TREATMENT OF CANCER USING COMBINATION THERAPIES COMPRISING GDC-6036 and GDC-0077

Abstract

This article provides combination therapies comprising KRas G12C inhibitors (e.g., GDC-6036) and PI3K inhibitors (e.g., Iffulix), and methods for using such combination therapies.

Description

[Technical Field]

[0001] This article provides combination therapies comprising a KRas G12C inhibitor (e.g., GDC-6036) and a PI3K inhibitor (GDC-0077, inavolisib) and methods of using such combination therapies. [Previous Technology]

[0002] The Kirsten rat sarcoma virus oncogene homolog (KRAS) is a core component of the RAS / MAPK signaling pathway, an intracellular protein network that transmits extracellular growth factor signals to regulate cell proliferation, differentiation, and survival. Mutations in KRAS can lead to alterations in several amino acids, including glycine 12 (G12), glycine 13, and glutamic acid 61, and are commonly found in solid tumors and are associated with tumorigenesis and aggressive tumor growth. Oncogenic KRAS mutations that change from G12 to cysteine ​​(G12C) are prevalent in non-small cell lung cancer (NSCLC) (~12%), colorectal cancer (CRC) (~4%), and other tumor types (≤4%).

[0003] Advanced tumors bearing the KRas G12C mutation (hereinafter referred to as KRas G12C-positive tumors), including, for example, lung cancer (e.g., NSCLC), CRC, and pancreatic cancer, are incurable and have a poor prognosis. Patients with advanced KRas G12C-positive cancer may benefit limitedly from chemotherapy and targeted therapy, thus limiting effective treatment options.

[0004] Phosphopeptidyl inositol 3-kinase (PI3K) is a lipid kinase that, upon activation by growth factor receptors and integrins, regulates cell proliferation, survival, and migration. PI3K catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP 2) to generate phosphatidylinositol-3,4,5-triphosphate (PIP 3), which is the second messenger involved in the phosphorylation of other components in the AKT and AKT / mTOR pathways. Up to 70% of breast cancers have some form of molecular aberration in the PI3K / AKT / mTOR pathway. Activating mutations in PIK3CA, which encodes the PI3K p110α subunit, are very common in breast cancer and solid malignancies.

[0005] Although PI3Kα inhibitors have been approved or are in clinical development for the treatment of patients with hormone receptor (HR) positive, HER2 negative, locally advanced or metastatic breast cancer with PIK3CA mutations, effective therapies and combination therapies are still needed for the treatment of cancers such as lung cancer, colorectal cancer and pancreatic cancer with KRas G12C mutations. [Summary of the Invention]

[0006] This document provides solutions to this and other problems in this technology.

[0007] In one embodiment, this article provides a combination therapy comprising GDC-6036 as described herein or a pharmaceutically acceptable salt thereof and Ivlixim or a pharmaceutically acceptable salt thereof.

[0008] In another embodiment, this document provides a method for treating a patient with lung cancer mediated by a KRas G12C mutation, the method comprising administering an effective amount of a combination therapy comprising: administering an effective amount of GDC-6036 or a pharmaceutically acceptable salt thereof once daily (QD) according to a dosing regimen comprising one or more cycles, and administering an effective amount of effulcisil as described herein or a pharmaceutically acceptable salt thereof once daily (QD) according to a dosing regimen comprising one or more cycles. In one such embodiment, the dosing regimen comprises 21 days or 28 days.

[0009] In another embodiment, this article provides a method for treating a patient with lung cancer mediated by a KRas G12C mutation, the method comprising administering an effective amount of a combination therapy comprising: GDC-6036 as described herein or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles, and an effective amount of epefliximab as described herein or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles.

[0010] In another embodiment, this article provides a method for treating a patient with a solid tumor mediated by a KRas G12C mutation, the method comprising administering an effective amount of a combination therapy comprising: GDC-6036 as described herein or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more cycles as described herein, and an effective amount of epefliximab as described herein or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more cycles as described herein.

[0011] In another embodiment, this article provides a method for treating a patient with tissue-undetermined cancer containing a KRas G12C mutation, the method comprising: (i) determining whether a KRas G12C mutation is present or absent in a sample taken from a patient suspected of having cancer; and (ii) administering an effective amount of a combination therapy when the patient sample contains a KRas G12C mutation, the combination therapy comprising: (a) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more cycles as described herein; and (b) Ivlixim or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more cycles as described herein.

[0012] In another embodiment, this article provides the use of a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof and sefliximab or a pharmaceutically acceptable salt thereof for the treatment of lung cancer, CRC or pancreatic cancer as described herein.

[0013] In another embodiment, this article provides the use of a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof and sefliximab or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of lung cancer, CRC or pancreatic cancer.

[0014] In embodiments of the methods and uses described herein, administration of sefliximab (GDC-0077) does not require prior testing or evaluation of the presence or absence of one or more PI3KCA mutations.

Implementation Method

[0016] Cross-reference to related applications

[0017] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 328149, filed April 6, 2022, the whole and all purposes of which are incorporated herein by reference. Definitions

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd edition, J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, apparatus, and materials similar to or equivalent to those described herein may be used to practice this invention.

[0019] The following definitions are provided to facilitate understanding of certain terms that are frequently used herein, but are not intended to limit the scope of this disclosure. All references cited herein are incorporated herein by reference in their entirety.

[0020] As used herein, unless otherwise specified, when the terms "about" and "approximately" refer to a dose, amount, or weight percentage of a component of a composition or dosage form, they mean a dose, amount, or weight percentage known to those skilled in the art to provide an equivalent pharmacological effect from the specified dose, amount, or weight percentage. Such equivalent dose, amount, or weight percentage may be within a range of 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage.

[0021] As used herein, "KRas G12C inhibitor" refers to a covalent inhibitor that specifically binds to a mutant KRas protein containing a Gly to Cys mutation at the position corresponding to residue 12.

[0022] "GDC-6036" refers to a compound having the following structure: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one. In one embodiment, GDC-6036 is an adipate.

[0023] Ivlixi, CAS Registration No. 2060571-02-8, Jiannan Dec, USA 9650393; named (S)-2-((2-((S)-4-(difluoromethyl)-2-side-oxy-3-azolidinyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazop-9-yl)amino)propionic acid, refers to a compound having the following structure: The chemical name is (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-side-oxy-3-azolidinyl]-5,6-dihydroimidazo[1,2-d][1,4]benzooxazop-9-yl]amino]propionic acid. Ivlixi is also known as GDC-0077, RG6114, or RO7113755.

[0024] Iffulliximab is a potent, orally bioavailable, clinical-stage class I PI3Kα isoform (PI3Kα) selective inhibitor with >300-fold biochemical inhibition against other class I PI3Kβ, δ, and γ isoforms. Furthermore, it exhibits increased efficacy against tumor cells carrying mutant PI3K compared to wild-type (WT) PI3K cells (Braun, M. et al., "Discovery of GDC-0077: A highly selective inhibitor of PI3K-alpha that induces degradation of mutant-p110 alpha protein" Abstracts of Papers, 254th ACS National Meeting & Exposition, Washington, DC, USA, August 20-24, 2017, MEDI-22; Garland, K. et al., "Discovery of novel class of alpha selective PI3K inhibitors" Abstracts of Papers, 254th ACS National Meeting & Exposition, Washington, DC, USA, August 20-24, 2017, MEDI-103; Hong, R. et al., "GDC-0077 is a selective PI3K alpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies" 2017 San Antonio Breast Cancer Symposium, Dec. 5-9 2017, San Antonio, TX, Abstract Publication Number: PD4-14; Edgar, K.et al., "Preclinical characterization of GDC-0077, a specific PI3K alpha inhibitor in early clinical development" Cancer Research77(13 Supplement): Abstract 156 July 2017). .

[0025] GDC-0077 exerts its activity by binding to the ATP-binding site of PI3K, thereby inhibiting the phosphorylation of membrane-bound 4,5-phosphatidylinositol diphosphate (PIP2) to 3,4,5-phosphatidylinositol triphosphate (PIP3). Inhibition of PIP2 to PIP3 phosphorylation reduces downstream activation of AKT and pS6, leading to decreased cell proliferation, metabolism, and angiogenesis. Non-clinical studies have demonstrated that GDC-0077 specifically degrades mutant p110α, inhibits the proliferation of PIK3CA mutant breast cancer cell lines and induces their apoptosis, suppresses tumor growth in a human breast cancer xenograft model bearing PIK3CA mutations, and reduces downstream PI3K pathway markers (including phosphorylated form of protein kinase B (pAKT), PRAS40 phosphorylated at threonine 246 (pPRAS40), and S6RP phosphorylated at serine 235 / 236 (pS6RP)).

[0026] The term "medically acceptable" means a molecular entity and composition that, when administered to animals such as, for example, humans (where appropriate), does not produce adverse, allergic, or other adverse reactions.

[0027] The compounds of the present invention may be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic and organic acids that retain the bioavailability and properties of a free base and are not biologically or otherwise undesirable. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and similar acids. Organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid types, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthraquinone, benzoic acid, cinnamic acid, mandelic acid, pyric acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and similar acids. In one embodiment, the salt is formed from adipic acid.

[0028] The term "medically acceptable base addition salt" includes base addition salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, thiazolinone, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methyl-reduced glucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and their analogues. Specific organic nontoxic bases include isopropylamine, diethylamine, ethanolamine, thiazolinone, dicyclohexylamine, choline, and caffeine.

[0029] In some embodiments, the salt is selected from hydrochloride, bromate, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, hydrogen sulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, glycoside, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furonate or 3-furonate), and napadisylate. (Naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanedisulfonate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesotribenzenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-amymose, L-amymose, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesotribenzenesulfonate), napsylate (2-naphthalenesulfonate), camphorsulfonate (camsylate) (camphor-10-sulfonates, such as (1S)-(+)-10-camphor sulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate) and pyrate (2,2'-dihydroxy-1,1'-dinathylmethane-3,3'-dicarboxylate).

[0030] The terms “inhibition” and “reduction” or any variations thereof include any measurable reduction or complete inhibition to achieve the desired result. For example, a reduction in activity compared to normal activity may be a reduction of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range thereof.

[0031] The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one embodiment, cancer is lung cancer. In another embodiment, cancer is non-small cell lung cancer (NSCLC). In another embodiment, cancer is a solid tumor. In another embodiment, cancer is colorectal cancer (e.g., metastatic CRC), breast cancer, or pancreatic cancer. As used herein, "cancer" refers to cancer characterized by having a KRas G12C mutation.

[0032] As used herein, "treatment" includes treatment with an effective amount of a therapeutic agent (e.g., GDC-6036 or Ivlixi) or a combination of therapeutic agents (e.g., GDC-6036 or Ivlixi). In one embodiment, treatment refers to treatment with an effective amount of GDC-6036 or its pharmaceutically acceptable salt and Ivlixi. Treatment can be first-line treatment (e.g., the patient may not have previously received treatment or prior systemic therapy), or second-line or advanced treatment. For example, a patient is considered successfully "treated" if one or more symptoms associated with the cancer described herein are reduced or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), reducing symptoms caused by the disease, improving the quality of life of the patient with the disease, reducing the dosage of other medications required to treat the disease, and / or prolonging the patient's survival.

[0033] The term "delayed disease progression" refers to the delay, blockage, slowing, stabilization, and / or postponement of the development of the cancer described herein. This delay can vary in duration, depending on the cancer described herein and / or the patient's medical history. As will be apparent to those skilled in this art, a sufficient or significant delay can effectively encompass prevention, as the patient has not developed cancer.

[0034] In this document, "effective amount" means the amount of the therapeutic agent (e.g., GDC-6036 and / or estradiol) described herein that achieves a therapeutic effect. In some instances, the effective amount of a therapeutic agent or combination of therapeutic agents is the amount of the agent or combination of agents that achieves the clinical endpoints provided herein. In one embodiment, the effective amount means the amount of GDC-6036 or a pharmaceutically acceptable salt thereof and the amount of estradiol. The effective amount described herein may vary depending on factors such as disease state, patient age, sex and weight, and the desired response induced by the agent in the patient. The effective amount is also the amount by which any toxic or adverse effect of the treatment is exceeded by the beneficial effect of the treatment. In some embodiments, the effective amount of the drug may have the following effects: reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or stopping) the infiltration of cancer cells into peripheral organs; inhibiting (i.e., slowing or stopping) tumor metastasis; inhibiting (i.e., slowing or stopping) tumor growth; and / or alleviating one or more of the symptoms associated with the disease. The effective amount may be administered in one or more doses. The effective amount of the drug, compound, pharmaceutical composition, or combination therapy described herein may be an amount sufficient to directly or indirectly achieve a therapeutic effect.

[0035] "Objective response rate" or "ORR" refers to the percentage of patients who have two consecutive complete or partial responses with a confirmed interval of ≥ 4 weeks, as determined by investigators according to RECIST v1.1.

[0036] "Duration of response" or "DOR" refers to the time from the first appearance of a documented objective remission to the time from disease exacerbation or death from any cause as determined by the investigator according to RECIST v1.1, whichever occurs first.

[0037] "Disease-free survival" or "PFS" refers to the time from registration to the date on which the disease worsens or death from any cause is first recorded, as determined by the investigator according to RECIST v1.1, whichever comes first.

[0038] As used herein, “complete response” and “CR” refer to the disappearance of all target lesions and (if applicable) the standardization of tumor marker levels.

[0039] As used herein, "partial response" and "PR" refer to the persistence of one or more non-target lesions and / or (if applicable) tumor marker levels remaining above normal limits. PR may also indicate a reduction of ≥ 30% in the sum of the diameters of target lesions, without CR, new lesions, or clear deterioration of non-target lesions.

