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Defactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer | Clinical Trials | Clareo Health

RECRUITINGPHASE2

Defactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer

A Phase 2 Study of Defactinib and Avutometinib, in Combination With Nivolumab for Patients With Anti-PD1 Refractory LKB1-Mutant Advanced Lung Adenocarcinoma

NCT06495125•Emory University

View on ClinicalTrials.gov

Summary

This phase II trial tests how well defactinib and avutometinib in combination with nivolumab works in treating patients with LKB1-mutant non-small cell lung cancer that has not responded (refractory) to an anti-PD1 treatment and may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Defactinib and avutometinib belong to a class of drugs called kinase inhibitors. These drugs target kinase proteins found in tumor cells. Tumor cells need these proteins to survive and grow. By blocking these proteins, defactinib and avutometinib may cause tumors to stop growing or grow more slowly. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the tumor and may interfere with the ability of tumor cells to grow and spread. Giving defactinib and avutometinib in combination with nivolumab may kill more tumor cells in patients with anti-PD1 refractory LKB1-mutant advanced non-small cell lung cancer.

Detailed Description

PRIMARY OBJECTIVE: I. To determine the efficacy (6-months progression free survival \[PFS\] rate) of defactinib and avutometinib when combined with nivolumab in patients with LKB1 mutated lung adenocarcinoma. SECONDARY OBJECTIVE: I. To evaluate response rate, overall survival and toxicity assessment. TERTIARY/EXPLORATORY OBJECTIVE: I. Biomarker evaluation will be conducted on archived tumor samples and on-study biopsies obtained in a subset of patients. OUTLINE: Patients receive defactinib orally (PO) twice daily (BID) on days 1-21, avutometinib PO twice weekly on Monday and Thursday, Tuesday and Friday or Wednesday and Saturday for 21 days and nivolumab intravenously (IV) on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, blood sample collection, computed tomography (CT) or positron emission tomography (PET) on study. After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Eligibility

Age

18 - No limit years

Sex

ALL

Healthy Volunteers

Inclusion Criteria

•Patients must have been histologically or cytologically diagnosed with non-small cell lung cancer, specifically lung adenocarcinoma
•Patients must have advanced stage disease that is not amenable to combined modality therapy or surgical resection
•Patients must have known LKB1 mutation
•COHORT A ONLY: Patients must have known KRAS mutation
•Patients must have progressed on prior therapy with immune checkpoint inhibitor alone and first line chemotherapy, either combined or sequentially, for advanced stage disease. No other lines of chemotherapy in the advanced stage therapy is allowed. The exception is patients with KRAS G12C are also allowed the use of one line of targeted Food and Drug Administration (FDA) approved therapy
•Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan
•Age ≥ 18 years
•Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
•Adequate recovery from toxicities related to prior treatments to at least grade 1 by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Exceptions include alopecia and peripheral neuropathy grade ≤ 2
•Absolute neutrophil count ≥ 1,500/mcL
+9 more criteria

Exclusion Criteria

•Patients who have had systemic therapy within 3 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
•Patients who are receiving any other investigational agents
•Patients with unstable or symptomatic brain metastasis or known leptomeningeal disease. Asymptomatic brain metastases are allowed if they meet the following criteria:
•* Have been treated and have been stable for greater than or equal to 4 weeks as documented by radiologic imaging
•* Have not required increasing doses of corticosteroids within 2 weeks prior to study treatment
•Patients with history of pre-existing auto-immune conditions that would pose a higher risk for toxicity with nivolumab will be excluded
•Patients who experienced serious auto-immune toxicity with prior immune checkpoint inhibitor therapy
•History of allergic reactions attributed to compounds of similar chemical or biologic composition to avutometinib or defactinib
•Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
•Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that is active and/or requires therapy
+12 more criteria

Locations (3)

Emory University Hospital Midtown

Atlanta, Georgia, United States

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, United States

Emory Saint Joseph's Hospital

Atlanta, Georgia, United States

Key Dates

Start Date

July 31, 2024

Primary Completion Date

March 17, 2028

Completion Date

September 17, 2028

Last Updated

April 17, 2025

Enrollment

ESTIMATED participants

Conditions

Advanced Lung AdenocarcinomaRefractory Lung AdenocarcinomaStage III Lung Cancer AJCC v8Stage IV Lung Cancer AJCC v8

Interventions

Avutometinib

DRUG

Biopsy

PROCEDURE

Biospecimen Collection

PROCEDURE

Computed Tomography

PROCEDURE

Defactinib

DRUG

Nivolumab

BIOLOGICAL

Positron Emission Tomography

PROCEDURE

Contacts

Conor Steuer, MD

CONTACT

404-778-5378 csteuer@emory.edu

Mashunte Holmes, PhD

CONTACT

404-754-4990 mashunte.holmes@emory.edu

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Data Source & Attribution

This clinical trial information is sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

ClinicalTrials.gov last update: April 17, 2025Data synced to Clareo: March 29, 2026

Modifications: This data has been reformatted for display purposes. Eligibility criteria have been parsed into inclusion/exclusion sections. Location data has been geocoded to enable distance-based search. For the authoritative and most current information, please visit ClinicalTrials.gov.

Neither the United States Government nor Clareo Health make any warranties regarding the data. Check ClinicalTrials.gov frequently for updates.

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Defactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer

Inclusion Criteria

Exclusion Criteria

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