab -2 months after the last dose of panitumumab
  • panitumumab -2 months after the last dose of panitumumab
  • Anti-tumor therapy such as chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, or hormonal therapy (except for subjects with breast cancer receiving it as adjuvant therapy).
  • Strong CYP3A4 inducers including herbal supplements such as St. John's wort) unless approved by the principal investigator and medical monitor.
  • the dose limiting toxicity (DLT) window (i.e., DLT-evaluable period) will be the first 28 days of sotorasib and panitumumab treatment (starting cycle 1, day 1).
  • the grading of adverse events (AEs) will be based on the guidelines provided in the CTCAE version 5.0.
  • a subject will be DLT evaluable if the subject has completed the DLT window as described above and received > 80% of the planned dose of sotorasib and panitumumab and at least 1 treatment/dose of mFOLFOX6 within the first 28 days.
  • DLT is defined as any adverse event meeting the criteria listed below occurring during the first treatment cycle and attributable to sotorasib and/or panitumumab.
  • Hy's Law case i.e., severe drug-induced liver injury [DILI]
  • DLT severe drug-induced liver injury
  • a Hy's Law case is defined as: AST or ALT values of > 3 x ULN AND with serum total bilirubin level (TBL) of > 2 x ULN without signs of cholestasis and with no other clear alternative reason to explain the observed liver related laboratory abnormalities.
  • panitumumab should be held as well.
  • sotorasib re-challenges for isolated alkaline phosphatase elevations that resolve to baseline or grade 1 .
  • Dose decrements below 240 mg are not allowable. Subjects may restart at same dose without dose reduction.
  • Hepatotoxicity Response Subjects with abnormal hepatic laboratory values (i.e. , alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBL)) and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as described below) may meet the criteria for withholding or permanent discontinuation of sotorasib.
  • ALP alkaline phosphatase
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • TBL total bilirubin
  • ILR international normalized ratio
  • AST/ALT and/or TBL values include, but are not limited to: Hepatobiliary tract disease; Viral hepatitis ⁇ e.g., hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); Right sided heart failure, hypotension or any cause of hypoxia to the liver causing ischemia; Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary supplements, plants and mushrooms; Heritable disorders causing impaired glucuronidation ⁇ e.g., Gilbert's syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation ⁇ e.g.
  • Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and/or the laboratory abnormalities resolve to normal or baseline, as described in the below.
  • ALP alkaline phosphatase
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • I NR international normalized ratio
  • TBL total bilirubin
  • ULN upper limit of normal
  • panitumumab dose reductions are listed in the table below.
  • panitumumab dose modification guidelines due to dermatological toxicities are provided in the table below.
  • panitumumab dose modification guidelines due to dermatological toxicities are provided in the table below.
  • Proactive skin treatment including skin moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) may be useful in the management of skin toxicities.
  • Subjects may be advised to apply moisturizer and sunscreen to face, hands, feet, neck, back and chest every morning during treatment, and to apply the topical steroid to face, hands, feet, neck, back and chest every night.
  • Treatment of skin reactions should be based on severity and may include a moisturizer, sunscreen (SPF > 15 UVA and UVB), and topical steroid cream (not stronger than 1% hydrocortisone) applied to affected areas, and/or oral antibiotics, as prescribed by a physician.
  • sunscreen SPF > 15 UVA and UVB
  • topical steroid cream not stronger than 1% hydrocortisone
  • panitumumab for any grade 3 or 4 panitumumab-related toxicity with the following exceptions:
  • Panitumumab will only be withheld for symptomatic grade 3 or 4 hypomagnesemia and/or hypocalcemia that persists despite aggressive magnesium and/or calcium replacement
  • Panitumumab will only be withheld for grade 3 or 4 nausea, diarrhea, or vomiting that persists despite maximum supportive care
  • Infusion reactions may manifest as fever, chills, dyspnea, bronchospasm, hypotension, or anaphylaxis.
  • the table below describes the recommended dose modifications for the next dose based on the worst toxicity observed. If in the judgment of the investigator, the toxicity is primarily from 1 drug, the investigator can dose reduce only the suspected agent. If, in the opinion of the investigator, a more severe dose reduction or dose hold is needed, that is permissible. a There will be no leucovorin dose reduction. If the 5-fl uorouracil dose is omitted, the leucovorin is also omitted.
