Combination Study of RMC-4630 and Sotorasib for NSCLC Subjects with KRASG12C Mutation After Failure of Prior Standard Therapies

Phase 1

• Conditions: on-Small Cell Lung Cancer Subjects with KRASG12C Mutation After Failure of Prior Standard Therapies; MedDRA version: 21.1Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2021-003254-23-FR
• Lead Sponsor: Revolution Medicines, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-12-22
• Last Update Posted: 2 September 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

1. Subject must be =18 years of age at the time of signing the informed consent form (ICF).
2. 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 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.
3. Subject must have measurable disease per RECIST v1.1, criteria.
4. Subject must have a life expectancy of at least 3 months.
5. The subject’s ECOG PS of 0 to 1 with no deterioration in PS 2 weeks prior to C1D1. Rescreening is required if PS is >1 for any reason prior to C1D1.
6. Subject must have the ability to typically ingest and retain PO medications.
7. 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 (<2.0 × ULN for subject with documented Gilbert’s
syndrome or <3.0 × ULN for subject for whom the indirect bilirubin level suggests an extrahepatic source of elevation)
c. Subject must have renal function as follows: Serum creatinine =1.5 × ULN or creatinine clearance (CrCl) of >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).
8. 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.
9. Male subject is eligible to participate if he agrees to the following during the treatment period and for =3 months after the last dose of study treatment:
a) Refrains from donating sperm (any donation of sperm should be conducted prior to study start) PLUS, either:
b) Abstain from intercourse as his preferred and usual lifestyle (abstinent on a longterm and persistent basis) and agree to remain abstinent, OR
c) Must a

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, a subject who was previously treated for these conditions who have had stable CNS diseases are eligible to participate in the study, as long as stable disease is documented by a brain MRI performed within 28-days (D) 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 <50%, whichever is lower.
4 Any prior history of (or active) ILD or pneumonitis, or prior thoracic radiotherapy within 2M of enrollment.
5 Subject has a history or current evidence of retinal pigment epithelial detachment (RPED), central serous retinopathy, retinal vein occlusion (RVO), or predisposing factors to RPED or RVO
6 Visible retinal pathology as assessed on ophthalmic examination that is considered a significant risk factor for RVO or RPED by ophthalmologist
7 Have of Grade =2 proteinuria
8 Have a history of cerebrovascular accident or transient ischemic attack previous 6M of signing the ICF
9 Have a known activating SHP2 mutation
10 Have an active autoimmune disease requiring systemic treatment within the past 2 years of signing the ICF; includes current autoimmune sequelae or previous Grade >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, and/or impact their ability to comply with the protocol. Any subject who had a pulmonary embolism within 3M of C1D1 will also 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 C1

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified