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Study of Avutometinib, Sotorasib, and Defactinib for Patients with KRAS G12C Mutant Non-Small Cell Lung Cancer

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is focused on studying a type of lung cancer known as Non-Small Cell Lung Cancer (NSCLC) that has a specific mutation called KRAS G12C. The study is testing a combination of treatments to see how effective they are in treating this type of cancer. The treatments being studied include Avutometinib (VS-6766), Sotorasib, and possibly Defactinib. These medications are taken orally, meaning they are swallowed in the form of capsules or tablets.

The purpose of the study is to find the best dose of these medications when used together and to see how well they work in treating the cancer. The study is divided into two parts. In the first part, different doses of the medications are tested to find the most suitable one. In the second part, the effectiveness of the chosen doses is evaluated. Some participants may receive a combination of Avutometinib and Sotorasib, while others may also receive Defactinib. A placebo may be used in some cases.

Participants in the study will take the medications and be monitored for any side effects or changes in their cancer. The study will look at how long the cancer stays under control, how long the benefits of the treatment last, and overall survival rates. The trial is expected to continue until early 2026, with the aim of providing valuable information on the treatment of KRAS G12C mutant NSCLC.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Joining the study
Upon joining the study, the patient will be informed about the trial's purpose and procedures. The patient must meet specific criteria, such as being 18 years or older and having a confirmed KRAS G12C mutation in non-small cell lung cancer (NSCLC).
Step 2
Part A: dose evaluation
The patient will participate in the dose evaluation phase to determine the optimal combination of medications. This involves taking avutometinib (VS-6766) and sotorasib (LUMYKRAS 120 mg film-coated tablets) orally. The exact dosage and frequency will be adjusted to find the recommended phase 2 dose (RP2D).
During this phase, the patient will be monitored for any dose-limiting toxicities and adverse events. Regular physical examinations and laboratory tests will be conducted to ensure safety and tolerability.
Step 3
Part B: dose expansion
Once the RP2D is established, the patient will enter the dose expansion phase. The goal is to evaluate the effectiveness of the treatment at the determined dose.
The patient will continue to take the medications orally as prescribed. The response to the treatment will be assessed using criteria such as partial or complete response, stable disease, and progression-free survival.
Step 4
Monitoring and follow-up
Throughout the trial, the patient will undergo regular monitoring to track any adverse events and the overall response to the treatment. This includes physical examinations, laboratory tests, and assessments of disease progression.
The patient's overall survival and clinical benefit rate will be evaluated, considering factors like the duration of response and disease control rate.
Step 5
End of trial
The trial is expected to conclude by February 28, 2026. At the end of the trial, the patient will have a final assessment to determine the overall outcomes and any long-term effects of the treatment.

Who can join the trial?

21 criteria

Must be a male or female patient who is 18 years of age or older.
Must have a type of lung cancer called non-small cell lung cancer (NSCLC) that is either spread to other parts of the body (metastatic) or is advanced and cannot be removed by surgery.
Must have a specific genetic change called a KRAS G12C mutation, confirmed by a test.
Must have received certain cancer treatments before, such as immunotherapy or chemotherapy, and possibly targeted therapy for specific genetic changes.
Must have had at least one, but no more than two, previous treatments for advanced lung cancer.
May have had chemotherapy after surgery for early-stage disease, but it won't count as a previous treatment unless the cancer came back during or shortly after the treatment.
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For patients who have used a G12C inhibitor before:
- In Part A of the study, patients can have used a G12C inhibitor before or not. If they have, they must have shown some improvement or stable disease for at least four treatment cycles.
- In Part B, Cohort 1, patients must not have used a G12C inhibitor before.
- In Part B, Cohort 2, patients must have shown some improvement or stable disease for at least four treatment cycles if they used a G12C inhibitor before.
- Must have measurable disease, meaning the cancer can be measured using specific criteria.
- Must have a performance status of 0 or 1, which means they are fully active or have some symptoms but can still do light work.
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  Must have adequate organ function, which includes:
  - Enough healthy blood cells, including hemoglobin, platelets, and neutrophils.
  - Proper liver function, with certain liver tests within normal limits.
  - Proper kidney function, with a creatinine clearance rate of at least 50 mL/min.
  - Normal blood clotting ability, unless on blood thinners.
  - Normal levels of a protein called albumin in the blood.
  - Normal levels of an enzyme called creatine phosphokinase (CPK).
  - Proper heart function, with a heart pumping ability of at least 50%.
  - Must have a normal heart rhythm, with a specific measurement called QTc interval within normal limits.
  - Must have recovered from any side effects of previous treatments to a mild level, except for hair loss or mild nerve damage.
  - If able to have children, must agree to use effective birth control during the study and for a certain period after the last dose of the study treatment.

Who cannot join the trial?

8 criteria

Patients with other types of cancer besides non-small cell lung cancer cannot participate. Non-small cell lung cancer is a type of lung cancer.
Patients who are not within the specified age range for the study cannot participate. The study is for certain age groups only.
Patients who are not able to follow the study procedures or take the study medications as required cannot participate.
Patients who have certain medical conditions that might interfere with the study cannot participate. These conditions are not specified but are determined by the study team.
Patients who are pregnant or breastfeeding cannot participate in the study.
Patients who have participated in another clinical trial recently may not be eligible to participate.
Patients who have allergies or reactions to the study medications cannot participate.
Patients who have a history of certain heart conditions or other serious health issues may not be eligible to participate.

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Verified sites

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Responsive
Academisch Ziekenhuis Leiden
Leiden, The Netherlands
Responsive
Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
Rotterdam, The Netherlands
Responsive
Universitair Ziekenhuis Gent
Gent, Belgium

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Investigated drugs

Avutometinib (VS-6766)
is a medication being studied for its potential to treat non-small cell lung cancer that has a specific mutation known as KRAS G12C. It is being tested to find the best dose that can be used in combination with another medication to see if it can effectively help patients with this type of cancer.
Sotorasib
is another medication involved in the study, which is already known for its ability to target the KRAS G12C mutation in non-small cell lung cancer. In this trial, it is being combined with avutometinib to see if the two medications together can provide better results for patients with this specific cancer mutation.

What is already known about the treatment

Avutometinib
Avutometinib is administered orally and is currently being studied in clinical trials for its potential use in treating non-small cell lung cancer, particularly in patients with the KRAS G12C mutation. It is not yet widely recognized in medical literature as a standard treatment. The medication works by inhibiting specific proteins involved in cell growth and division, which may help slow down or stop the growth of cancer cells. Avutometinib is classified as a targeted cancer therapy.
Sotorasib
Sotorasib is taken orally and is approved for use in treating non-small cell lung cancer with the KRAS G12C mutation. It is well-documented in medical literature as a targeted therapy. Sotorasib functions by specifically inhibiting the KRAS G12C protein, which plays a role in the growth and survival of cancer cells. It belongs to the class of targeted cancer therapies.

Investigated diseases

Non-small cell lung cancer – This is a type of lung cancer that includes several subtypes, such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. It is the most common type of lung cancer, accounting for about 85% of all cases. The disease typically begins in the tissues of the lungs and can spread to other parts of the body. Symptoms may include a persistent cough, chest pain, and shortness of breath. As the disease progresses, it may lead to more severe respiratory issues and other systemic symptoms. Early detection is crucial for managing the disease effectively.