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

NCT06495125 | Recruiting Phase 2 DMC FDA Drug

• 5 other identifiers: STUDY00006144NCI-2024-04302WINSHIP5947-23P01CA257906P30CA138292
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Advanced Lung Adenocarcinoma; Refractory Lung Adenocarcinoma; Stage III Lung Cancer AJCC v8; Stage IV Lung Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• Progression free survival (PFS)

  PFS will be defined as the time from the date of first protocol therapy to the date of first documentation of disease progression or death due to any cause, whichever occurs first. PFS will be evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. PFS will be calculated with a 95% confidence interval using Kaplan-Meier method based on the efficacy evaluable population.

  At 6 months

Secondary Outcomes (4)

• PFS

  At start of treatment to progression or death up to 5 years

• Overall survival (OS)

  At start of treatment to death up to 5 years

• Duration of response (DOR)

  At response to recurrent or progressive disease up to 5 years

• Incidence of adverse events (AEs)

  Up to 30 days after last dose of study treatment

Study Arms (1)

Treatment (defactinib, avutometinib, nivolumab)

EXPERIMENTAL

Patients receive defactinib PO 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 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, CT or PET on study.

Drug: Avutometinib; Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Defactinib; Biological: Nivolumab; Procedure: Positron Emission Tomography

Interventions

Avutometinib DRUG

Given PO

Also known as: CH-5126766, CH5126766, CKI-27, R-7304, Raf/MEK Inhibitor VS-6766, RG 7304, RG-7304, RG7304, RO5126766, VS 6766, VS-6766, VS6766

Treatment (defactinib, avutometinib, nivolumab)

Biopsy PROCEDURE

Undergo biopsy

Also known as: BIOPSY_TYPE, Bx

Treatment (defactinib, avutometinib, nivolumab)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (defactinib, avutometinib, nivolumab)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Treatment (defactinib, avutometinib, nivolumab)

Defactinib DRUG

Given PO

Also known as: PF-04554878, VS-6063

Treatment (defactinib, avutometinib, nivolumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: ABP 206, BCD-263, BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar ABP 206, Nivolumab Biosimilar BCD-263, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo

Treatment (defactinib, avutometinib, nivolumab)

Positron Emission Tomography PROCEDURE

Undergo PET

Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging, PT

Treatment (defactinib, avutometinib, nivolumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Hemoglobin ≥ 8.0
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin \< 3.0 mg/dL (51 umole/L)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (or \< 5 x ULN in patients with liver metastases)
• Creatinine clearance ≥ 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal

You may not qualify if:

• 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
• Active skin disorder that has required systemic therapy within the past 1 year. Surgically removed early stage skin cancers are allowed. Topical creams are allowed as well
• History of rhabdomyolysis
• Concurrent ocular disorders:
• Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes
• Patients 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

Sponsors & Collaborators

• Emory University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (3)

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

NOT YET RECRUITING

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

RECRUITING

Emory Saint Joseph's Hospital

Atlanta, Georgia, 30342, United States

RECRUITING

MeSH Terms

Conditions

Adenocarcinoma of Lung; Lung Neoplasms

Interventions

RO5126766; Biopsy; Specimen Handling; defactinib; Nivolumab; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Conor E Steuer

  Emory University Hospital/Winship Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Conor Steuer, MD

CONTACT

404-778-5378; csteuer@emory.edu

Mashunte Holmes, PhD

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 2, 2024
• First Posted: July 10, 2024
• Study Start: July 31, 2024
• Primary Completion (Estimated): March 17, 2028
• Study Completion (Estimated): September 17, 2028
• Last Updated: April 17, 2025

Record last verified: 2025-04

Locations

US (3)