[0040] "Dosing period" or "cycle" means a period of time during which one or more of the drugs described herein (e.g., GDC-6036 and Iffulcil) are administered, and, if necessary, a period of time during which one or more of the drugs described herein are not administered. For example, a cycle may be 21 days in total and includes administration of one or more of the drugs described herein (e.g., GDC-6036 and Iffulcil) on each day of that cycle. In another example, a cycle may be 28 days in total and includes 21 days of administration of one or more of the drugs described herein (e.g., GDC-6036 and Iffulcil) and a 7-day suspension period. "Suspension period" means a period of time during which at least one of the drugs described herein (i.e., GDC-6036 and Iffulcil) is not administered. In one embodiment, a suspension period means a period of time during which none of the drugs described herein (i.e., GDC-6036 and Iffulcil) are administered. In some instances, the pauses described herein may include administration of an agent other than GDC-6036 or Ivliximab. In such cases, administration of another agent during the pause should not interfere with or impair administration of the agent described herein. In one instance, a cycle as used herein refers to a 21-day cycle without a pause. In another instance, the total duration of a cycle may be 28 days and may include administration of one or more of the agents described herein (e.g., GDC-6036 and Ivliximab) once daily (QD) on each day of the cycle.

[0041] "Dosing regimen" refers to a time period comprising one or more cycles in which the drug described herein is administered, wherein each cycle may include administration of the drug described herein at different time points or at different amounts.

[0042] "QD" refers to the medication described herein administered once daily.

[0043] "BID" refers to administering the medication described herein twice daily.

[0044] "PO" refers to the reagent described herein administered orally.

[0045] “IV” means intravenous administration of any drug described herein.

[0046] Graded adverse events refer to a severity grading table established by NCI CTCAE. In one embodiment, adverse events are graded according to the following table. grade Severity 1 Mild; asymptomatic or with mild symptoms; clinical or diagnostic observation only; or no intervention indicated. 2 Moderate; instructing minimal, localized, or non-invasive intervention; or instrumental activities of daily living appropriate to the age limit. a 3 Severe or medically significant but not immediately life-threatening; instructs hospitalization or prolongs hospitalization; causes disability; or limits self-care activities in daily life. b, c 4 Indicates life-threatening consequences or urgent need for intervention. d 5 Deaths related to adverse events d

[0047] The term "patient" refers to a person who is ill. A patient can be an adult.

[0048] The term "drug leaflet" is used to refer to instructions that are usually included in the commercial packaging of therapeutic products, which contain information on the indications, usage, dosage, route of administration, combination therapy, contraindications and / or warnings for using such therapeutic products.

[0049] As used herein, "in combination with" means administering a treatment in addition to another treatment, such as a treatment regimen including the administration of succinate and GDC-6036 or their pharmaceutically acceptable salts as described herein. Therefore, "in combination with" means administering another treatment before, during or after administering a treatment to a patient.

[0050] A drug administered "concurrently" with one or more other drugs may be administered during the same treatment cycle, on the same day of treatment, or, as appropriate, concurrently with one or more other drugs. For example, in a cancer therapy administered every three weeks, each concurrently administered drug may be administered on day 1 of the three-week cycle. Combination therapy

[0051] This article provides combination therapies (compositions) comprising KRas G12C inhibitors as described herein (e.g., GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate)) and PI3K inhibitors (e.g., sefliximab).

[0052] In one embodiment, this document provides a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt) and efliximab. In one embodiment, the combination therapy described herein may be used to treat certain solid tumors containing KRas G12C mutations.

[0053] In one embodiment, the combination therapy described herein can be used to treat certain types of lung cancer as described herein that contain the KRas G12C mutation. In one such embodiment, the lung cancer is non-small cell lung cancer (NSCLC) containing the KRas G12C mutation.

[0054] In another embodiment, the combination therapy described herein can be used to treat other solid tumors containing KRas G12C mutations. In one embodiment, the solid tumor is colorectal cancer, pancreatic cancer, or breast cancer.

[0055] In one embodiment, this document provides a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more cycles, and Ivliximide administered once daily (QD) according to a dosing regimen comprising one or more cycles. In this embodiment, the presence or absence of a KRasG12C mutation is assessed and the combination therapy described herein is administered only if a KRasG12C mutation is present. In one embodiment, the presence or absence of a mutant PIK3CA is not assessed.

[0056] In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles, and Iffulcillin or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, when the dosing regimen comprises one or more 21-day cycles, the dosing regimen includes a discontinuation period in which one or both of GDC-6036 and Iffulcillin are not administered. In this embodiment, the combination therapy may be used to treat solid tumors (e.g., lung cancer) containing the KRas G12C mutation as described herein. In one such embodiment, the presence or absence of mutant PIK3CA is not evaluated.

[0057] In another embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles, and Iffulix or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In this embodiment, the combination therapy can be used to treat solid tumors (e.g., lung cancer) containing the KRas G12C mutation as described herein. In one such embodiment, the presence or absence of the mutant PIK3CA is not evaluated.

[0058] In one embodiment of the combination therapy described herein, GDC-6036 or a pharmaceutically acceptable salt thereof is administered at a fixed dose once daily (QD). In one embodiment, the administration is oral (PO), wherein GDC-6036 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is formulated as a film-coated tablet (and administered in that form).

[0059] In one embodiment of the combination therapy described herein, GDC-6036 or a pharmaceutically acceptable salt thereof is administered at approximately 5 mg-600 mg, 5 mg-500 mg, 5 mg-400 mg, 5 mg-300 mg, 5 mg-250 mg, 5 mg-200 mg, 5 mg-150 mg, 5 mg-100 mg, 5 mg-50 mg, 5 mg-25 mg, 25 mg-600 mg, 25 mg-500 mg, 25 mg-400 mg, 25 mg-300 mg. Administered in doses of 25mg-250mg, 25mg-200mg, 25mg-150mg, 25mg-100mg, 25mg-50mg, 50mg-800mg, 50mg-700mg, 50mg-600mg, 50mg-500mg, 50mg-400mg, 50mg-300mg, 50mg-250mg, 50mg-200mg, 50mg-150mg, or 50mg-100mg QD. In another embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in doses of about 5mg, 25mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 400mg, or 500mg. In another embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in amounts of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in amounts of about 100 mg, 200 mg, or 400 mg. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in amounts of about 100-300 mg. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in amounts of about 200 mg. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in amounts of about 300-600 mg. In another such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg. In a preferred embodiment, GDC-6036 of the combination therapy described herein is administered in the form of adipic acid salt. In these embodiments, the amount of GDC-6036 or a pharmaceutically acceptable salt thereof is administered relative to the amount in the form of free base.

[0060] The inclusion of one or more therapeutic agents in a combination therapy can alter the efficacy and dosage of each agent in the dosing regimen. Therefore, in one embodiment, the amount of GDC-6036 or a pharmaceutically acceptable salt thereof is administered at a lower starting dose for the entire or part of the cycle described herein, as described herein. In one embodiment, GDC-6036 may be administered at a lower dose for at least 1, 2, or 3 days before increasing the dose. In one such embodiment, the amount of GDC-6036 or a pharmaceutically acceptable salt thereof is a starting dose of 200 mg. In another such embodiment, the amount of GDC-6036 or a pharmaceutically acceptable salt thereof is a starting dose of 300 mg. In this embodiment, the amount of GDC-6036 may be increased by 50 or 100 mg (e.g., from a 200 mg starting dose to a 250 or 300 mg dose; from a 300 mg dose to a 400 mg dose). In one embodiment, the starting dose of GDC-6036 is 200 mg, and the dose is increased to 400 mg.

[0061] In some embodiments, epoxilisi is administered in an amount of 3, 6, or 9 mg, for example, in one or more oral tablets. In some embodiments, epoxilisi is administered orally at a daily dose of 9 mg. In some of these embodiments, epoxilisi is administered, for example, in an oral tablet at a dose of 9 mg. In some embodiments, epoxilisi is administered orally at a daily dose of 6 mg, for example, in one or more oral tablets. In some of these embodiments, epoxilisi is administered, for example, in an oral tablet at a dose of 3 mg.

[0062] In one embodiment, epoxilisi, as a component of the combination therapy described herein, is administered as a 6 mg QD (quantity over day) to each drug in a dosing regimen comprising a 21-day cycle once daily (QD). In another embodiment, epoxilisi, as a component of the combination therapy described herein, is administered as a 9 mg QD (quantity over day) to each drug in a dosing regimen comprising a 21-day cycle once daily (QD). In yet another embodiment, epoxilisi, as a component of the combination therapy described herein, is administered as a 3 mg QD (quantity over day) to each drug in a 21-day cycle once daily (QD). In one such embodiment, the amount of epoxilisi administered is reduced from the starting dose to 6 mg or 3 mg, as described herein.

[0063] In one embodiment, the amount of sefliximab is lower than the starting dose. In one such embodiment, the amount of sefliximab is 6 mg. In one such embodiment, the amount of sefliximab may be increased to 9 mg.

[0064] In one embodiment, the starting dose of GDC-6036 is 200 mg, and the starting dose of epoxetine is 6 mg. In another embodiment, the starting dose of GDC-6036 is 400 mg, and the starting dose of epoxetine is 6 mg. In yet another embodiment, the starting dose of GDC-6036 is 200 mg, and the starting dose of epoxetine is 9 mg.

[0065] In one embodiment, the combination therapy described herein is used to treat lung cancer containing a KRas G12C mutation. In one such embodiment, the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt) and sefliximab, wherein both agents are administered according to a dosing regimen comprising once daily (QD) administration over a 21-day cycle. In another such embodiment, the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt) and sefliximab, wherein both agents are administered according to a dosing regimen comprising once daily (QD) administration over a 28-day cycle. In these embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In one such embodiment, the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0066] In another embodiment, a combination therapy for treating lung cancer containing a KRas G12C mutation is provided, wherein the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt), wherein GDC-6036 is administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and sefliximab, wherein sefliximab is administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles. In another embodiment, a combination therapy for treating lung cancer containing a KRas G12C mutation is provided, wherein the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt), wherein GDC-6036 is administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and sefliximab, wherein sefliximab is administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In a preferred embodiment, the lung cancer is NSCLC (e.g., metastatic NSCLC).

[0067] In another embodiment, a combination therapy for treating lung cancer containing a KRas G12C mutation is provided, wherein the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered once daily (QD) at a dose of about 50 mg to 500 mg according to one or more 21-day dosing regimens; and epifalixidase, wherein epifalixidase is administered once daily (QD) at a dose of about 3 mg, 6 mg, or 9 mg according to one or more 21-day dosing regimens. In one such embodiment, epifalixidase is administered at a dose of 6 mg. In another embodiment, epifalixidase is administered at a dose of 9 mg. In yet another embodiment, epifalixidase is administered at a dose of 3 mg. In one embodiment, the lung cancer is NSCLC. In one embodiment, GDC-6036 is administered at a dose of 200 or 400 mg, and Ivlixi is administered at a dose of 6 or 9 mg.

[0068] In another embodiment, a combination therapy for treating lung cancer containing a KRas G12C mutation is provided, wherein the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate), wherein GDC-6036 is administered once daily (QD) at a dose of about 50 mg to 500 mg according to one or more 28-day dosing regimens; and epifalixib, wherein epifalixib is administered once daily (QD) at a dose of about 3 mg, 6 mg, or 9 mg according to one or more 28-day dosing regimens. In one such embodiment, epifalixib is administered at a dose of 6 mg. In another embodiment, epifalixib is administered at a dose of 9 mg. In yet another embodiment, epifalixib is administered at a dose of 3 mg. In one embodiment, the lung cancer is NSCLC. In one embodiment, GDC-6036 is administered at a dose of 200 or 400 mg, and Ivlixi is administered at a dose of 6 or 9 mg.

[0069] In another embodiment is the combination therapy described herein for treating solid tumors containing KRas G12C mutations. In one particular embodiment, the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt) and epifalicylate, wherein the combination therapy is used to treat solid tumors containing KRas G12C mutations as described herein. In one such embodiment, the solid tumor is CRC, breast cancer, or pancreatic cancer. In one embodiment, GDC-6036 is administered at a dose of 200 or 400 mg, and epifalicylate is administered at a dose of 6 or 9 mg.

[0070] In another embodiment, a combination therapy for treating solid tumors containing KRas G12C mutations as described herein is provided, wherein the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt), wherein GDC-6036 is administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and epifalixib, wherein epifalixib is administered once daily (QD) at a dose of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and epifalixib is administered at 6 or 9 mg.

[0071] In another embodiment, a combination therapy for treating solid tumors containing KRas G12C mutations as described herein is provided, wherein the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt), wherein GDC-6036 is administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and epifalixib, wherein epifalixib is administered once daily (QD) at a dose of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and epifalixib is administered at 6 or 9 mg.

[0072] In another embodiment, there is a combination therapy described herein for treating tissue-undetermined cancers containing KRas G12C mutations. In one particular embodiment, the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt) and efliximab, wherein the combination therapy is used to treat tissue-undetermined cancers containing KRas G12C mutations as described herein.

[0073] In another embodiment, a combination therapy is provided for the treatment of tissue-undetermined cancers containing KRas G12C mutations, wherein the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt), wherein GDC-6036 is administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and epifalixib, wherein epifalixib is administered once daily (QD) at a dose of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and epifalixib is administered at 6 or 9 mg.

[0074] In another embodiment, a combination therapy for treating tissue-undetermined cancers containing KRas G12C mutations is provided, wherein the combination therapy comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipicate), wherein GDC-6036 is administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and epifalixib, wherein epifalixib is administered once daily (QD) at a dose of about 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and epifalixib is administered at 6 or 9 mg. Treatment Methods

[0075] In one embodiment, this article provides a method for treating a patient with lung cancer containing a KRas G12C mutation, the method comprising administering to the patient an effective amount of a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipic acid salt) and sefliximab.

[0076] In one embodiment of the method provided herein, the lung cancer is non-small cell lung cancer (NSCLC). In another embodiment of the method provided herein, the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In one such embodiment, the cancer is lung adenocarcinoma. In another such embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0077] This document also provides a method (M1) for treating NSCLC with a KRas G12C mutation, wherein the method comprises administering to the patient an effective dose of the combination therapy as described herein, the combination therapy comprising (i) GDC-6036 or a pharmaceutically acceptable salt thereof, administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and (ii) epoxetine, administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles. In one embodiment of the method provided herein, the method is used to treat adenocarcinoma. In one embodiment of the method provided herein, the method comprises two or more cycles. In one such embodiment, the method is used to treat first-line NSCLC.

