Phase 1/2 Evaluation of Avutometinib and Sotorasib in KRAS G12C Mutant Non-Small Cell Lung Cancer Patients
- Trial ID
- 2023-505107-24-00
- Protocol
- VS-6766-203
- Sponsor
- Verastem Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **Recommended Phase 2 Dose (RP2D)** for the combination of avutometinib and sotorasib in patients with **KRAS G12C mutant non-small cell lung cancer (NSCLC)**. This involves evaluating the optimal combination regimen in Part A and subsequently assessing its efficacy in the expansion phase, Part B. Establishing the RP2D is clinically relevant as it guides the dosing strategy for further efficacy evaluations, potentially improving therapeutic outcomes for patients with this specific genetic mutation in NSCLC.
Secondary objectives include:
- Characterizing the safety and toxicity profile of avutometinib in combination with sotorasib in KRAS G12C mutant NSCLC.
- Evaluating additional efficacy parameters for the optimal regimen identified in Part A.
- Determining the pharmacokinetics (PK) of avutometinib, sotorasib, defactinib, and relevant metabolites.
Participants
The clinical trial involves a total of **105 participants** diagnosed with **non-small cell lung cancer**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including adequate organ function and a known KRAS G12C mutation. The trial population is characterized by individuals who have previously received anti-programmed cell death protein 1 or anti-programmed death-ligand 1 immunotherapy and/or platinum-based combination chemotherapy, as well as targeted therapy for actionable oncogenic driver mutations. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not specify particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have measurable disease according to RECIST 1.1 criteria and have recovered from prior treatment-related toxicities to at least Grade 1, with exceptions for alopecia and peripheral neuropathy. The study includes a vulnerable population, ensuring comprehensive evaluation and monitoring throughout the trial.
Plans and Procedures
The clinical trial is designed to evaluate the combination of **avutometinib** and **sotorasib** in patients with **non-small cell lung cancer** (NSCLC) harboring the KRAS G12C mutation. This study is structured as a Phase 1/2 trial, incorporating a randomized, double-blind, and controlled methodology. The trial is divided into two parts: Part A focuses on dose evaluation to determine the Recommended Phase 2 Dose (RP2D) for the combination regimen, while Part B aims to assess the efficacy of the RP2D. The estimated duration of the trial extends until February 2026, with recruitment having commenced in September 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, organ function, and prior treatment history. Following successful screening, participants will enter the treatment phase, where they will receive the investigational drugs orally. Regular follow-up visits will be scheduled to monitor safety, tolerability, and response to treatment, including assessments of dose-limiting toxicities, adverse events, and clinical laboratory values. The end-of-study visit will conclude the participant's involvement, during which final evaluations will be conducted to assess overall response and any long-term effects of the treatment.
The expected length of participant involvement in the trial is contingent upon individual response and tolerability, with conditions for early termination including significant adverse events or disease progression. Participants are required to adhere to the study protocol, including the use of effective contraception, and must demonstrate adequate recovery from prior treatment-related toxicities. The primary endpoints of the trial include the determination of dose-limiting toxicities and the overall response rate, while secondary endpoints encompass measures such as progression-free survival and overall survival. The trial aims to provide valuable insights into the potential therapeutic benefits of the combination regimen in this specific patient population.
Treatment
The clinical trial involves the administration of **LUMYKRAS** 120 mg film-coated tablets, which contain the active substance **sotorasib**. This medication is provided in the form of film-coated tablets and is intended for **oral use**. The dosage and frequency of administration are determined based on the trial protocol, with the aim of evaluating its efficacy in combination with other treatments. The product is manufactured by Amgen Europe B.V. and is authorized under the marketing authorization number EU/1/21/1603/001. The chemical origin of the active substance ensures its purity and consistency for clinical use.
Another experimental medication used in the trial is **VS-6766**, which contains the active substance **avutometinib**. This medication is provided in the form of hard capsules and is also administered orally. The trial seeks to determine the optimal dosage regimen for avutometinib in combination with sotorasib. The product is developed by Verastem, Inc., and is identified by the sponsor product code VS-6766. The chemical nature of avutometinib ensures its stability and effectiveness in the trial setting.
The trial also includes the administration of **VS-6063**, which contains the active substance **defactinib**. This medication is provided in tablet form and is administered orally. The trial aims to assess the efficacy of defactinib in combination with other investigational drugs. The product is manufactured by Verastem, Inc., and is identified by the sponsor product code VS-6063. The chemical origin of defactinib supports its use in a controlled clinical environment.