  • Levoleucovorin 200 mg/m 2 may be used instead of leucovorin.
  • 5-FU 5-fluorouracil
  • IV intravenous
  • FOLFOX 5 fluorouracil, leucovorin, and oxaliplatin
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events a There will be no leucovorin dose reduction. If the 5-FU dose is held, the leucovorin dose should be held.
  • NCI CTCAE (Version 5.0)
  • c Absolute neutrophil count ⁇ 1000/mm 3 and temperature > 38.5°C.
  • d Despite maximum supportive care.
  • e Dose modifications are based on worst toxicity observed on planned treatment days only.
  • antiemetic agents e.g., oral or IV dexamethasone, 5-hydroxyyptamine3 [5-HT3] receptor antagonists. Avoid the use of the 5-HT3 receptor antagonist onandestron in subjects enrolled in Part 1 Cohort C and Part 2 Cohort J and consider use of granisetron or palanosetron.
  • Antiemetic agents should be given on the day of treatment, starting at least 30 minutes prior to administration of oxaliplatin.
  • Alternative and additional antiemetics may be used, where clinically indicated, at the discretion of the investigator.
  • Prophylactic or therapeutic administration of IV or subcutaneous atropine for cholinergic symptoms may be used at the discretion of the investigator.
  • Growth factor support and medications for diarrhea management may be used at the discretion of the investigator.
  • the extent of disease will be evaluated by contrast-enhanced MRI/CT according to RECIST v1.1. In order to reduce radiation exposure for subjects, the lowest dose possible should be utilized whenever possible.
  • the screening scans must be performed within 28 days prior to enrollment and will be used as baseline. Imaging performed as part of standard of care that falls within the screening window given for scans may be used for the baseline scan as long as it meets the scan requirements for screening. All subsequent scans will be performed in the same manner as at screening, with the same contrast, preferably on the same scanner. Radiological assessment must include CT of the chest, and contrast-enhanced CT or MRI of the abdomen and pelvis, as well as assessment of all other known sites of disease as detailed within the Site Imaging Manual.
  • Radiographic response requires confirmation by a repeat, consecutive scan at least 4 weeks after the first documentation of response and may be delayed until the next scheduled scan to avoid unnecessary procedures.
  • All subjects, subjects with a history of brain metastases, and subjects with signs and symptoms suggestive of brain metastases must have MRI of the brain performed within 28 days prior to first dose of sotorasib. Subsequently, brain scans may be performed at any time if needed, in the judgement of the managing physician. All brain scans on protocol are required to be MRI unless MRI is contraindicated, and then CT with contrast is acceptable.
  • Radiological imaging assessment at the end of the study or during the end of treatment (EOT) visit should be performed only for subjects that discontinue treatment for a reason other than disease progression per RECIST v1 .1 guidelines.
  • Measurable Tumor Lesions - Non-nodal lesions with clear borders that can be accurately measured in at least 1 dimension with longest diameter > 10 mm in CT/MRI scan with slice thickness no greater than 5 mm. When slice thickness is greater than 5 mm, the minimum size of measurable lesion should be twice the slice thickness.
  • lymph node must be > 15 mm in short axis when assessed by CT/MRI (scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis is measured and followed. Nodal size is normally reported as two dimensions in the axial plane. The smaller of these measures is the short axis (perpendicular to the longest axis).
  • Non-measurable Lesions All other lesions, including small lesions (longest diameter ⁇ 10 mm or pathological lymph nodes with > 10 mm but to ⁇ 15 mm short axis with CT scan slice thickness no greater than 5 mm) are considered non-measurable and characterized as non-target lesions.
  • non-measurable lesions include: Lesions with prior local treatment: tumor lesions situated in a previously irradiated area, or an area subject to other loco-regional therapy, should not be considered measurable unless there has been demonstrated progression in the lesion; Biopsied lesions; Categorically, clusters of small lesions, bone lesions, inflammatory breast disease, and leptomeningeal disease are non-measurable.