[0078] This document also provides a method (M2) for treating NSCLC with a KRas G12C mutation, wherein the method comprises administering to the patient an effective dose of the combination therapy as described herein, the combination therapy comprising (i) GDC-6036 or a pharmaceutically acceptable salt thereof, administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and (ii) epoxetine, administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In one embodiment of the method provided herein, the method is used to treat adenocarcinoma. In one embodiment of the method provided herein, the method comprises two or more cycles. In one such embodiment, the method is used to treat first-line NSCLC.

[0079] This document also provides a method (M3) for treating a patient with NSCLC containing a KRas G12C mutation, wherein the method comprises administering to the patient an effective dose of a combination therapy comprising a dosing regimen as described herein, the dosing regimen comprising: (i) administering 50 mg to 500 mg of GDC-6036 or a pharmaceutically acceptable salt thereof once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and (ii) administering approximately 3 mg, 6 mg, or 9 mg of epefliximab once daily (QD) according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, the dosing regimen includes a discontinuation period in which one or both of GDC-6036 and / or epefliximab are not administered. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and epefliximab is administered at 6 or 9 mg.

[0080] This article also provides a method (M4) for treating a patient with NSCLC containing a KRas G12C mutation, wherein the method comprises administering to the patient an effective dose of a combination therapy comprising a dosing regimen as described herein, the dosing regimen comprising: (i) administering 50 mg to 500 mg of GDC-6036 or a pharmaceutically acceptable salt thereof once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and (ii) administering approximately 3 mg, 6 mg, or 9 mg of epefliximab once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and epefliximab is administered at 6 or 9 mg.

[0081] In Examples M1-M4, the methods may further include (a) determining whether the KRasG12C mutation is absent or present in a sample taken from a patient suspected of having cancer; and (b) administering to the patient a combination therapy as described herein, the combination therapy comprising an effective amount of GDC-6036 or a pharmaceutically acceptable salt thereof and epfulixim as described herein. In one such embodiment, the method further includes (c) not assessing the presence or absence of mutant PIK3CA prior to administering epfulixim as described herein.

[0082] In another embodiment, this document provides a method (M5) for treating a patient with a solid tumor containing a KRas G12C mutation, the method comprising administering to the patient an effective amount of a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipicate) and epfuliximab. In one embodiment, the method comprises administering to the patient an effective amount of the combination therapy as described herein, the combination therapy comprising: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and (ii) epfuliximab or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles. In one embodiment, the dosing regimen includes a discontinuation period in which one or both of GDC-6036 and / or epfuliximab are not administered. In one embodiment, the discontinuation period is 7 days.

[0083] In another embodiment, this document provides a method (M6) for treating a patient with a solid tumor containing a KRas G12C mutation, the method comprising administering to the patient an effective amount of the combination therapy as described herein, the combination therapy comprising: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and (ii) Ivliximab or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In one embodiment of method M5 or M6 provided herein, the method comprises two or more cycles. In one such embodiment of method M5 or M6, GDC-6036 is administered in an amount of about 50 mg to 500 mg, and Ivliximab is administered in an amount of 3 mg, 6 mg, or 9 mg. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and efliximab is administered at 6 or 9 mg. In another embodiment, the presence of a KRasG12C mutation in the patient is assessed, but the presence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein. In one embodiment of the methods described herein, M5 or M6, the solid tumor is colorectal cancer (CRC). In one such embodiment, the CRC is metastatic CRC (mCRC).

[0084] This document further provides a method (M7) for treating a patient with tissue-undetermined cancer containing a KRasG12C mutation, wherein the method comprises (i) determining whether a KRasG12C mutation is present or absent in a sample taken from a patient suspected of having cancer; and (ii) administering an effective amount of combination therapy when the patient sample contains a KRasG12C mutation, the combination therapy comprising: (a) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to one or more 21-day dosing regimens; and (b) Iffulixeil or a pharmaceutically acceptable salt thereof administered once daily (QD) according to one or more 21-day dosing regimens. In one such embodiment, the patient sample is not evaluated for the presence or absence of the mutant PIK3CA prior to administration of Iffulixeil as described herein. In one embodiment of method M7, the dosing regimen includes a discontinuation period during which one or both of GDC-6036 and / or sefliximab are not administered. In one embodiment, the discontinuation period is 7 days.

[0085] This document further provides a method (M8) for treating a patient with tissue-undetermined cancer containing a KRasG12C mutation, wherein the method comprises (i) determining whether a KRasG12C mutation is present or absent in a sample taken from a patient suspected of having cancer; and (ii) administering an effective amount of combination therapy when the patient sample contains a KRasG12C mutation, the combination therapy comprising: (a) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and (b) Iffulixeil or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, the patient sample is not evaluated for the presence or absence of the mutant PIK3CA prior to administration of Iffulixeil as described herein.

[0086] In one embodiment of methods M7 and M8, patient samples are further analyzed for the absence or presence of PI3K mutations such as those described herein.

[0087] In one embodiment of the method described herein, GDC-6036 or a pharmaceutically acceptable salt thereof is administered at approximately 5 mg-600 mg, 5 mg-500 mg, 5 mg-400 mg, 5 mg-300 mg, 5 mg-250 mg, 5 mg-200 mg, 5 mg-150 mg, 5 mg-100 mg, 5 mg-50 mg, 5 mg-25 mg, 25 mg-600 mg, 25 mg-500 mg, 25 mg-400 mg, 25 mg-300 mg. Administered in doses of 25mg-250mg, 25mg-200mg, 25mg-150mg, 25mg-100mg, 25mg-50mg, 50mg-800mg, 50mg-700mg, 50mg-600mg, 50mg-500mg, 50mg-400mg, 50mg-300mg, 50mg-250mg, 50mg-200mg, 50mg-150mg, or 50mg-100mg QD. In another embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in doses of about 5mg, 25mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 400mg, or 500mg. In another embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in doses of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In another embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in doses of about 100 mg, 200 mg, or 400 mg. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in doses of 100 mg once daily (QD) as described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in doses of 200 mg once daily (QD) as described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in doses of 400 mg once daily (QD) as described herein. In another embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 100-300 mg. In yet another such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 300-600 mg. In a preferred embodiment, the GDC-6036 of the combination therapy described herein is administered in the form of adipic acid salt. In these embodiments, the amount of GDC-6036 or a pharmaceutically acceptable salt thereof is administered relative to the amount in the free base form.

[0088] In one embodiment, sefliximab is administered at a dose of 6 mg once daily (QD) as described herein. In another embodiment, sefliximab is administered at a dose of 9 mg once daily (QD) as described herein. In yet another embodiment, sefliximab is administered at a dose of 3 mg once daily (QD) as described herein.

[0089] In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg according to the method described herein, and Ivliximab is administered in a dose of 6 mg according to the method described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in a dose of 400 mg according to the method described herein, and Ivliximab is administered in a dose of 6 mg according to the method described herein.

[0090] In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg according to the method described herein, and Ivliximab is administered in a dose of 3 mg according to the method described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg according to the method described herein, and Ivliximab is administered in a dose of 9 mg according to the method described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in a dose of 400 mg according to the method described herein, and Ivliximab is administered in a dose of 3 mg according to the method described herein. In one embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in a dose of 400 mg according to the method described herein, and Ivliximab is administered in a dose of 9 mg according to the method described herein.

[0091] In some cases, the dose of sefliximab may be adjusted from an initial dose of 6 mg to 9 mg. When a patient described herein is given 6 mg of sefliximab as described herein and cannot tolerate this administration, the dose of sefliximab given to the patient may be reduced to 3 mg. Similarly, when a patient described herein is given 9 mg of sefliximab as described herein and cannot tolerate this administration, the dose of sefliximab given to the patient may be reduced to 6 mg or 3 mg. As used herein, "tumor undetermined" refers to any solid tumor tested for the presence or absence of the KRas G12C mutation as described herein.

[0092] The methods provided herein may include administering the combination therapy described herein as part of a dosing regimen. In one embodiment, the dosing regimen comprises one or more cycles. In another embodiment, the dosing regimen comprises at least two cycles. In another embodiment, the dosing regimen comprises two to three cycles. In yet another embodiment, the dosing regimen comprises at least four, six, eight, ten, or twelve cycles. In yet another embodiment, the dosing regimen is provided herein comprising 2, three, four, five, six, eight, ten, twelve, sixteen, eighteen ... In one embodiment, the dosing regimen includes administering the combination therapy described herein at any number of cycles until the desired response (e.g., PFS, OS, ORR, and / or DOR) is achieved (e.g., an improvement in PFS, OS, ORR, and / or DOR compared to the control group described herein). In another embodiment, the dosing regimen includes administering the combination therapy described herein at any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that prevent further administration. In this embodiment, the amount of the administered agent (e.g., GDC-6036 or its pharmaceutically acceptable salt or levamisole) may be adjusted to reduce or eliminate AEs and allow for the addition of cycles to the dosing regimen. In yet another embodiment, the dosing regimen includes administering the combination therapy described herein at any number of cycles until the disease worsens.

[0093] In some cases, the methods described herein include administering one or more additional therapies, wherein the additional therapies are one or more side effect limiters (e.g., agents designed to reduce the occurrence and / or severity of treatment side effects, such as antiemetics, corticosteroids (e.g., prednisone or equivalent agents, e.g., at a dose of 1-2 mg / kg / day), hormone replacement drugs, etc.).

[0094] Patients described herein must be evaluated and have a confirmatory test result for the KRas G12C mutation as described herein. In one such embodiment, the patient has previously been treated with one or more prior therapies. Patients described herein with a confirmed test result for NSCLC and the KRas G12C mutation must not have known secondary oncogenic drivers (e.g., for NSCLC: sensitized EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion); or for adenocarcinoma of the colon or rectum: BRAF V600E mutation, ERBB2 amplification). In one such embodiment, the patient has previously been treated with one or more prior therapies. In one embodiment, these secondary oncogenic drivers are determined using NGS (e.g., by Foundation Medicine, Inc. (FMI) NGS assay).

[0095] In one embodiment, the patient as provided herein must be evaluated and have a confirmatory test result for the KRas G12C mutation as described herein, and the patient has not been evaluated for the presence or absence of a mutant PIK3CA with mutations at one or more of the following locations: 88, 106, 111, 118, 345, 420, 453, 542, 545, 546, 1043, 1047, and 1049 (e.g., H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, K111, G106, G118, and R88).

[0096] In one embodiment, the patient described herein has received prior treatment with a KRas G12C specific inhibitor.

[0097] In another embodiment, the patients described herein have not received chemotherapy, immunotherapy, or biotherapy as anticancer therapy within 3 weeks prior to administration of the combination therapy described herein, or have not received hormone therapy within 2 weeks prior to administration of the combination therapy described herein, except in the following circumstances: (a) hormone therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for hormone-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (b) a regulatory-approved kinase inhibitor may be used up to 2 weeks prior to administration of the combination therapy described herein, provided that any drug-related toxicities have been fully resolved; or (c) treatment with an investigational agent within 3 weeks or five half-lives (whichever is shorter) prior to administration of the combination therapy described herein.

[0098] In another embodiment, the patients described herein did not receive radiation therapy (other than palliative radiation to bone metastases and radiation to CNS metastases as described above) as cancer therapy within 4 weeks prior to the initiation of the combination therapy described herein. In yet another embodiment, the patients described herein did not receive palliative radiation to bone metastases within 2 weeks prior to the initiation of the combination therapy described herein.

[0099] In another embodiment, the patient described herein has no history of idiopathic pulmonary fibrosis, tissue pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on a chest X-ray computed tomography (CT) scan.

[0100] This document further provides the use of the combination therapy described herein, comprising GDC-6036 or a pharmaceutically acceptable salt thereof, with estradiol for the treatment of lung cancer as described herein (UL1). In one embodiment, the use of the combination therapy described herein, comprising GDC-6036 or a pharmaceutically acceptable salt thereof, with estradiol for the treatment of NSCLC as described herein (UL2).

[0101] This document further provides the use of combination therapy for the treatment of lung cancer as described herein (UL3), wherein the combination therapy comprises: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and (ii) epoxilisi administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, epoxilisi is administered in an amount of about 6 mg. In one embodiment, GDC-6036 is administered in an amount of 200 or 400 mg, and epoxilisi is administered in an amount of 6 or 9 mg. In another embodiment, the presence or absence of a KRasG12C mutation in the patient is assessed, but the presence or absence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0102] This document further provides the use of combination therapy for the treatment of lung cancer as described herein (UL4), wherein the combination therapy comprises: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and (ii) epefliximab administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, epefliximab is administered in an amount of about 6 mg. In one embodiment, GDC-6036 is administered in an amount of 200 or 400 mg, and epefliximab is administered in an amount of 6 or 9 mg. In another embodiment, the presence or absence of a KRasG12C mutation in the patient is assessed, but the presence or absence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0103] This document further provides the use of the combination therapy described herein for the treatment of lung cancer as described herein (UL5), wherein the combination therapy comprises: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and (ii) Ivliximab administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and Ivliximab is administered at 6 or 9 mg. In another embodiment, the presence or absence of a KRasG12C mutation in the patient is assessed, but the presence or absence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0104] This document further provides the use of the combination therapy described herein for the treatment of lung cancer as described herein (UL6), wherein the combination therapy comprises: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and (ii) Ivliximab administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and Ivliximab is administered at 6 or 9 mg. In another embodiment, the presence or absence of a KRasG12C mutation in the patient is assessed, but the presence or absence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0105] This document further provides the use of the combination therapy described herein, comprising GDC-6036 or a pharmaceutically acceptable salt thereof, with sefliximab, for the manufacture of a medicament for the treatment of lung cancer as described herein (UL7).

