Non-Small Cell Lung Cancer Subjects with KRASG12C Mutation After Failure of Prior Standard Therapies MedDRA version: 21.1 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Revolution Medicines, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subject must be =18 years of age at the time of signing the ICF. 2. Subject is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 3. Subject must have pathologically documented, locally advanced or metastatic KRASG12C NSCLC (not amenable to curative surgery) that has progressed on prior standard therapies (no more than 3 prior lines of therapies are allowed), as follows: a. Subject with actionable oncogenic driver mutations (eg, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase [ALK], and reactive oxygen species proto-oncogene 1 [ROS1)] must have received standard-of-care anticancer treatments, including approved drugs for oncogenic drivers in their tumor type. b. Subject’s tumor must harbor a KRASG12C mutation assessed by a CLIA-/CAP-certified laboratory or equivalent per region. c. Subjects with locally advanced KRASG12C NSCLC must have received prior radio-chemotherapy followed by immunotherapy (applicable only in France) 4. Subject must have measurable disease per RECIST v1.1, criteria. 5. Subject must have a life expectancy of at least 3 months. 6. The subject’s ECOG PS of 0 to 1 with no deterioration in PS at 2 weeks prior to C1D1. Rescreening is required if PS is >1 for any reason prior to C1D1. 7. Subject must have the ability to typically ingest and retain PO medications. 8. Subject must have adequate hematological and biological function, as follows: a. Bone marrow function: i. Absolute neutrophil count (ANC) =1.5 × 109/L without use of hematopoietic growth factors ii. Hemoglobin =9 g/dL; subject must not have received a red blood cell (RBC) transfusion within 28 days of Screening iii. Platelets =100 × 109/L; subject must not have received a platelet transfusion within 14 days of Screening b. Subject must have hepatic function as follows: i. AST and ALT =2.5 × upper limit of normal (ULN) ii. Bilirubin =1.5 × ULN (50 mL/min (using the Cockcroft-Gault formula or 24-hour urine collection) d. Subject must have coagulation function as follows: Prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) <1.3 × ULN, or within target range if taking prophylactic anticoagulant(s). 9. Female subject is eligible to participate if she meets the following criteria: a. Is not a woman of childbearing potential (WOCBP), OR b. Is a WOCBP and using a contraceptive method that is highly effective (ie, with a failure rate of <1% per year), preferably with low user dependency, during the treatment period and for at least 2 months after the last dose of study treatment and agree not to donate eggs (ie, ova and oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment. Hormonal contraception efficacy may potentially be decreased due to interaction with sotorasib; therefore, male condoms must be used in addition to any hormonal-based contraception methods. 10. Male subject is eligible to participate if he agrees to the foll
Exclusion criteria
Exclusion criteria: Subjects with: 1.Primary central nervous system tumor(s) 2 Have known or suspected leptomeningeal or brain metastases or spinal cord compression. However, subjects who were previously treated for these conditions who have had stable CNS diseases are eligible to participate in the study, as long as SD is documented by a brain MRI performed within 28 days of C1D1 3 Have any of the following cardiac abnormalities: a Medically uncontrolled hypertension b Congestive heart failure Class =2 c Acute coronary syndrome; myocardial infarction within 6M of ICF, d History or evidence of current, uncontrolled, clinically significant, unstable arrhythmias: i Subject with medically controlled atrial fibrillation >1M prior to Study Day 1 is eligible. ii Subject who has a pacemaker in place to control atrial arrhythmias is a candidate for the study e History of congenital long QT syndrome or prolonged corrected QT interval (QTc) >470 msec for females and > 450 msec for males using Fridericia’s formula or uncorrectable abnormalities in serum electrolytes: i Subject may use average of triplicate readings for assessing QTc interval. ii Subject with an implantable defibrillator is not eligible to participate in the study f Current cardiomyopathy or history within in the past 12M prior to ICF g Baseline left ventricular ejection fraction below the institutional lower limit of normal or 2 autoimmune sequelae from checkpoint inhibitors or other immunomodulatory treatments that require systemic therapy. Subject with autoimmune endocrine disorder on hormonal supplementation may be enrolled, even if Grade >2 upon initial presentation, 11 Have known HIV infection 12 Have an active/chronic hepatitis B or C virus infection 13 Have a known impairment of gastrointestinal function that may significantly alter the absorption of RMC-4630 14 Have a history of severe allergic reactions 15 Have major surgical procedures =28 D or non-study-related minor procedures =7D prior to Cycle 1 Day 1 (C1D1) 16 Have any clinically significant concurrent medical condition that would, in the opinion of the investigator, jeopardize subject safety, and/or impact their ability to comply with the protocol. Any subject who had a pulmonary embolism within 3M of C1D1 will be excluded 17 Have had prior therapy with one or both of the following agents, meets criteria for exclusion: a KRASG12C inhibitor and b. SHP2 inhibitor 18 Have had treatment with chemotherapy or biologics/monoclonal antibodies <21D or 5 half-lives before C1D1 19 Have had treatment with non-thoracic radiation therapy <14D before C1D1 20 Have had treatment with tyrosine kinase inhibitor (TKI), hormonal therapy <7D before C1D1 21 Have had treatment with immunotherapy 14-21D before C1D1, depending on cycle length of drug 22 Have had trea
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the antitumor effects of RMC-4630 and sotorasib in locally advanced or metastatic NSCLC subjects with KRASG12C mutation with and without coexisting genetic aberrations in specific genes such as STK11/LKB1, KEAP1, and PIK3CA after failure of prior standard therapy;Secondary Objective: 1- To characterize the safety, tolerability, and PK of RMC-4630 in combination with sotorasib for subjects with KRASG12C mutant NSCLC after failure of prior standard therapy 2- To further characterize efficacy of RMC-4630 in combination with sotorasib as assessed by DOR, DCR, PFS, and OS in subjects with KRASG12C mutant locally advanced or metastatic NSCLC after failure of prior standard therapy Exploratory • To explore PK relationships with safety and/or efficacy endpoints • To investigate potential biomarkers by biochemical and/or genetic analysis of blood and/or tumor tissue samples;Primary end point(s): Objective response rate as assessed per Response Evaluation Criteria in Solid Tumours, Version 1.1;;Timepoint(s) of evaluation of this end point: By March 31, 2023 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Incidence, nature, and severity of treatment-emergent adverse event, SAEs, clinically significant changes in laboratory tests, ECGs, and vital signs • Trough and approximate peak concentrations of RMC-4630 and sotorasib • duration of response, disease control rate and progression-free survival as assessed per RECIST v1.1, and overall survival Exploratory • Sotorasib and RMC-4630 exposure/safety and exposure/efficacy relationships • Quantification of biomarker expression (protein, RNA, and DNA levels) as appropriate in ctDNA and archival tumor tissues (or fresh, if archival tumor is not available);Timepoint(s) of evaluation of this end point: By March 31, 2023 | — |
Countries
Australia, Canada, France, Germany, Italy, Korea, Republic of, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactClinical Program Manager, Clinical
Revolution Medicines, Inc.
Outcome results
None listed