  • Measurement of Lesions The longest diameter of selected lesions should be measured in the plane in which the images were acquired (axial plane). All measurements should be taken and recorded in metric notation. All baseline evaluations should be performed as closely as possible to the beginning of treatment and not more than 4 weeks before study Day 1 .
  • CT/ MRI - Contrast-enhanced CT or MRI should be used to assess all lesions. Optimal visualization and measurement of metastasis in solid tumors requires consistent administration (dose and rate) of IV contrast as well as timing of scanning. CT and MRI should be performed with ⁇ 5 mm thick contiguous slices.
  • Target Lesions All measurable lesions up to a maximum of two (2) lesions per organ and five (5) lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline.
  • -Target lesions should be selected on the basis of their size (lesions with the longest diameter) and suitability for accurate repeated measurements.
  • -Pathologic lymph nodes (with short axis > 15 mm) may be identified as target lesions. All other pathological nodes (those with short axis > 10 mm but ⁇ 15 mm) should be considered non-target lesions.
  • Non-Target Lesions All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, and these lesions should be followed as "present”, “absent”, or “unequivocal progression” throughout the study. In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case report form (e.g., "multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).
  • the best overall response is the best response recorded from the start of the study treatment until the end of treatment or disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
  • the subject's best response assignment depends on the findings of both target and non-target disease and also take into consideration the appearance of new lesions.
  • Non-CR/non-PD is preferred over “SD” for non-target disease since SD is increasingly used as endpoint for assessment of efficacy in some trials so as to assign this category when no lesions can be measured is not advised.
  • Nodal lesions - Lymph nodes identified as target lesions should always have the actual short axis measurement recorded, even if the nodes regress to below 10 mm on study. In order to qualify for CR, each node must achieve a short axis ⁇ 10 mm, NOT total disappearance. Nodal target lesion short axis measurements are added together with target lesion' longest diameter measurements to create the sum of target lesion diameters for a particular assessment (time point).
  • Target lesions that become "too small to measure” While on study, all lesions (nodal and non-nodal) recorded at baseline should have their measurements recorded at each subsequent evaluation. If a lesion becomes less than 5 mm, the accuracy of the measurement becomes reduced. Therefore, lesions less than 5 mm are considered as being “too small to measure”, and are not measured. With this designation, they are assigned a default measurement of 5 mm. No lesion measurement less than 5mm should be recorded, unless a lesion totally disappears and "0” can be recorded for the measurement.
  • New lesions The term “new lesion” always refers to the presence of a new finding that is definitely tumor. New findings that only may be tumor, but may be benign (infection, inflammation, etc.) are not selected as new lesions, until that time when the review is certain they represent tumor.
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • PET/CT PET/computed tomography
  • fine needle aspirate/biopsy to confirm the CR status.
  • Duration of overall response The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date the recurrent or progressive disease is objectively documented or death, whichever is earlier.
  • Duration of Stable Disease - SD is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started, or death, whichever is earlier.
  • Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or dyspnea.
  • Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation or dyspnea.
  • Class IV Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest. If any physical activity is undertaken, discomfort is increased.
  • NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events v5.0

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Abstract

L'invention concerne des méthodes de traitement du cancer comprenant une mutation KRAS G12C chez un patient ayant besoin d'un traitement, la méthode comprenant l'administration au patient (a) d'une quantité thérapeutiquement efficace de sotorasib ou d'un sel pharmaceutiquement acceptable de celui-ci, (b) d'une quantité thérapeutiquement efficace d'un anticorps du récepteur du facteur de croissance épidermique (EGFR), et (c) (1) d'une quantité thérapeutiquement efficace d'oxaliplatine, (2) d'une quantité thérapeutiquement efficace de leucovorine ou d'une quantité thérapeutiquement efficace de lévoleucovorine, et (3) d'une quantité thérapeutiquement efficace de 5-fluorouraciIe (5-FU).