[0106] This document further provides the use of the combination therapy described herein for the manufacture of a medicament for the treatment of lung cancer as described herein (UL8), wherein the combination therapy comprises: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles; and (ii) epoxetine administered once daily (QD) according to a dosing regimen comprising one or more 21-day cycles. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, epoxetine is administered in an amount of about 3 mg, 6 mg, or 9 mg. In one embodiment, GDC-6036 is administered in an amount of 200 or 400 mg, and epoxetine is administered in an amount of 6 or 9 mg. In another embodiment, the presence or absence of a KRasG12C mutation in the patient is assessed, but the presence or absence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0107] This document further provides the use of the combination therapy described herein for the manufacture of a medicament for the treatment of lung cancer as described herein (UL9), wherein the combination therapy comprises: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles; and (ii) epoxetine administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles. In one such embodiment, GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, epoxetine is administered in an amount of about 3 mg, 6 mg, or 9 mg. In one embodiment, GDC-6036 is administered in an amount of 200 or 400 mg, and epoxetine is administered in an amount of 6 or 9 mg. In another embodiment, the presence or absence of a KRasG12C mutation in the patient is assessed, but the presence or absence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0108] In the embodiments described herein (UL1-UL8), the patients described herein were diagnosed with NSCLC mediated by KRas G12C mutation.

[0109] This article further provides the use of the combination therapy of GDC-6036 or its pharmaceutically acceptable salt with estradiol as described herein for the treatment of solid tumors as described herein (UC1).

[0110] This document further provides the use of the combination therapy described herein for the treatment of solid tumors as described herein (UC2), wherein the combination therapy comprises: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) at a dose of about 50-500 mg according to a dosing regimen comprising one or more 21-day cycles; and (ii) Iffulcillin administered once daily (QD) at a dose of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 21-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and Iffulcillin is administered at 6 or 9 mg. In another embodiment, the presence or absence of a KRasG12C mutation in the patient is assessed, but the presence or absence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0111] This document further provides the use of the combination therapy described herein for the treatment of solid tumors as described herein (UC3), wherein the combination therapy comprises: (i) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) at a dose of about 50-500 mg according to a dosing regimen comprising one or more 28-day cycles; and (ii) Iffulcillin administered once daily (QD) at a dose of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and Iffulcillin is administered at 6 or 9 mg. In another embodiment, the presence or absence of a KRasG12C mutation in the patient is assessed, but the presence or absence of a mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0112] In the embodiments described herein for the uses UC1-UC3, the patients described herein were diagnosed with CRC mediated by KRas G12C mutation.

[0113] This document further provides the use of the combination therapy described herein for the treatment of tissue-undetermined cancers containing the KRasG12C mutation as described herein (UA1), wherein samples taken from suspected confirmed cancer patients are tested for the presence or absence of the KRasG12C mutation; and when the patient sample contains the KRasG12C mutation, an effective amount of the combination therapy is administered: (a) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) at a dose of about 50-500 mg according to one or more 21-day dosing regimens; and (b) Iffulliximab administered once daily (QD) at a dose of 3 mg, 6 mg, or 9 mg according to one or more 21-day dosing regimens. In this embodiment, GDC-6036 and Iffulliximab may be administered as described herein and according to the uses and methods provided herein. In one embodiment, GDC-6036 is administered at 200 or 400 mg, and Iffulix is ​​administered at 6 or 9 mg. In another embodiment, the presence of the patient's KRasG12C mutation is assessed, but the presence of mutant PIK3CA is not assessed prior to administration of the combination therapy described herein.

[0114] This document further provides the use of the combination therapy described herein for the treatment of tissue-undetermined cancers containing the KRasG12C mutation as described herein (UA2), wherein samples taken from suspected confirmed cancer patients are tested for the presence or absence of the KRasG12C mutation; and when the patient sample contains the KRasG12C mutation, an effective amount of the combination therapy is administered: (a) GDC-6036 or a pharmaceutically acceptable salt thereof administered once daily (QD) at a dose of approximately 50-500 mg according to a dosing regimen comprising one or more 28-day cycles; and (b) Ivliximab administered once daily (QD) at a dose of 3 mg, 6 mg, or 9 mg according to a dosing regimen comprising one or more 28-day cycles. In this embodiment, GDC-6036 and Ivliximab may be administered as described herein and according to the uses and methods provided herein. In one embodiment, patient samples are not evaluated for the presence or absence of mutant PIK3CA prior to administration of the combination therapy described herein.

[0115] In one embodiment of use UA1 and UA2, patient samples are further analyzed for the absence or presence of PI3K mutations such as those described herein.

[0116] The development of combination therapies is challenging, including, for example, selecting agents for combination therapies that can lead to improved efficacy while maintaining acceptable toxicity. A specific challenge is distinguishing the incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., GDC-6036 or its pharmaceutically acceptable salt with efliximab) is administered with a dosing regimen that includes staggered dosing schedules. In one such embodiment, compared to control (e.g., SOC therapy, treatment with one of the agents described herein alone, such as GDC-6036 or efliximab), the number of adverse events (AEs) in patients is reduced or their severity is lowered.

[0117] Generally, it is understood that in the event of an adverse event, there are four options: (1) continue treatment as is, with concomitant treatment as appropriate; (2) adjust the dosage of one or more agents in the dosing regimen; (3) suspend the administration of one or more agents in the dosing regimen; or (4) discontinue the administration of one or more agents in the dosing regimen. In one embodiment, the amount of GDC-6036 administered is unchanged. In another embodiment, the amount of epefliximab administered is unchanged. In one embodiment, when the administration of the agents described herein (e.g., GDC-6036 or its pharmaceutically acceptable salt or epefliximab) is interrupted, the next administration of each agent occurs on the same day that the administration of GDC-6036 is resumed. In one embodiment, GDC-6036 or its pharmaceutically acceptable salt is not administered with food (i.e., the patient should not eat for at least 2 hours before and at least 1 hour after administration).

[0118] In one embodiment, the patient described herein experiences gastrointestinal toxicity as an adverse event (AE) of grade 2 or less. In one such embodiment, gastrointestinal toxicity is diarrhea, nausea, or vomiting. In another embodiment, the patient described herein experiences phototoxicity. In such embodiments, the patient should apply sunscreen and wear protective clothing when outdoors.

[0119] Concomitant therapies may also be administered to patients described herein, including: (a) antiepileptic drugs or warfarin; (b) oral contraceptives or other permissible maintenance therapies; (c) antiemetics and antidiarrheals, provided that such drugs should not be administered prophylactically prior to initial treatment with the investigational drug; (d) analgesics administered according to standard clinical practice; (e) bisphosphonates and denosumab for bone metastases or osteoporosis; or (f) multivitamins, calcium, and vitamin C, D, and E supplements.

[0120] The patients described in this article may not receive the following treatments concurrently: (1) strong / moderate CYP3A4 inhibitors (e.g., atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, acetomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivatan, fluvoxamine, diltiazem, nefazodone, mibeladil, verapamil and grapefruit juice or grapefruit supplement) or (2) strong / moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, ectravirine, modafinil, hypericin (St. John's wort) and cyproterone acetate.

[0121] In another embodiment, the patient described herein is not given a drug that reduces gastric acid production, such as a proton pump inhibitor or an H2 receptor antagonist.

[0122] In another embodiment, the following treatments are not administered to the patients described herein: (a) any other investigational therapy (excluding GDC-6036 or efliximab) within 3 weeks or five half-lives (whichever is shorter) prior to or during the administration of the combination therapy described herein; (b) concomitant therapies for cancer, whether FDA-approved or experimental, including chemotherapy, radiotherapy, immunotherapy, biotherapy, herbal remedies, or hormone therapy, except in the following cases: (i) hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for hormone-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (ii) hormone replacement therapy or oral contraceptives; (c) radiotherapy for a clearly progressive disease, except for new brain metastases in the following systemic response cases: patients whose systemic disease has been demonstrated to be under control (defined as having achieved clinical benefit [i.e., PR, CR for ≥3 months]). Patients with brain metastases that are radiotherapy-eligible, or SD, will be allowed to continue receiving GDC-6036 therapy during the study period until they experience systemic progression of their disease and / or further progression in the brain (based on investigator assessment). (d) Quinidine or other antiarrhythmic drugs; or (e) hematopoietic community stimulating factors (CSFs; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; saxaglastine, pegylated filgrastim, erythropoietin, dabepone, and thrombopoietin) starting or increasing 7 days before day 1 of cycle 1.

[0123] In one embodiment of such a method, the patient is diagnosed with the cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is collected before any of the therapies described herein are administered. In one such embodiment, the sample is collected before at least one of the agents described herein is administered. In some embodiments, tumor samples may be collected at specified time intervals during treatment with the combination therapies described herein to evaluate the treatment.

[0124] Determining whether a tumor or cancer contains a KRas G12C mutation can be done by assessing the nucleotide sequence encoding the K-Ras protein, by assessing the amino acid sequence of the K-Ras protein, or by assessing the characteristics of a putative K-Ras mutant protein. The sequence of wild-type human K-Ras (e.g., accession number NP203524) is known in the art. In one such embodiment, the KRas G12C mutation is assessed using, for example, immunohistochemistry (IHC) or NGS sequencing from samples from the patient described herein.

[0125] In one embodiment of the method provided herein, after treatment with combination therapy according to the method provided herein, the patient is diagnosed with CR. In one embodiment of the method provided herein, after treatment with combination therapy according to the method provided herein, the patient is diagnosed with PR. In one embodiment of the method provided herein, after treatment with combination therapy according to the method provided herein, the patient is diagnosed with stable disease (SD).

[0126] This document also provides methods for inhibiting tumor growth or inducing tumor regression in patients described herein by administering the combination therapies described herein. In one embodiment provided herein, a method for inhibiting tumor growth in a patient suffering from the cancer described herein is performed by administering a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof and estradiol for one or more cycles as described herein (e.g., 21-day or 28-day cycles). In one embodiment provided herein, a method for inhibiting tumor growth in a patient suffering from NSCLC or CRC as described herein is performed by administering a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof and estradiol for one or more cycles as described herein (e.g., 21-day or 28-day cycles).

[0127] In one embodiment provided herein, a method for inducing or improving tumor regression in a patient with the cancer described herein is provided by administering a combination therapy comprising GDC-6036 or a pharmaceutically acceptable saline thereof and estradiol for one or more cycles as described herein (e.g., 21-day or 28-day cycles). In one embodiment provided herein, a method for inducing or improving tumor regression in a patient with NSCLC or CRC described herein is provided by administering a combination therapy comprising GDC-6036 or a pharmaceutically acceptable saline thereof and estradiol for one or more cycles as described herein (e.g., 21-day or 28-day cycles). Kit

[0128] The combination therapies described herein may be provided as kits comprising one or more of the agents described herein for administration. In one embodiment, the kit comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate) for administration in combination with Ivliximab. In another embodiment, the kit comprises GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate) packaged together with Ivliximab, wherein the kit contains separately formulated doses of each agent.

[0129] This document also provides an article or kit comprising GDC-6036 or a pharmaceutically acceptable salt thereof (e.g., GDC-6036 adipate) and sefliximab. In some cases, the article further comprises one or more drug manifests containing instructions for treating or delaying the progression of solid tumors (e.g., lung cancer or CRC) using the agents described herein. In one such embodiment, the cancer is NSCLC.

[0130] In some cases, efliximab and GDC-6036 or their pharmaceutically acceptable salts (e.g., GDC-6036 adipate) are in the same or different containers. Suitable containers include, for example, bottles, vials, bags, and syringes. Containers can be formed from a variety of materials, such as glass, plastics (e.g., polyvinyl chloride or polyolefins), or metal alloys (e.g., stainless steel or Hastelloy). In some cases, the container holds the formulation, and the label on or associated with the container indicates the direction of use. The product or kit may further include other materials required from a commercial and user perspective, including additional buffers, diluents, filters, needles, syringes, and a package insert with instructions for use. In some cases, the product further includes one or more other agents (e.g., additional chemotherapeutic agents or antitumor agents). Suitable containers for one or more pharmaceutical agents include, for example, bottles, vials, bags, and syringes.

[0131] Any product or kit described herein may include instructions to administer GDC-6036 or its pharmaceutically acceptable salts (e.g., GDC-6036 adipic acid salt) and / or sefliximab to a patient according to any of the methods described herein. Biomarkers

[0132] In one embodiment, prior to administration of the combination therapy as described herein, the patient must be evaluated for and have a confirmed KRasG12C mutation. In one such embodiment, the presence or absence of mutant PIK3CA is not evaluated prior to administration of the combination therapy as described herein.

[0133] In one embodiment, alkylation of KRas G12C with GDC-6036 or a pharmaceutically acceptable salt thereof is measured in a patient. In one such embodiment, the alkylation of KRas G12C provided herein is measured and tested using a sample. In another embodiment, ctDNA biomarkers (e.g., KRas G12C) from peripheral blood are evaluated.

[0134] In one embodiment, KRAS / MAPK target genes (e.g., DUSP6, SPRY4), pathway components (e.g., pERK, pS6) and related biomarkers (e.g., Ki67) are modulated by analyzing paired pre-treatment and in-treatment fresh tumor biopsies.

[0135] Ifliximab is a selective inhibitor of the class I PI3Kα isoform (p110α). Unbound by any particular theory, by inhibiting PIP2 phosphorylation to PIP3, Ifliximab reduces the activation of downstream pathway effectors, including AKT, PRAS40, and S6RP, which can serve as biomarkers for PD treated with GDC-6036 and Ifliximab. Examples

[0136] The following are some exemplary embodiments of the present invention.

[0137] Example 1. A combination therapy comprising: (a) GDC-6036 as described herein or a pharmaceutically acceptable salt thereof; and (b) Ivlixim as described herein or a pharmaceutically acceptable salt thereof.

[0138] Example 2. The combination therapy as in Example 1, wherein GDC-6036 is its adipic acid salt.

[0139] Example 3. A combination therapy as in Example 1 or 2, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a dosing regimen comprising one or more cycles.

[0140] Example 4. The combination therapy as in Example 3, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered once daily (QD) on days 1-21 of a dosing regimen comprising one or more 21-day cycles, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets or capsules.

[0141] Example 5. The combination therapy as in Example 3, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets or capsules.

[0142] Example 6. A combination therapy as in any of Examples 1 to 5, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg.

[0143] Example 7. A combination therapy as in any of Examples 1 to 6, wherein GDC-6036 or its pharmaceutically acceptable salt is administered in amounts of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg.

[0144] Example 8. A combination therapy as in any of Examples 1 to 6, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg or 400 mg.

[0145] Example 9. A combination therapy as in any of Examples 1 to 6, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 200 mg.

[0146] Example 10. A combination therapy as in any of Examples 1 to 6, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg.

[0147] Example 11. A combination therapy as in any of Examples 1 to 10, wherein sefliximab or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a dosing regimen comprising one or more cycles.

[0148] Example 12. The combination therapy as in Example 11, wherein sefliximab or a pharmaceutically acceptable salt thereof is administered once daily (QD) on days 1-21 of a dosing regimen comprising one or more 21-day cycles.

[0149] Example 13. A combination therapy as in any of Examples 1 to 12, wherein sefliximab or a pharmaceutically acceptable salt thereof is administered once daily (QD) according to a dosing regimen comprising one or more 28-day cycles.

[0150] Example 14. A combination therapy as in any of Examples 1 to 13, wherein the dosing regimen includes a discontinuation period of not administering GDC-6036 and either or both of Ivlixim.

[0151] Example 15. A combination therapy as in any of Examples 1 to 14, wherein sefliximab is administered at a dose of about 3, 6 or 9 mg.

[0152] Example 16. A combination therapy of any of Examples 1 to 15, wherein sefliximab is administered at a dose of 6 mg.

[0153] Example 17. A combination therapy of any of Examples 1 to 15, wherein sefliximab is administered at a dose of 9 mg.

[0154] Example 18. A combination therapy of any of Examples 1 to 17 for the treatment of lung cancer containing KRas G12C mutation.

[0155] Example 19. The combination therapy as in Example 18, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0156] Example 20. A combination therapy of any of Examples 1 to 17 for the treatment of colorectal cancer (CRC) containing KRas G12C mutation.

[0157] Example 21. A combination therapy as in any of Examples 1 to 20, wherein the patient is assessed for the presence or absence of a KRasG12C mutation prior to administration.

[0158] Example 22. A combination therapy as in any of Examples 1 to 21, wherein the presence or absence of mutant PIK3CA is not assessed prior to administration.

[0159] Example 23. A method of treating a patient with lung cancer mediated by a KRas G12C mutation, the method comprising administering an effective amount of a combination therapy comprising: (a) administering once daily (QD) GDC-6036 or a pharmaceutically acceptable salt thereof as described herein according to a dosing regimen comprising one or more cycles; and (b) administering once daily (QD) Iffulixe or a pharmaceutically acceptable salt thereof as described herein according to a dosing regimen comprising one or more cycles.

[0160] Example 24. The method as in Example 23, wherein the lung cancer is NSCLC.

[0161] Example 25. The method as in Example 23 or 24, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer or large cell lung cancer.

[0162] Example 26. A method of treating a patient with a solid tumor containing a KRasG12C mutation, the method comprising administering an effective amount of a combination therapy comprising: (a) administering once daily (QD) GDC-6036 or a pharmaceutically acceptable salt thereof as described herein, according to a dosing regimen comprising one or more cycles; and (b) administering once daily (QD) Iffulixe or a pharmaceutically acceptable salt thereof as described herein, according to a dosing regimen comprising one or more cycles.

[0163] Example 27. The method of Example 26, wherein the solid tumor is colorectal cancer (CRC).

[0164] Example 28. The method of any of Examples 23 to 27, further comprising: (a) determining whether a KRasG12C mutation is present or absent in a sample taken from a patient suspected of having cancer; and (b) administering to the patient a combination therapy as described herein, the combination therapy comprising an effective amount of GDC-6036 or a pharmaceutically acceptable salt thereof and seflixithide.

[0165] Example 29. A method for treating a patient with a tissue-undetermined cancer containing a KRasG12C mutation, the method comprising administering an effective amount of a combination therapy comprising: (i) determining whether a KRasG12C mutation is present or absent in a sample taken from a patient suspected of having cancer; and (ii) administering an effective amount of the combination therapy in the case that the patient sample contains a KRasG12C mutation, the combination therapy comprising: (a) administering GDC-6036 or a pharmaceutically acceptable salt thereof as described herein once daily (QD) according to a dosing regimen comprising one or more cycles; and (b) administering epefliximab or a pharmaceutically acceptable salt thereof as described herein once daily (QD) according to a dosing regimen comprising one or more cycles.

[0166] Example 30. The method of any of Examples 23 to 29, wherein the dosing regimen comprises one or more 21-day cycles.

[0167] Example 31. The method of Example 30, wherein the dosing regimen includes a discontinuation period during which one or both of GDC-6036 and levamisole are not administered.

[0168] Example 32. The method of any of Examples 23 to 29, wherein the dosing regimen comprises one or more 28-day cycles.

[0169] Example 33. A combination therapy as in any of Examples 23 to 32, wherein GDC-6036 is its adipic acid salt.

[0170] Example 34. The method of any of Examples 23 to 33, wherein GDC-6036 or its pharmaceutically acceptable salt is administered orally in the form of tablets or capsules.

[0171] Example 35. The method of any of Examples 23 to 34, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg.

[0172] Example 36. The method of any of Examples 23 to 35, wherein GDC-6036 or its pharmaceutically acceptable salt is administered in amounts of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg.

[0173] Example 37. The method of any of Examples 23 to 36, wherein GDC-6036 or its pharmaceutically acceptable salt is administered in an amount of about 100 mg, 200 mg or 400 mg.

[0174] Example 38. The method of any of Examples 23 to 37, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 200 mg.

[0175] Example 39. The method of any of Examples 23 to 37, wherein GDC-6036 or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg.

[0176] Example 40. The method of any of Examples 23 to 39, wherein sefliximab is administered in an amount of about 3 mg, 6 mg or 9 mg.

[0177] Example 41. The method of any of Examples 23 to 40, wherein sefliximab is administered in an amount of 6 mg.

[0178] Example 42. The method of any of Examples 23 to 40, wherein sefliximab is administered in an amount of 9 mg.

[0179] Example 43. The method of any of Examples 23 to 42, wherein the patient is not assessed for the presence or absence of mutant PIK3CA prior to administration.

[0180] Example 44. Use of a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof and Ivlixim or a pharmaceutically acceptable salt thereof for the treatment of lung cancer, CRC or pancreatic cancer as described herein.

[0181] Example 45. As used in Example 42, wherein the cancer is lung cancer or CRC, and further comprises a dosing regimen comprising: (i) administering GDC-6036 or a pharmaceutically acceptable salt thereof according to a dosing regimen QD comprising one or more cycles; and (ii) administering seflixithide according to the dosing regimen QD comprising one or more cycles.

[0182] Example 46. Use of a combination therapy comprising GDC-6036 or a pharmaceutically acceptable salt thereof and sefliximab or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of lung cancer, CRC or pancreatic cancer.

[0183] Example 47. As used in Example 44, wherein the cancer is lung cancer or CRC, and further comprises a dosing regimen comprising: (i) administering GDC-6036 or a pharmaceutically acceptable salt thereof according to a dosing regimen QD comprising one or more cycles; and (ii) administering seflixithide according to the dosing regimen QD comprising one or more cycles.

[0184] Example 48. Used as in Example 44, wherein the cancer is CRC, and further comprising a dosing regimen comprising: (i) administering GDC-6036 or a pharmaceutically acceptable salt thereof according to a dosing regimen QD comprising one or more 21-day cycles; and (ii) administering seflixithide according to a dosing regimen comprising one or more 21-day cycles.

[0185] Example 49. Used as in any of Examples 42 to 46, wherein the dosing regimen comprises one or more 21-day cycles.

[0186] Example 50. Used as in any of Examples 42 to 46, wherein the dosing regimen comprises one or more 28-day cycles.

[0187] The following examples are presented in an illustrative rather than restrictive manner. Examples

[0188] Example 1: Combination of GDC-6036 and Ivliss

[0189] The Kirsten rat sarcoma virus oncogene homolog (KRAS) gene encodes a GTPase that plays a central role in the communication of cell growth and survival. KRAS mutations that result in amino acid substitutions at glycine 12 (G12), glycine 13 (G13), and glutamic acid 61 (Q61) are common in tumors and are associated with tumorigenesis and the maintenance of invasive tumor growth (Der et al. Nature 1983;304(5926):507-13; Parada et al. Nature 1982;297(5866):474-8; Santos et al. Nature 1982;298(5872):343-7; Taparosky et al. Nature 1982;300(5894):762-5; Capon et al. Nature 1983;304(5926): 507-13). KRAS G12C mutations are prevalent in non-small cell lung cancer (NSCLC), colorectal cancer and other tumor types (Prior et al. Cancer Res 2012;72(10):2457-67; Vogelestein et al. Science 2013;339(6127):1546-58).

[0190] GDC-6036 is an oral anticancer therapeutic agent that selectively targets KRAS G12C, resulting in covalent and irreversible inhibition of KRAS G12C. GDC-6036 does not target other mutations in KRAS, wild-type KRAS, or other members of the RAS family. Treatment of KRAS G12C-positive cells or tumors with GDC-6036 weakens KRAS pathway signaling, inhibits cell / tumor cell growth, and induces apoptosis.

[0191] The in vivo antitumor efficacy of GDC-6036 alone (50 mg / kg, PO, QD) or in combination with GDC-0077 (25 mg / kg, PO, QD) in xenograft tumor models of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) bearing KRas G12C mutations was evaluated. Single-agent treatment with GDC-6036 resulted in near-tumor arrest (93% tumor growth inhibition [TGI]), while treatment with GDC-0077 resulted in tumor growth inhibition (74% TGI). Improved antitumor efficacy (113% TGI) was observed when GDC-6036 was administered in combination with sefliximab.

[0192] Mice. Female nude mice aged 9–10 weeks were obtained from Charles River Laboratory (Hollister, CA), with an average weight of 24.5 g. Mice were housed at Genentech in standard rodent miniature isolation cages and acclimatized to the study conditions for at least 3 days prior to tumor cell implantation. Only animals that appeared healthy and without obvious abnormalities were used for the study.

[0193] Research. Human non-small lung cancer NCI-H2122 cells were obtained from the American Type Culture Collection (Rockville, MD) and carried the G12C oncogenic mutation in K-RAS. Cells were cultured in vitro, harvested in the logarithmic growth phase, and resuspended at a 1:1 ratio in Hank balanced salt solution containing Matrigel (BD Biosciences; San Jose, CA). The cells were then subcutaneously implanted into the right chest of 160 nude mice. Each mouse was injected with 100 μL of 10 × 10⁶ cells. Tumors were monitored until they reached a mean tumor volume of 150–290 mm³. Mice were divided into 10 groups (n=10 mice per group) based on tumor volume. At the start of administration, the mean tumor volume across all groups was 213 mm³.

[0194] Mice were administered a mediator (150 μL 0.5% MC and 100 μL 0.5% MCT), 50 mg / kg GDC-6036 (expressed as free base equivalents), or 25 mg / kg GDC-0077 (expressed as free base equivalents), or a combination of GDC-6036 and sefliximab. All treatments were administered once daily (QD) via gavage or orally (PO) for 21 days. The study design is summarized in Table 1.

[0195] Table 1: Number / Gender treat Dosage level (mg / kg) way Number of days of medication Dosage concentration (mg / mL) 10 / F Mediator 0 PO 21 QD 0 10 / F GDC-6036 50 PO 21 QD 8.33 10 / F GDC-0077 25 PO 21 QD 6.25 10 / F + GDC6036 + GDC-0077 50 + 25 PO 21 QD 8.33, 6.25 Conc. = concentration; PO = oral; QD = once daily The mediator control consisted of 0.5% (w / v) methylcellulose (100 μL) + 0.5% (w / v) methylcellulose; and 0.2% Tween80™ (150 μL). Dosage levels and concentrations were expressed as free base equivalents and administered once daily (QD) for 21 days.

[0196] Tumor and Weight Measurements. Tumor volume was measured in two dimensions (length and width) using an Ultra Cal-IV caliper (model 54-10-111; Fred V. Fowler Co.; Newton, MA) and analyzed using Excel version 14.2.5 (Microsoft Corporation; Redmond WA). Tumor volume was calculated using the following formula: Tumor size (mm³) = (longer measurement × shorter measurement²) × 0.5

[0197] Note the antitumor response; partial response (PR) was defined as a reduction in tumor volume >50% from the initial tumor volume, and complete response (CR) was defined as a reduction in tumor volume of 100%. Animal weight was measured using an Adventura Pro AV812 balance (Ohaus Corporation; Pine Brook, NJ). The percentage change in body weight was calculated using the following formula: Body weight change (%) = [(current body weight / initial body weight) – 1) × 100]

[0198] Tumor growth analysis. A generalized additive mixture model (GAMM) was used to analyze the changes in transformed tumor volume over time, as this method addresses both repeated measurements from the same individual and appropriate exits before the end of the analysis. Since tumors typically grow exponentially, a natural logarithmic transformation was performed on the tumor volume prior to the analysis. Tumor volume changes over time in each group were described using custom fittings (i.e., regression splines with automatically generated 3-spline bases) generated in R version 3.4.2 (2017-09-28) (R Development Core Team 2008; R Foundation for Statistical Computing; Vienna, Austria). This R version integrates software from open-source packages including Ime4, mgcv, gamm4, multcomp, settings, and plyr, as well as several packages from the tidyverse, such as magrittr, dplyr, tidyr, and ggplot2.

[0199] Body weight analysis. A generalized additive mixture model (GAMM) was also used to analyze changes in original body weight (i.e., grams) over time. After data fitting, the original body weight data at each time point from all individual animals and all groups were standardized and replotted in two different ways: 1) standardized to the initial body weight and reported as a percentage to obtain % body weight change; and 2) standardized to the maximum body weight to date and reported as a percentage to obtain % body weight loss.

