Phase II Study of Adagrasib + Stereotactic Radiosurgery (SRS) for Patients With Metastatic KRAS G12C-mutated NSCLC With Untreated Brain Metastases

Plain English Summary

Adagrasib + SRS for Patients With Metastatic KRAS G12C-mutated NSCLC With Untreated Brain Metastases is a Phase 2 clinical trial sponsored by Ryan Gentzler, MD studying Non Small Cell Lung Cancer, NSCLC, KRAS G12C. This trial tests a combination of a targeted drug called adagrasib and a focused radiation treatment (stereotactic radiosurgery) for lung cancer that has spread to the brain. It is for patients with a specific type of non-small cell lung cancer (NSCLC) that has a KRAS G12C mutation and has spread to the brain. Participation involves taking adagrasib by mouth and undergoing stereotactic radiosurgery. Patients will be monitored for side effects and treatment response. Alternative treatments may include other targeted therapies, chemotherapy, immunotherapy, or different radiation techniques, depending on the patient's specific situation and prior treatments. The trial aims to enroll 30 participants.

Official Summary

This is a single arm phase 2 trial is to evaluate the efficacy of SRS plus adagrasib for the treatment of brain metastases for patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC). A total of 30 patients will be enrolled on this study.

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients must be 18 years or older with a specific type of lung cancer (NSCLC) that has spread to the brain and has a KRAS G12C mutation. Patients should have at least one untreated tumor in the brain that is at least 2mm but no larger than 3cm, and be able to undergo focused radiation. Patients with certain other health conditions, such as uncontrolled infections or heart rhythm problems, may not be eligible. Patients who have previously been treated with a KRAS G12C inhibitor drug are not eligible. This trial is studying Non Small Cell Lung Cancer, NSCLC, KRAS G12C, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures how well the combination treatment controls tumors in the brain over the first 3 months, indicating its effectiveness in stopping or slowing the growth of these specific t The specific primary outcome measures are: Intracranial disease control rate (DCR) (3 months). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses a critical need for effective treatments for lung cancer that has spread to the brain, a common and challenging complication of the disease, by combining a targeted therapy with a Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Non Small Cell Lung Cancer, NSCLC, KRAS G12C, where improved treatment options are needed.

Investor Insight

This trial targets a specific genetic mutation (KRAS G12C) in a subset of lung cancer patients, representing a growing area of precision medicine with significant market potential for targeted therapi Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about how adagrasib and stereotactic radiosurgery work together and what side effects you might expect. Understand the schedule of clinic visits, scans, and treatments, and how to manage daily life while participating. Discuss any other medications you are taking to ensure they don't interfere with the trial treatments. This trial is currently recruiting participants. The trial is being conducted at 3 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 30 participants

Interventions

• DRUG: Adagrasib — Adagrasib 600mg orally
• RADIATION: Stereotactic Radiosurgery — Delivered as per standard of care

Primary Outcomes

• Intracranial disease control rate (DCR) (3 months)

Secondary Outcomes

• Adverse events (52 months)
• Intracranial overall response rate (ORR) (52 months)
• Overall response rate (ORR) (52 months)
• Progression free survival (PFS) (52 months)
• Overall survival (OS) (52 months)

Full Eligibility Criteria

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
2. Age ≥ 18 years at the time of consent.
3. ECOG Performance Status of 0-1 within 28 days prior to registration.
4. Confirmation of stage IV non-small cell lung cancer (NSCLC) per AJCC, 8th edition, or metastatic recurrence after treatment for earlier stage disease.
5. Known to have a KRAS G12C mutation. KRAS G12C mutation can be determined based on local tissue and/or ctDNA testing.
6. Presence of brain metastases that meet the following criteria:

   * Patients must have at least 1 untreated enhancing intracranial lesion, per local radiology interpretation, measuring at least 2mm. NOTE: intracranial lesions do not need to be measurable by RECIST 1.1 criteria to be eligible.
   * Must have no single metastasis measuring larger than 3 cm.
   * Patients with surgically resected brain metastases are eligible provided there are additional brain metastases amenable to SRS
   * Patients with progression of previously radiated or surgically resected CNS metastases are eligible if solid component of lesion has enlarged and there is no concern for radionecrosis based on investigator discretion.
   * Patients who received SRS within 4 weeks prior to registration are eligible provided baseline brain MRI prior to SRS treatment is within 4 weeks of study registration and SRS treatment meets requirements in #7 below.
   * Symptomatic brain metastases are permitted if the following criteria are met:

     * No evidence of cerebral herniation or symptomatic leptomeningeal disease
     * No seizures within past 14 days; antiepileptic medications are permitted
     * Patients on steroids must have stable or improving neurologic symptoms that have not worsened during a steroid taper. Must be receiving the equivalent of dexamethasone 8 mg total daily dose or less at the time of registration.
7. CNS lesions have already been treated with SRS (within 3 weeks prior to Cycle 1 Day 1) or are amenable to SRS as determined by radiation oncologist and/or neurosurgeon. SRS treatment must use GammaKnife or linear accelerator-based treatments with nominal x-ray energy of 6MV or greater.
8. No contraindications to SRS. Patients on anticoagulation must be able to hold anticoagulation for SRS treatment based on investigator discretion.
9. Patients may be treatment-naïve OR have received up to 2 prior lines of systemic therapy. Treatment with systemic therapy for Stage I-III disease \> 12 months prior to development of metastases do not count as a line of therapy. Treatment with platinum-doublet chemotherapy and checkpoint inhibitor immunotherapy (PD-1, PD-L1, CTLA-4, etc.) either in combination or sequentially counts as one line of therapy.
10. Demonstrate adequate organ function as defined below. All screening labs to be obtained within 28 days prior to registration.

    * Hemoglobin (Hgb): ≥ 8.0 g/dL in the absence of transfusions within 7 days prior to testing.
    * Calculated creatinine clearance: ≥ 60 mL/min
    * Bilirubin: ≤ 1.5 mg/dL
    * Aspartate aminotransferase (AST): ≤ 3.0 × ULN
    * Alanine aminotransferase (ALT): ≤ 3.0 × ULN
11. Females of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to treatment initiation.
12. Females of childbearing potential who are sexually active with a male able to father a child must be willing to abstain from heterosexual activity or to use an effective method(s) of contraception. Males able to father a child who are sexually active with female of childbearing potential must be willing to abstain from heterosexual activity or to use an effective method(s) of contraception.
13. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. Testing is not required at screening unless mandated by local policy.
14. Patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial. Testing is not required at screening unless mandated by local policy.
15. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

Exclusion Criteria:

1. Prior treatment with KRAS G12C tyrosine kinase inhibitor.
2. Active infection requiring systemic therapy with the exception of #13 and #14 above.
3. Uncontrolled, significant intercurrent or recent illness.
4. Prolonged QTc interval \> 480 milliseconds or history of congenital Long QT Syndrome
5. C

Trial Locations

• Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States
• University of Virginia Health System, Charlottesville, Virginia, United States
• Virginia Commonwealth University, Richmond, Virginia, United States

Frequently Asked Questions

Related Conditions

• Non-Small Cell Lung Cancer
• Lung Cancer
• Metastatic Cancer
• Brain Metastases
• KRAS G12C Mutation
• Oncology
• Radiation Oncology
• Targeted Therapy
• Thoracic Oncology
• Cancer Treatment

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