Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib (with or without Defactinib) in G12C NSCLC Patients (RAMP203)

Phase 1

Recruiting

• Conditions: on-small cell lung cancer; MedDRA version: 21.1Level: PTClassification code: 10061873Term: Non-small cell lung cancer Class: 100000004864; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

• Registration Number: CTIS2023-505107-24-00
• Lead Sponsor: Verastem Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-07-13
• Last Update Posted: 22 July 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: All
• Target Recruitment: 153

Inclusion Criteria

1. Male or female patients = 18 years of age., 10. Must have adequate organ function defined by the following laboratory parameters: a). Adequate hematologic function including: hemoglobin (Hb) = 9.0 g/dL; platelets = 100,000/mm3; and absolute neutrophil count (ANC) = 1500/mm3. If a red blood cell transfusion has been administered the Hb must remain stable and =9 g/dL for at least 1 week prior to first dose of study therapy. b). Adequate hepatic function: (i) total bilirubin = 1.5 × upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 µmol/L) upon discussion with Medical Monitor; (ii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 × ULN (or < 5 x ULN in patients with liver metastases). c). Adequate renal function with creatinine clearance rate of = 50 mL/min as calculated by the Cockcroft-Gault formula or serum creatinine of = 1.5 ULN. d). International normalized ratio (INR) = 1.5 and partial thromboplastin time (PTT) = 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation. e). Albumin =3.0 g/dL (451 µmol/L). f). Creatine phosphokinase (CPK) = 2.5 x ULN. g). Adequate cardiac function with left ventricular ejection fraction = 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan., 11. Baseline corrected QT interval (QTc) interval < 470 ms for females and =450 ms for males (average of triplicate readings) (CTCAE Grade 1) using Fredericia’s QT correction formula. NOTE: This criterion does not apply to patients with a right or left bundle branch block., 12. Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v5.0. Exceptions include alopecia and peripheral neuropathy Grade = 2. Patients with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the Sponsor., 13. Male and female patients with reproductive potential agree to use a highly effective method of contraceptive (per Clinical Trial Facilitation Group [CTFG] recommendations in Section 11.3.1) during the trial and for 3 months following the last dose of study intervention for male patients, and 1 month following the last dose of study intervention for female patients., 2. Histologic or cytologic evidence of NSCLC without histological evidence of a small cell or neuroendocrine components that are either metastatic (Stage 4) or locally advanced (Stage 3B-C) and unresectable (IASLC 8th edition)., 3. Patients must have a known KRAS G12C mutation determined using a validated test prior to enrollment. Adequate material (as defined in the lab manual) must be available prior to study therapy to be used for central confirmation of KRAS mutation status. Central confirmation does not need to be completed prior to enrollment., 4. The patient must have received, in any setting, anti-programmed cell death protein 1 or anti-programmed death-ligand 1 immunotherapy (unless not indicated) AND/OR platinum-based combination chemotherapy; AND targeted therapy for actionable oncogenic driver mutations (ie, EGFR, ALK, and ROS1) excluding KRAS G12C., 5. The patient must have received appropriate treatment with at least 1 prior systemic regimen, but no more than 2 prior systemic regimens, for Stage 3B-C or 4 NSCLC., 6. The patient may have previously received adjuvant chemotherapy for early-stage disease. Adjuvant or neoadjuvant chemotherapy-based regimen

Exclusion Criteria

1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy except sotorasib or another KRAS G12C inhibitor for Part A or Cohort 2 in Part B which must be discontinued at least 6 days prior to Day 1 of study therapy., 5. History of treatment with a direct and specific inhibitor of MEK., 6. History of treatment with a KRAS G12C inhibitor in order to be enrolled in the cohort evaluating the combination in those patients who are G12C inhibitor treatment naive (Cohort 1)., 9. Part A: Leptomeningeal metastases or any central nervous system (CNS) metastases. Part B: Leptomeningeal metastases. Any active CNS metastases <4 weeks prior to first dose of study therapy. Active” is defined as any symptomatic, <4-week washout from any therapy such as radiation, surgery or corticosteroids, neurological instability attributable to such metastases, or evidence of interim progression. Patients with new asymptomatic brain metastases must receive radiation therapy and/or surgery for brain metastases. Following treatment, these patients may then be eligible if all other criteria are met., 7. Use of proton pump inhibitors (PPIs) within 3 days and H2 receptor antagonists within 1 day prior to Study Day 1 and during time on study.., 8. Exposure to medicines (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interaction with study interventions within 14 days prior to the first dose of study intervention and during the course of therapy, including: a). Strong CYP3A4 inhibitors or inducers, due to potential drug-drug interactions with sotorasib (CYP3A4 inducer only), avutometinib and defactinib. See Table 26, Table 27, and Table 28 for representative lists of CYP3A4 inhibitors and inducers and substrates. b). Strong CYP2C9 inhibitors or inducers, due to potential drug-drug interactions with defactinib. This exclusion only applies to patients treated with defactinib. See Table 26, Table 27, and Table 28 for representative lists of CYP2C9 inhibitors and inducers. c). Strong P-glycoprotein (P-gp) inhibitors or inducers or sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy. See Table 29 for representative lists of P-gp inhibitors and inducers. d). Exposure to strong Breast Cancer Resistance Protein (BCRP) inhibitors or inducers within 14 days prior to the first dose and during the course of therapy. See Table 30 for representative lists of BCRP inhibitors., 10. Weight loss >10% within 4 weeks prior to first dose of study therapy., 11. Known severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection (clinical symptoms) = 28 days prior to first dose of study therapy., 12. Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and/or requires therapy., 13. Active skin disorder that has required systemic therapy within the past 1 year., 14. History of rhabdomyolysis., 17. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or severe obstructive pulmonary disease., 15. History of interstitial lung disease (ILD)., 16. Concurrent ocular disorders: a). Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes. b). Patient with hi

Study & Design

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