[0200] Results. Efficacy and body weight of NCI-H2122 xenografts. Antitumor efficacy was evaluated in nude mice bearing human NCI-H2122 NSCLC xenografts following treatment with GDC-6036 alone (50 mg / kg, PO, QD), single-agent GDC-0077 (25 mg / kg, PO, QD), or a combination of GDC-6036 and GDC-0077. Single-agent treatment resulted in tumor growth inhibition (TGI) compared to the mediator control, with GDC-6036 resulting in a 93% TGI and GDC-0077 resulting in a 74% TGI (Figure 1 and Tables 2 and 3). Improved antitumor efficacy was observed in the combination of GDC-6036 and efliximab, resulting in a 113% TGI and 2 / 10 PR (Figure 1). All treatments were well tolerated, as measured by percentage change in body weight (Figure 2 and Table 2).

[0201] Table 2: Antitumor activity of GDC-6036 alone and in combination with GDC-0077 in human NCI-H2122 NSCLC xenograft tumors. treat Dosage level (mg / kg) TI PR CR %TGI (estimated) %TGI (Lower CI) %TGI (Upper CI) Mediator 0 10 / 10 0 0 0 0 0 GDC-6036 50 10 / 10 0 0 93 80 100 GDC-0077 25 10 / 10 0 0 74 60 85 GDC-6036+ GDC-0077 50 + 25 10 / 10 0 0 113 107 121 TI = Tumor incidence; %TGI = Percentage of tumor growth inhibition; PR = Partial response; CR = Complete response; CI = Confidence interval. The mediator control was 0.5% (w / v) methylcellulose + 0.5% (w / v) methylcellulose; 0.2% Tween80™.

[0202] The combination of GDC-6036 and Ifliximab is being further tested in various other NSCLC cell lines carrying the KRasG12C mutation, including H23P, KYSE410, H1792, H2030, HCC4017, HCC4019, and HOP62. Synergistic effects have been observed in some cell lines at concentrations as low as 40 nM (Figs. 3A-3H).

[0203] The combination of GDC-6036 and epfuliximab was further tested in various CRC cell lines carrying the KRasG12C mutation. Adding GDC-0077 to GDC-6036 further inhibited cell proliferation, even in the most resistant cell line (SW1436). See Figures 5A–5C. A synergistic effect of the combination of GDC-6036 and GDC-0077 was observed in a CR5048 patient-derived xenograft model (Figure 4 and Table 3).

[0204] Table 3 Model treat Dosage level (mg / kg), Scheduling TI PR CR % TGI (estimate) % TGI (CI below) % TGI (CI) Mediator 0 (media) 10 / 10 0 0 0 0 0 CR5048 GDC-6036 30, PO, QD 10 / 10 0 0 90 78 100 CR5048 GDC-0077 25, PO, QD 10 / 10 0 0 52 16 73 CR5048 GDC-6036 + GDC-0077 30 + 25 10 / 10 4 0 97 88 106 CI = Confidence Interval; CR = Complete Response; PR = Partial Response; QD = Once Daily; TI = Tumor Incidence. Note: % TGI = Percentage of Tumor Growth Inhibition Based on AUC (Formula in Data Analysis Section). Mediator = 0.5% (w / v) Methylcellulose

[0205] Combined antitumor efficacy studies in various human NSCLC and CRC xenograft tumor models and cell lines bearing KRas G12C mutations have shown that the KRAS-G12C inhibitor GDC-6036, as a single agent, can inhibit tumor growth. These data indicate that the combination of GDC-6036 and GDC-0077 leads to improved antitumor activity compared to single-agent observations that induce partial tumor regression in human NSCLC and CRC xenograft tumor models.

[0206] Example 2: KRAS is the most common mutated oncogene in up to 25% of cancers and is associated with resistance to standard-of-care therapy and poor overall prognosis. Although selective inhibitors have been developed as anticancer therapies targeting other nodes in the RAS / MAPK pathway, KRAS oncogenes were considered untreatable before the recent discovery of the switch II pocket (Ostrem, et al., Nature 2013;503:548-51). Based on this finding, covalent small molecule inhibitors targeting KRAS, and particularly KRAS G12C mutations, are being evaluated in early clinical development.

[0207] Other KRAS G12C Inhibitors. AMG 510 (sotorasib) is a small molecule that irreversibly inhibits KRAS G12C by locking it into its inactive GDP-binding state. AMG 510 is currently being investigated in ongoing clinical studies. Patients in these studies had received a median of 3 (range, 0 to 11) of first-line anticancer therapy for metastatic disease prior to enrollment in the study. Overall, treatment-related adverse events were reported in 56.6% of patients; 11.6% of patients experienced treatment-related grade 3 or 4 events, and 1.6% of patients experienced treatment-related serious adverse events. Grade 3 events occurring in more than one patient included elevated ALT, diarrhea, anemia, elevated AST, and elevated alkaline phosphatase. One patient experienced a grade 4 treatment-related ALT elevation, and one patient discontinued AMG 510 due to grade 3 treatment-related ALT and AST elevations. Despite reported antitumor activity, adverse events associated with AMG 510 were observed. In 32.2% of NSCLC patients, a confirmed objective response was achieved, with a median duration of response of 10.9 months (range, 1.1+ to 13.6). The median progression-free survival (PFS) in NSCLC patients was reported to be 6.3 months (range, 0.0+ to 14.9+) (Hong et al., New Eng J Med 2020;383:1207-17).

[0208] MRTX849 is a mutation-selective small molecule KRAS G12C inhibitor that is being evaluated in clinical trials for patients with advanced solid tumors harboring KRAS G12C mutations. Data from a total of 17 patients (10 NSCLC patients and 4 CRC patients) were recently reported, of whom 12 had received at least one prior oncology evaluation (6 NSCLC patients and 4 CRC patients). Most patients had received three or more prior anticancer regimens prior to enrollment (12 of the 17 patients, 71%). The following treatment-related adverse events were reported in 10% of patients: diarrhea, nausea, elevated AST, vomiting, fatigue, elevated ALT, elevated creatinine, abdominal distension, abdominal pain, elevated ALP, anemia, decreased appetite, dehydration, dry mouth, taste disturbance, dyspnea, QT prolongation, hypomagnesemia, and rash. Grade 3 events included fatigue, decreased appetite, and dyspnea (1 patient each). At all evaluated dose levels, 3 out of 6 NSCLC patients and 1 out of 4 CRC patients achieved partial response (Jänne et al., AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, October 2019).

[0209] As shown in GDC-6036. The specificity of GDC-6036 for KRAS G12C and its mechanism of action result in effective and irreversible inhibition of KRAS G12C, with the aim of achieving a broad therapeutic index, maximizing antitumor activity while minimizing treatment-related toxicities. Specific therapies targeting KRAS G12C-positive cancers may provide more tolerable and effective treatment options for patients with advanced cancer carrying KRAS G12C.

[0210] In vitro and in vivo pharmacological studies have shown that GDC-6036 is a highly potent and selective covalent inhibitor of KRAS G12C, exhibiting 20,000-fold higher selectivity for growth inhibition in KRAS G12C-positive cancer cell lines compared to KRAS G12C-negative cancer cell lines. Mechanism-of-action studies of GDC-6036 have shown that, in addition to KRAS target genes (such as DUSP6 and SPRY4), downstream MAPK pathway components (such as phosphorylated (p)ERK and pS6) are also inhibited, and apoptosis induction was observed in KRAS G12C-positive cancer cell lines. Furthermore, GDC-6036 possesses potent single-agent activity and inhibits tumor growth in numerous non-clinical xenograft models of KRAS G12C-positive lung tumors. These in vitro and in vivo pharmacological studies support the use of GDC-6036 to treat patients with locally advanced or metastatic KRAS G12C-positive solid tumors.

[0211] Results of the non-clinical toxicology studies completed to date provide a reliable characterization of the toxicity profile of GDC-6036 and support its administration in cancer patients. Comprehensive non-clinical toxicity studies were completed to evaluate the potential single-dose and repeated-dose oral toxicities, genotoxicities, phototoxicities, and safety pharmacology of GDC-6036. Because the KRAS G12C mutation is absent in healthy animals, there is no pharmacologically relevant non-clinical species to inhibit KRAS G12C.

[0212] Early Phase I clinical data from ongoing studies of AMG 510 and MRTX849 as monotherapy indicate that KRAS G12C inhibitors are tolerable and have promising antitumor activity in patients with metastatic NSCLC and CRC (Janne et al. 2019; Hong et at. New Eng J Med 2020;383:1207-17). However, there remains a significant unmet need to improve the reported antitumor activity and durability in NSCLC and CRC, and it is important to maintain a tolerable safety profile when using these inhibitors as monotherapy.

[0213] The basic principle of combination therapy. Unbound by any particular theory and based on a mechanistic understanding of the RTK-RAS-MAPK pathway, it is hypothesized that RAS / MAPK and PI3K / AKT are intricately interconnected signaling pathways that are frequently dysregulated in human cancers. These two pathways not only share common upstream signaling inputs, but they can also play a compensatory role when one or the other is inhibited by targeted therapy. Recent studies have also identified genetic alterations in key PI3K pathway components (including PIK3CA and PTEN) when tumors clinically develop resistance to KRAS G12C inhibitors (Awad et al. 2021; Zhao et al. 2021), suggesting that activation of the PI3K signaling pathway may act as a resistance mechanism to KRAS G12C inhibitors. Therefore, it may be necessary to simultaneously block both the RAS / MAPK and PI3K / AKT pathways to maximize clinical benefit. The combination of GDC 6036 (a highly selective KRAS G12C inhibitor that is a mutational ...

[0214] Multiple non-clinical studies have demonstrated that the combination of KRAS G12C inhibitors and PI3K inhibitors exhibits a broad synergistic effect in various in vitro and in vivo models, most of which do not carry dysregulation of PI3K pathway components (Misale et al. 2015; Canon et al. 2019; Lou et al. 2019). Mechanistically, the combination of KRAS G12C and PI3K inhibitors can simultaneously downregulate both phosphate-AKT and phosphate-S6RP, resulting in more reliable induction of cell death and inhibition of proliferation compared to KRAS G12C inhibitors alone (Misale et al. 2018). Consistent with these observations, non-clinical data (Example 1) of the combination of GDC-6036 and epfliximab also showed a greater synergistic effect of tumor reduction in KRAS G12C-positive cell lines and multiple xenograft mouse models compared to the use of either treatment alone.

[0215] The starting dose of the combination of epifalicylate and GDC-6036 will be 6 mg PO QD in each 21-day cycle. The combination of GDC-6036 and epifalicylate is expected to be well tolerated. Potential overlapping toxicities include GI toxicity and oral mucosal irritation, which are expected to be monitored and managed with supportive care and possible dose adjustments.

[0216] Patients will have locally advanced, recurrent, or metastatic incurable solid tumors bearing a KRAS G12C mutation and have progressed after at least one available standard therapy; or for such patients, standard therapy has proven ineffective, intolerable, or deemed inappropriate; or for such patients, a clinical trial of the investigational agent represents the recognized standard of care. Furthermore, patients may have previously received KRAS G12C inhibitor therapy.

[0217] Biomarkers. This study will identify and / or evaluate biomarkers that predict the response to GDC-6036 as a single agent or in combination with a PI3K inhibitor (i.e., predictive biomarkers), biomarkers as early active alternatives, biomarkers associated with progression to a more severe disease state (i.e., prognostic biomarkers), biomarkers associated with acquired resistance to KRAS G12C inhibitors (e.g., GDC-6036), biomarkers associated with susceptibility to adverse events or that could lead to improved monitoring or study of adverse events (i.e., safety biomarkers), biomarkers that could provide evidence of the activity of GDC-6036 in combination with epifalicylate (i.e., pharmacodynamic [PD] biomarkers), or biomarkers that could increase knowledge and understanding of disease biology and drug safety. Corresponding biomarker endpoints include the relationship between exploratory biomarkers in blood, plasma, and tumor tissue and safety, PK, activity, or other biomarker endpoints.

[0218] Patients undergo screening for up to 28 days, followed by a treatment period and a safety follow-up period, during which patients will be followed up on safety outcomes after their final dose of the study drug or until they receive another anticancer therapy (whichever comes first).

[0219] Patients may continue treatment with GDC-6036 if the researchers determine that there is no unacceptable toxicity or clear disease progression.

[0220] Adverse events will be closely monitored in all patients throughout the study and at specific treatment periods, either after the final dose of the study treatment or before initiating another anticancer therapy (whichever occurs first). Adverse events will be classified according to the NCI CTCAE v5.0 classification.

[0221] Ifliximab is a selective inhibitor of class I PI3Kα isoform (p110α). By inhibiting the phosphorylation of PIP2 to PIP3, Ifliximab reduces the activation of downstream pathway effectors, including AKT, PRAS40, and S6RP, which can serve as biomarkers for PD treated with GDC-6036 and Ifliximab.

[0222] KRas G12C mutation status assessed from tissue and circulating tumor DNA. Approximately 12% of NSCLC, 4% of CRC, 2% of pancreatic cancer, and many other solid tumors (each with a prevalence of ≤4%) carry KRas G12C mutations. GDC-6036 is a potent and highly selective inhibitor that targets KRas G12C but not other mutations in KRAS, wild-type KRAS, or other members of the RAS family. Therefore, only patients with tumors carrying KRas G12C mutations are eligible for the combination therapy described herein. KRAS mutation status can be determined using the FoundationOne® CDx (F1CDx) assay, FDA-approved broad companion diagnostic (CDx) assays, FoundationOne® liquid CDx (F1L CDx) assay, and other FDA-approved (FDA 2020) or fully validated laboratory-developed tests performed in a Clinical Laboratory Improvement Amendments (CLIA) accredited or equivalent facility. Previous studies have shown that the occurrence of KRas G12C mutations is an early event (Jamal-Hanjani et al. N Engl J Med 2017;376:2109-21), suggesting that archival analysis is sufficient as an alternative to selecting KRas G12C-positive tumor patients for GDC-6036 treatment.