PCT/US2024/054745 2023-11-07 2024-11-06 Méthodes de traitement du cancer Pending WO2025101623A1 (fr)

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Patent Citations (1)

* Cited by examiner, † Cited by third party
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Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
"Cecil Textbook of Medicine", 1985, W.B. SAUNDERS & CO., pages: 2317 - 2341
"National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 (NCI CTCAE", 27 November 2017, NATIONAL CANCER INSTITUTE
ANONYMOUS: "A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC)", CLINICALTRIALS.GOV, 11 October 2023 (2023-10-11), pages 1 - 10, XP093240740, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT04929223?tab=history&a=29#study-design-card> *
BOKEMEYER ET AL., ANN ONCOL, vol. 22, no. 7, 2011, pages 1535 - 1546
CANON ET AL., NATURE, vol. 575, no. 7781, 2019, pages 217
CERAMI ET AL., CANCER DISCOV, vol. 2, no. 5, 2012, pages 401
CERVANTES A ET AL., ANN ONCOL, vol. 34, no. 1, 25 October 2022 (2022-10-25), pages 10 - 32
CERVANTES A. ET AL: "Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up", ANNALS OF ONCOLOGY, vol. 34, no. 1, 1 January 2023 (2023-01-01), pages 10 - 32, XP093240731, ISSN: 0923-7534, DOI: 10.1016/j.annonc.2022.10.003 *
CERVANTES ET AL., EMSO MCRC GUIDELINES, 2023
CHANG ET AL., PNAS, vol. 79, 1982, pages 4848 - 4852
DOUILLARD ET AL., J CLIN ONCOL, vol. 28, no. 31, 2010, pages 4706 - 4705
EISENHAUER ET AL., EUR. J. CANCER, vol. 45, 2009, pages 228 - 247
FAKIH MARWAN G. ET AL: "Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 389, no. 23, 22 October 2023 (2023-10-22), US, pages 2125 - 2139, XP093240209, ISSN: 0028-4793, DOI: 10.1056/NEJMoa2308795 *
GAO ET AL., SCIENCE SIGNALING, vol. 6, no. 269, 2013, pages 1
GIUSTI ET AL., ONCOLOGIST, vol. 12, 2007, pages 577 - 583
HALL ET AL., NATURE, vol. 303, 1983, pages 396
HARVEY, NATURE, vol. 204, 1964, pages 1104
HONG ET AL., N. ENGL. J. MED., vol. 383, 2020, pages 1207
JANES ET AL., CELL, vol. 172, no. 3, 2018, pages 578 - 589
KIRSTENMAYER, J. NATIONAL CANCER INST., vol. 39, 1967, pages 311 - 335
KUBOKI Y ET AL: "Sotorasib in combination with panitumumab in refractory KRAS G12C-mutated colorectal cancer: Safety and efficacy for phase Ib full expansion cohort", ANNALS OF ONCOLOGY, vol. 33, 1 September 2022 (2022-09-01), pages S680, XP093241013, ISSN: 0923-7534, DOI: 10.1016/j.annonc.2022.07.452 *
LANMAN ET AL., J. MED. CHEM., vol. 63, 2020, pages 52
MAUGHAN ET AL., THE LANCET, vol. 377, no. 9783, 2011, pages 18 - 24
MCCORMICK, J. MOL. MED. (BERL)., vol. 94, 2016, pages 253 - 258
NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY: COLON CANCER VERSION 4/2020
NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY: COLON CANCER, 25 April 2023 (2023-04-25)
NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY: RECTAL CANCER, 26 May 2023 (2023-05-26)
OKEN ET AL., AM J CLIN ONCOL, vol. 5, no. 6, 1982, pages 649 - 655
OSTREM ET AL., NATURE, vol. 503, 2013, pages 548 - 551
OSTREMSHOKAT, NATURE REV DRUG DISCOV, vol. 15, no. 11, 2016, pages 771 - 785
PATRICELLI ET AL., CANCER DISCOVERY, vol. 6, 2016, pages 316 - 329
PRIOR ET AL., CANCER RES., vol. 72, 2012, pages 2457 - 2467
SIMANSHU ET AL., CELL, vol. 170, 2017, pages 17 - 33
TAPAROWSKY ET AL., CELL, 1983, pages 581 - 586
VAN CUTSEM ET AL., J. CLIN. ONCOL., vol. 25, 2007, pages 1658 - 1664
XIE ET AL., FRONT PHARMACOL, vol. 8, 2017, pages 823
ZUBROD ET AL., J CHRONIC DISEASE, vol. 11, 1960, pages 7 - 33

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