All medications in this trial are administered orally, and participant compliance is monitored according to the study protocol. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective is to determine the recommended phase 2 dose (RP2D) for the combination of avutometinib and sotorasib, followed by an evaluation of efficacy in the expansion phase.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Part A of the trial include the evaluation of dose-limiting toxicities (DLTs), adverse events (AEs), serious adverse events (SAEs), physical examinations, clinical laboratory values, and tolerability, which will be measured by dose interruptions or reductions. For Part B, the primary endpoint is the confirmed Objective Response Rate (ORR), which is defined as the sum of partial response (PR) and complete response (CR) according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
Secondary endpoints include the assessment of adverse events, serious adverse events, physical examinations, clinical laboratory values, and tolerability, similar to the primary endpoints. Additional secondary endpoints are the Duration of Response (DOR), Disease Control Rate (DCR) defined as the sum of complete response, partial response, and stable disease, and Clinical Benefit Rate (CBR), which includes complete response, partial response, and stable disease lasting at least 6 months. Progression-Free Survival (PFS) is defined as the time from the first dose of study treatment to the first documentation of progressive disease or death from any cause. Overall Survival (OS) will also be measured. Pharmacokinetic (PK) parameters will be derived from plasma concentrations of **avutometinib**, **sotorasib**, **defactinib**, and relevant metabolites.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female patients ≥ 18 years of age.
- 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).
- 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.
- 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.
- 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.
- The patient may have previously received adjuvant chemotherapy for early-stage disease. Adjuvant or neoadjuvant chemotherapy-based regimens in early stages will not count as prior regimen unless disease progression occurred during or within 3 months following the last dose of therapy.
- For prior G12C inhibitor use: a). Part A (avutometinib + sotorasib): Either prior G12C inhibitor exposure or no exposure is allowed. If prior G12C inhibitor use, must have had a best response to prior G12C inhibitor of confirmed response (CR or PR) by RECIST 1.1 or SD for ≥4 cycles. b). Part B, Cohort 1: No prior therapy with G12C inhibitor. c). Part B, Cohort 2: Must have received prior G12C inhibitor for at least 12 weeks
- Measurable disease according to RECIST 1.1.
- An Eastern Cooperative Group (ECOG) performance status ≤ 1.
- 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.
- 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.
- 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.
- 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.
Exclusion Criteria
- 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.
- Active skin disorder that has required systemic therapy within the past 1 year.
- History of rhabdomyolysis.
- 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.
- History of interstitial lung disease (ILD).
- 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 history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO. c). Patients with active or chronic visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions.
- History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.
- Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
- Patients with a history of hypersensitivity to any of the active (avutometinib or sotorasib as applicable) or inactive (croscarmellose sodium, hydroxypropyl methylcellulose, lactose monohydrate, mannitol, magnesium stearate, microcrystalline cellulose) ingredients of the investigational products.
- Female patients who are pregnant or breastfeeding.
- Any other medical condition (e.g. cardiac, gastrointestinal, pulmonary, psychiatric, neurological, genetic, etc.) that in the opinion of the investigator would place the patient at unacceptably high risk for toxicity.
- History of treatment with a direct and specific inhibitor of MEK.
- Major surgery within 4 weeks, minor surgery within 2 weeks, (excluding placement of vascular access), or palliative radiotherapy within 1 week of the first dose of study therapy.
- Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants.
- 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).
- Part A and Part B: Leptomeningeal metastases or active CNS metastases are excluded. However, subjects who have had brain metastases resected or have received radiation therapy ending at least 4 weeks prior to Study Day 1 are eligible if they meet all of the following criteria: a. residual neurological symptoms grade ≤ 2; b. on stable doses of corticosteroids, if applicable; and c. follow-up MRI shows no new lesions appearing.
- 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.
- Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with study interventions within 14 days prior to the first dose of study intervention and during the course of therapy, including: a. Strong CYP3A4 inducers, due to potential drug-drug interactions with sotorasib. See Table 22, and Table 23 for representative lists of CYP3A4 inhibitors, inducers, and substrates. b. Sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy.
- Weight loss >10% within 4 weeks prior to first dose of study therapy.
- Known severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection (clinical symptoms) ≤ 28 days prior to first dose of study therapy.
- Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and/or requires therapy.
- Patients that were previously treated with sotorasib and were dose reduced due to toxicity.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Sept 2023 | 12 |
 France | Not Recruiting | 01 Sept 2023 | 12 |
 The Netherlands | Not Recruiting | 01 Sept 2023 | — |
 Spain | Not Recruiting | 01 Sept 2023 | 12 |
| Netherlands | — | — | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
LUMYKRAS 120 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | — | — | PRD9412069 |
VS-6766 | Test | CAPSULE, HARD | ORAL USE | — | — | PRD8431568 |
VS-6063 | Test | TABLET | ORAL USE | — | — | PRD871319 |