[0223] Modulation of Pharmacodynamic Pathways. GDC-6036 is a KRas G12C inhibitor that locks downstream MAPK signaling into its inactive GDP-bound state by inhibiting KRas G12C alkylation. In non-clinical models, the amount of KRas G12C alkylation by GDC-6036 and the degree of MAPK pathway inhibition are correlated with the response to GDC-6036. Pre- and in-treatment tumor tissue collections will be able to assess the correlation between MAPK pathway inhibition and antitumor activity and GDC-6036 treatment. The degree of MAPK pathway inhibition can be assessed using RNA analysis of MAPK target genes (e.g., DUSP6, SPRY4) or immunohistochemical (IHC) analysis of phosphorylated downstream markers (e.g., pERK, pS6). Furthermore, in-treatment tumor tissue biopsy allows for direct assessment of the amount of KRas G12C alkylation achieved using GDC-6036. The evaluation of these PD biomarkers may inform future dosage selection.

[0224] Sequencing of genes associated with resistance to GDC-6036. DNA sequencing technologies, such as targeted next-generation sequencing (NGS) and whole-exome sequencing, may offer unique opportunities to identify biomarkers of response to and / or resistance to GDC-6036. Sequencing of cancer-related genes may lead to the identification of de novo and acquired mechanisms of resistance to GDC-6036.

[0225] Protein, RNA, and DNA analysis. Besides protein mutation activation, alterations in RNA expression levels or DNA can also modulate the activity of signaling pathways. RNA profiling of tumors will allow for intrinsic subtyping of participating patients. Analysis of the potential association between subtyping and patient outcomes can identify the patient subgroups most likely to respond to GDC-6036.

[0226] Plasma samples and other biomarkers for somatic tumor mutation analysis. Increasing evidence suggests that cell-free DNA obtained from blood samples of cancer patients contains ctDNA, which represents the DNA and mutational status of tumor cells (Diehl et al. 2008; Maheswaran et al. 2008). Validated assays can detect cancer-related mutations (e.g., KRAS) in plasma. The results of these assays may be correlated with the mutational status determined by analyzing tumor samples. Using ctDNA to monitor response to treatment is a very interesting area and could allow for the identification of specific therapy candidates and the monitoring of cancer mutational status over time in a clinical setting using an early, non-invasive, and quantifiable approach (Wan et al. Nat Rev Cancer 2017;17:223-38). Analysis of ctDNA collected at different times during study treatment and after progression of GDC-6036 treatment may help identify response mechanisms to study treatment and acquired resistance.

[0227] Blood samples for next-generation sequencing. Next-generation sequencing (NGS) technology can generate a large amount of sequencing data. Due to the tumorigenesis process, tumor DNA may contain both reported and unreported chromosomal alterations. To help control sequencing calls in previously unreported genomic alterations, pre-dose blood samples will be collected to determine whether the alterations are somatic.

[0228] Inclusion Criteria. Patients must meet the following study inclusion criteria: l Age ≥ 18 years; l Disease that can be evaluated or measured according to RECIST v1.1; l Eastern Cooperative Oncology Group (ECOG) performance status ≥ 0 or 1; l Life expectancy ≥ 12 weeks; l Adequate hematological and organ function within 14 days prior to the start of study treatment, defined as follows: o Absolute neutrophil count ≥ 1200 / µL; o Heme ≥ 9 g / dL; o Platelet count ≥ 100,000 / µL; o Total bilirubin ≤ 1.5 × ULN; o Serum albumin ≥ 2.5 g / dL; o AST and ALT ≤ 2.5 × ULN, except in the following cases: § Patients with a history of liver metastases may have AST and / or × ALT 5.0 ULN. o Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL / min, estimated based on Cockcroft-Gault glomerular filtration rate: (140 - age) × (weight in kg) × (0.85 for females) 72 × (serum creatinine in mg / dL) l For women of fertility: consent to abstinence (avoidance of heterosexual intercourse) or use of contraception, and consent not to donate eggs; l For men who have not undergone surgical sterilization: consent to abstinence (avoidance of heterosexual intercourse) or use of contraception, and consent not to donate sperm; l Confirmation of biomarker eligibility: valid results from blood center tests or local tests of blood or tumor tissue demonstrating the presence of a KRas G12C mutation (e.g., empirically validated polymerase chain reaction (PCR) or NGS assays performed in CLIA or equivalent accredited laboratories).

[0229] Additional Inclusion Criteria: l Histologically documented locally advanced, recurrent, or metastatic incurable malignancies. o Disease progression after at least one available standard therapy; or proven ineffective or intolerable to standard therapy; or a clinical trial of the investigational agent representing an accepted standard of care. l Fasting blood glucose ≤ 140 mg / dL and glycosylated hemoglobin (HbA1c) < 7%. l The patient may have received prior treatment with a KRas G12C-specific inhibitor. l Histologically documented locally advanced, recurrent, or metastatic incurable NSCLC (may include single-agent therapy or combination therapy with an investigational or approved PD-L1 / PD-1 inhibitor).

[0230] General Exclusion Criteria. Patients meeting any of the following criteria will be excluded. l Unable or unwilling to swallow tablets; l Unable to adhere to study and follow-up procedures; l Malabsorption syndrome or other symptoms interfering with intestinal absorption; l Known and untreated or active central nervous system (CNS) metastases; l Patients with a history of CNS metastasis treatment who meet all of the following criteria: o Measurable or evaluable disease outside the CNS; o No history of intracranial or spinal hemorrhage; o No requirement for continued use of corticosteroids for CNS metastases, discontinued corticosteroids ≥2 weeks prior to administration of the medication described herein, and no persistent symptoms attributable to CNS metastases; o No stereotactic radiotherapy within 7 days prior to Day 1 of Cycle 1 or no whole-brain radiotherapy within 14 days prior to Day 1 of Cycle 1; o No evidence of transitional progression between completion of CNS-directed therapy and radiographic examination; l Leptomeningeal disease or carcinomatous meningitis; l Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage (twice a week or more frequently); o Indwelling thoracic or peritoneal catheters may be permitted, provided the patient has fully recovered from surgery, is hemodynamically stable, and has improved symptoms; any active infection that may affect patient safety, or a serious infection requiring intravenous antibiotics within 7 days prior to day 1 of cycle 1; a significant clinical history of liver disease, including viral hepatitis or other hepatitis, current alcoholism, or cirrhosis; known HIV infection; uncontrolled hypercalcemia (>1.5 mmol / L ionized calcium or calcium >12 mg / dL or corrected serum calcium ≥ ULN) or symptomatic hypercalcemia requiring continued bisphosphonate therapy or denosumab. l Patients who have experienced major trauma or major surgery within 4 weeks prior to Day 1 of Cycle 1; l Patients with chronic diarrhea, short bowel syndrome, or significant upper gastrointestinal surgery (including gastrectomy), a history of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or any active intestinal inflammation (including diverticulitis); l Patients who have received chemotherapy, immunotherapy, or biotherapy as anticancer therapy within 3 weeks prior to administration of the drug described herein, or who have received hormone therapy within 2 weeks prior to administration of the drug described herein, except in the following cases: o Hormone therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for hormone-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); o Regulatory-approved kinase inhibitors may be used up to 2 weeks prior to the start of study treatment; o Patients who have received treatment with the study drug within 3 weeks or five half-lives (whichever is shorter) prior to administration of the drug described herein.l Received radiation therapy (except for palliative radiation to bone metastases and radiation to CNS metastases) as cancer therapy within 4 weeks prior to administration of the drugs described herein; l Received palliative radiation therapy to bone metastases within 2 weeks prior to administration of GDC-6036; l Unresolved adverse events from prior anticancer therapy; l History of other malignancies within 5 years prior to screening; l History or activity of clinically significant cardiovascular dysfunction, including: o History of stroke or transient ischemic attack within 6 months prior to administration of the drugs described herein; o History of myocardial infarction within 6 months prior to administration of the drugs described herein; o New York Heart Association class III or IV heart disease or congestive heart failure requiring medication; o History of uncontrolled arrhythmias, ventricular arrhythmias requiring medication, or active ventricular arrhythmias; o Coronary artery disease with symptomatic or unstable angina; o Congenital long QT syndrome or QT The interval was corrected using the Fridricia formula (QTcF) > 470 ms; o Currently receiving drug treatment known to prolong the QT interval; l Pregnancy or breastfeeding, or planning to become pregnant during the study period or within 6 months after the last dose of GDC-6036; or l History of idiopathic pulmonary fibrosis, tissue pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on chest X-ray computed tomography (CT) scan.

[0231] Other Exclusion Criteria l Type 1 and type 2 diabetes requiring anti-hyperglycemic agents l Any concurrent ocular or intraocular condition (e.g., cataracts or diabetic retinopathy) that, in the opinion of the researcher and / or the research ophthalmologist, would require medical or surgical intervention during the study to prevent or treat vision loss that may be caused by the condition l History of having active inflammation (e.g., uveitis or vitreitis) or infectious condition (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) in either eye or spontaneous or autoimmune-related uveitis in either eye l Patients requiring any daily supplemental oxygen l History of having or active inflammatory diseases (e.g., Crohn's disease or ulcerative colitis) or any active intestinal inflammation (including diverticulitis), including patients currently receiving immunosuppressants (e.g., sulfasalazine) are considered to have active diseases and are therefore ineligible. l Has a prior history of significant toxicity associated with another PI3K or mTOR inhibitor, requiring discontinuation of treatment.

[0232] Study on therapeutic preparations, packaging and processing.

[0233] GDC-6036 will be available as an active pharmaceutical ingredient (API) powder capsule (PIC) formulation in three strengths: 5 mg, 25 mg, and 100 mg (free base equivalent). GDC-6036 should be stored at 86℉ (30℃) or below and protected from moisture.

[0234] For home administration of GDC-6036, patients should be given an adequate number of capsules or tablets to continue until the next appointment or up to one cycle. Unless the patient visits a clinic, they will self-administer GDC-6036 as described herein. Unless otherwise instructed, patients should take GDC-6036 at approximately the same time each day. The number and strength of capsules or tablets to be taken will be instructed according to the specified dosage level and schedule.

[0235] Unless otherwise instructed, GDC-6036 should be taken on an empty stomach, i.e., food should be avoided for at least 2 hours before and 1 hour after this dose. There are no restrictions on water intake. Importantly, GDC-6036 capsules or tablets should be swallowed whole (not chewed) with at least 240 mL (8 fluid ounces) of water. If a patient misses any dose of GDC-6036 or spits out a capsule or tablet, the patient should be instructed to skip that dose and continue with the next scheduled dose. Missed doses will not be made up.

[0236] Ivliximab will be provided by the trial commissioner in tablet form in two strengths: 3 mg and 9 mg. Ivliximab will be administered orally at a dose of 6 mg once daily (QD) over a 21-day cycle, not exceeding a single-dose MTD of 9 mg once daily (QD). Ivliximab may be administered concurrently with GDC-6036, during which time patients may drink a few sips of water. Patients will self-administer Ivliximab unless it is administered at the clinic on the study visit day.

[0237] Unless otherwise instructed, patients should take epifalicylate at approximately the same time each day, regardless of meal times. If a patient misses any dose of epifalicylate (not taken within 6 hours of the scheduled dosing time) or spits up a tablet, the patient should skip that dose, record it, and continue with the next scheduled dose.

[0238] Companion therapy. Companion therapy consists of any medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient from 7 days prior to the first administration of at least one of the medications described herein until the last administration of at least one of the medications described herein.

[0239] Permitted therapies. Patients may take (a) antiepileptic drugs or warfarin; (b) oral contraceptives or other permitted maintenance therapies as specified in the eligibility criteria; (c) antiemetics and antidiarrheals should not be administered prophylactically before initial treatment with an investigational drug; (d) analgesics; (e) bisphosphonates and denosumab for bone metastases, osteopenia, or osteoporosis; or multivitamins, calcium, and vitamin C, D, and E supplements are permitted.

[0240] Prophylactic therapy. Medications that require caution due to their effects related to CYP enzymes and GDC-6036 include, for example, (1) strong / moderate CYP3A4. Inhibitors, including but not limited to: atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamine, diltiazem, nefazodone, mibefradil, verapamil, and grapefruit juice or grapefruit supplements; (2) strong / moderate CYP3A4 Inducing agents include, but are not limited to, the following: rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), and cyproterone. Full-dose oral or parenteral anticoagulants are permitted for therapeutic purposes provided that the INR and / or aPTT are within the therapeutic range (according to institutional standards) for 14 days prior to administration of any of the medications described herein, and the patient has received a stable dose of anticoagulant therapy for ≥ 1 week prior to initiation of study treatment. This list of medications is not intended to be exhaustive.

[0241] Coumarin (Coumarin®, warfarin) is strongly discouraged during treatment. If anticoagulation therapy is required, low molecular weight heparin is recommended as an alternative to coumarin, where clinically feasible. If no clinically feasible coumarin alternative is available, INR and prothrombin time must be monitored frequently.

[0242] Contraindicated Therapies. The following concomitant therapies are prohibited during and at least 7 days prior to the first administration of the drug described herein: l Investigational therapies administered within 3 weeks or five half-lives (whichever is shorter) prior to the first administration of the drug described herein; l Concomitant therapies for the treatment of cancer, whether FDA-approved or experimental, including chemotherapy, radiation therapy, immunotherapy, biotherapy, herbal remedies, or hormone therapy, except for: o Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for hormone-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); o Hormone replacement therapy or oral contraceptives. l Radiation therapy for clearly progressive disease, excluding new brain metastases in cases of systemic response: Patients whose systemic disease has been demonstrated to be under control (defined as having achieved clinical benefit [i.e., PR, CR, or SD for ≥3 months]) but have developed brain metastases that can be treated with radiation therapy will be allowed to continue receiving therapy using GDC-6036 during the study period until they experience systemic progression of their disease and / or further progression in the brain (based on investigator assessment); l Quinidine or other antiarrhythmic drugs; l Hematopoietic community stimulating factors (CSFs; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; sargramostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) starting or increasing 7 days before day 1 of cycle 1.

[0243] Warning Risks: l Potent CYP3A4 inhibitors, including but not limited to: atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, acetylenol, itraconazole, ketoconazole, voriconazole, posaconazole, conivatan, diltiazem, nefazodone, and mibeladil l Potent CYP3A4 inducers, including but not limited to: rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, nevirapine, hypericin (St. John's wort), and cyproterone acetate l P-gp inhibitors, including but not limited to: ritonavir, cyclosporine, verapamil, erythromycin, ketoconazole, itraconazole, quinidine, elacridar, and valspodar l BCRP inhibitors, including but not limited to: curcumin, cyclosporine A, eltrombopag

[0244] Risks associated with GDC-6036. Administration of GDC-6036 has been associated with diarrhea, nausea, vomiting, and minimal to mild elevation of transaminase levels. Other potential risks include oral mucosal irritation.

[0245] Risks associated with epoxetine. Based on the class effects established by PI3K and mTOR inhibitors in cancer patients, and using non-clinical data and clinical experience with epoxetine, hyperglycemia, stomatitis / oral mucositis, rash, diarrhea / colitis, and pneumonia are safety concerns associated with the use of epoxetine. Given that such adverse events may require dose interruption and / or dose reduction, or may lead to life-threatening situations, close monitoring and reliable risk mitigation strategies are necessary.

[0246] Hyperglycemia – Effects on glucose and / or insulin metabolism are known effects of PI3K inhibitors. In toxicology studies in rats and dogs, increased glucose was observed at all tested doses and appears to be dose-dependent. Patients receiving sefliximab have reported hyperglycemia and are not identified as having a risk associated with sefliximab. Therefore, patients with type 1 or type 2 diabetes requiring drug treatment and those with elevated fasting blood glucose at baseline (fasting blood glucose > 140 mg / dL or HbA1c ≥ 7%) will be excluded. Fasting blood glucose levels will be assessed at baseline and monitored. Patients should be advised to report symptoms associated with hyperglycemia, such as polydipsia, polyuria, polyphagia, blurred vision, or symptoms associated with acidosis, such as rapid or shallow breathing, confusion, fatigue, headache, or drowsiness. Metformin should be given to patients as a first-line treatment for hyperglycemia.

[0247] Stomatitis and oral mucositis. Treatment of related stomatitis / oral mucositis has been reported with the use of levamisole. Patients should be advised to report symptoms immediately. Intervention should begin at the earliest sign of oral mucosal inflammation. If available topically, the use of an alcohol-free dexamethasone mouthwash (0.5 mg dexamethasone per 5 mL) is recommended for the prevention or treatment of stomatitis / mucositis. According to the SWISH study (Rugo et al. 2017), patients can begin use concurrently with study treatment, four times daily for eight weeks (rinsing 10 mL for 2 minutes and spitting out), and / or reactively at the first appearance of symptoms. Other mouthwash formulations may be used (e.g., combinations of local anesthetics, antihistamines, corticosteroids, antacids, antifungals, and / or antibiotics) or topical corticosteroids (e.g., acetone-fluoxetine 0.05%-0.5%, acetone-fluoxetine 0.025%-0.05%, clobetasol propionate 0.025%). Patients should avoid products containing alcohol, hydrogen peroxide, iodine, or thyme, as these may worsen their condition. They should also avoid using irritating mouthwashes (e.g., Listerine®). Dietary adjustments should be made (e.g., avoiding spicy foods).

[0248] Gastrointestinal toxicity. GI inflammation was observed in a 4-week sefliximab toxicology study in dogs. Patients with inflammatory bowel disease (such as Crohn's disease or ulcerative colitis) and active bowel inflammation (such as diverticulitis) will be excluded. GI effects will be closely monitored through medical history and physical examination. The occurrence of clinically significant changes in abdominal pain, nausea, vomiting, and stool (such as diarrhea or bloody stools) may require more frequent monitoring, and the study drug may need to be discontinued if symptoms impair normal function. Clinical evaluation should be conducted to determine the infectious (e.g., Clostridium difficile, enteric bacteria, and cytomegalovirus) or inflammatory (e.g., inflammatory colitis) cause of diarrhea.

[0249] Dermatological events. Treatment-associated rashes with other PI3K inhibitors have been reported in clinical studies, typically presenting as maculopapular rashes, with or without pruritus. Rash and other dermatological events should be closely monitored and managed according to standards of care.

[0250] Other potential risks of using Ivlixi:

[0251] Pulmonary inflammation / pneumonia. In a 4-week toxicology study of levamisole in dogs, pulmonary inflammation was observed at the highest tested dose. This finding was observed only at doses considered intolerable in this species. Interstitial pulmonary inflammation / pneumonia has been observed in clinical studies using other PI3K inhibitors.

[0252] Immunosuppressive Effects. Immunosuppression and increased risk of infection are known to be associated with commercially available PI3K / mTOR pathway inhibitors. Toxicological studies have shown decreased reticulocyte, leukocyte, and absolute lymphocyte counts in animals treated with effluxit. Patients with HIV or immunodeficiency due to immunosuppressive therapy will be excluded. Patients will be monitored regularly for changes in circulating blood counts, including differential white blood cell counts, and should be monitored for fever and signs of infection.

[0253] Reproductive effects. In a 4-week repeated-dose toxicity study, potential adverse effects on male reproductive function were observed in one or more dogs, including localized densification of the seminiferous tubule contents and multinucleated spermatocytes in the testes, and epithelial cell degeneration / necrosis in the epididymis. At the end of the 4-week recovery period, localized densification of the seminiferous tubule contents persisted in one animal.

[0254] Ocular toxicity. In a 4-week toxicology study in rats, lens lesions were observed in the highest dose group of epefliximab (10 mg / kg; 4 out of 30 rats). This finding was characterized by minimal to mild lens fiber swelling, lens fiber separation, and / or subcapsular protein accumulation. It is unclear whether this lens finding was a direct effect of epefliximab or an indirect effect secondary to the significant hyperglycemia observed in this dose group. No epefliximab-related ocular findings were observed in rats at lower doses. In dogs, ocular-related findings included inflammation and lens fiber swelling. In dogs treated with epefliximab (1.5 mg / kg, reduced to 1.0 mg / kg) for 3 months, ocular inflammation was limited to localized, minimal neutrophilic infiltration at the corneal-limbal junction stroma. In a 4-week study in dogs, neutrophilic infiltrates in the marginal and scleral regions, mild endophthalmitis, and low-grade uveitis were observed in the highest dose group (treated with 5 mg / kg and reduced to 3 mg / kg) (this dose was considered intolerable). These findings were reversible and may be part of a systemic, widespread inflammatory condition. In a 3-month toxicity study, bilateral, reversible, very mild swelling of the lens fibers in the equatorial region was observed in one male and one female at 0.3 mg / kg and one male and one female treated with 1.5 mg / kg and reduced to 1.0 mg / kg in dogs administered ≥ 0.3 mg / kg of efliximab. Patients with any concurrent ocular or intraocular conditions (such as cataracts or diabetic retinopathy) requiring medical or surgical intervention were excluded. In addition, patients with active uveitis or vitreitis, a history of uveitis, or an active infection process in the eye will also be excluded.

[0255] Treatment Interruption. If GDC-6036 is discontinued from previous study treatment for more than 21 days due to toxicity, the study treatment should not be restarted. For unexpected medical events unrelated to study treatment toxicity or disease progression, GDC-6036 may be suspended for up to 21 days.

[0256] Adverse Events. An adverse event, as defined herein, refers to any adverse medical event in a clinical study subject who was administered the drug described herein in combination therapy, regardless of causal attribution. The terms “severe” and “serious” are not synonyms. Severity refers to the intensity of an adverse event (e.g., based on mild, moderate, or severe, or based on the NCI CTCAE classification); the event itself may have relatively minor medical significance (e.g., severe headache without any further findings).

[0257] Adverse events to be monitored include nausea, vomiting, diarrhea, stomatitis, mucositis, hepatitis or elevated ALT or AST, elevated bilirubin or clinical jaundice, systemic lupus erythematosus, nephritis, events suggestive of anaphylaxis, reactions to infusion media, CRS, influenza-like illness, systemic inflammatory response syndrome, atrial fibrillation, myocarditis, pericarditis, vasculitis, myositis, uveitis, retinitis, optic neuritis, autoimmune hemolytic anemia, Stevens-Johnson syndrome, bullous dermatitis, and toxic epidermolysis.

[0258] The following are adverse events of particular concern specific to Ivliximab: ≥ Grade 3 hyperglycemia; ≥ Grade 3 rash; ≥ Grade 3 diarrhea; ≥ Grade 2 pneumonia; ≥ Grade 2 colitis or enterocolitis; ≥ Grade 3 stomatitis or mucosal inflammation; ≥ Grade 3 elevated ALT or AST.

[0259] Throughout this specification and request, the terms "comprising," "containing," and "containing" are used in a non-exclusive sense unless the context requires otherwise. It should be understood that the embodiments described herein include embodiments "consisting of" and / or "substantially constituting of." It should further be understood that the expression "GDC-6036" as used herein refers to the free base compound and GDC-6036-adipate or other pharmaceutically acceptable salts thereof.

[0260] Essentially, where a range of values ​​is provided, it should be understood that, unless the context explicitly specifies otherwise, each intervention value within the upper and lower limits of that range, along with any other said or intervention range, is within the scope covered herein, up to one-tenth of the lower limit unit. The upper and lower limits of such smaller ranges may be independently included in the definition of a smaller range, which also covers any explicitly excluded restrictions within said range. Where said range includes one or two restrictions, the range excluding any or both of the included restrictions is also included herein.

[0261] Thanks to the teachings presented in the foregoing description and related illustrations, those skilled in the art will conceive of numerous modifications and other embodiments of the invention described herein. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terminology is used herein, it is for general and descriptive purposes only and not for limiting purposes. [Simplified Explanation of the Diagram]

[0015] Figure 1 depicts fitted tumor volumes after treatment with GDC-6036 alone, GDC-0077 alone, or the combination of GDC-6036 and efliximab. NCI-H2122 showed low sensitivity to KRAS-G12C inhibition; the maximum effect was stagnant. GDC-6036 alone: ​​TGI=93%; GDC-0077 alone: ​​TGI=74%; combination: TGI=113%. Figure 2 depicts changes in body weight after administration of GDC-6036 alone, GDC-0077 alone, or the combination of GDC-6036 and efliximab. All treatments were well tolerated. Figures 3A-3H depict the synergistic effects of the GDC-6036+GDC-0077 combination on various NSCLC KRas G12C mutant cell lines. (Figure 3A = H23P; Figure 3B = YSE410; Figure 3C = H1792; Figure 3D = H2122; Figure 3E = HOP62; Figure 3F = H2030; Figure 3G = HCC4017; and Figure 3H = HCC4019). Figure 4 depicts fitted tumor volumes in the CR5048 CRC xenograft model treated with GDC-6036 alone, GDC-0077 alone, or a combination of GDC-6036 and efliximab. Figures 5A–5C depict the synergistic effects of the combination of GDC-6036 and GDC-0077 on various CRC KRas G12C mutant cell lines. (Figure 5A = SW1463; Figure 5B = SW837; and Figure 5C = HCC1263).

Claims

1. Use of a pharmaceutical composition for the preparation of a pharmaceutical product for treating patients with non-small cell lung cancer (NSCLC) mediated by KRasG12C mutation, wherein the pharmaceutical composition comprises: (a) GDC-6036, or a pharmaceutically acceptable salt thereof, administered QD at a dose of 50 mg to 500 mg on days 1 to 21 of a first 21-day cycle according to a dosing regimen comprising one or more 21-day cycles; and (b) Ivliximab, or a pharmaceutically acceptable salt thereof, administered QD at a dose of about 3 mg, 6 mg, or 9 mg according to the dosing regimen comprising one or more 21-day cycles.

2. As requested in claim 1, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.

3. Use of a pharmaceutical composition for the preparation of a medicine for treating patients with colorectal cancer (CRC) mediated by KRasG12C mutation, wherein the pharmaceutical composition comprises: (a) GDC-6036, or a pharmaceutically acceptable salt thereof, administered QD in amounts from 50 mg to 500 mg according to a dosing regimen comprising one or more 21-day cycles; and (b) Ivliximab, or a pharmaceutically acceptable salt thereof, administered QD in amounts of about 3 mg, 6 mg, or 9 mg according to the dosing regimen comprising one or more 21-day cycles.

4. As requested in claim 3, wherein the cancer is metastatic colorectal cancer.

5. As claimed in claim 1 or 3, wherein the treatment further comprises: (a) determining the presence of a KRasG12C mutation in a sample taken from a patient suspected of having cancer; and (b) administering the pharmaceutical composition to the patient.

6. As requested in paragraph 1 or 3, wherein the dosing regimen includes a period during which neither GDC-6036 nor levamisole is administered, or both.

7. As used in claim 1 or 3, wherein GDC-6036 is its adipic acid salt.

8. For the purposes described in claim 1 or 3, wherein GDC-6036 or its pharmaceutically acceptable salt is administered orally in tablet or capsule form.

9. As requested in paragraph 1 or 3, wherein GDC-6036 or its pharmaceutically acceptable salts are administered in amounts of approximately 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg.

10. As requested in paragraph 1 or 3, wherein GDC-6036 or its pharmaceutically acceptable salt is administered in amounts of approximately 100 mg, 200 mg or 400 mg.

11. As requested in paragraphs 1 or 3, wherein GDC-6036 or its pharmaceutically acceptable salt is administered in an amount of approximately 200 mg.

12. As requested in paragraphs 1 or 3, wherein GDC-6036 or its pharmaceutically acceptable salt is administered in an amount of approximately 400 mg.

13. As requested in paragraph 1 or 3, wherein seftiofur is administered in a dose of 6 mg.

14. As requested in paragraphs 1 or 3, wherein levamisole is administered in a dose of 9 mg.

15. As requested in item 1 or 3, wherein the patient was not evaluated for the presence of the PIK3CA mutant prior to administration.

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