Recruiting

Phase 2

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

Sponsor:

Emory University

Code:

NCT06495125

Conditions

Advanced Lung Adenocarcinoma

Refractory Lung Adenocarcinoma

Stage III Lung Cancer AJCC v8

Stage IV Lung Cancer AJCC v8

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Avutometinib

Biopsy

Biospecimen Collection

Computed Tomography

Defactinib

Study Details

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

Study ID

NCT06495125

Start date

Jul 31, 2024

Status verified date

Mar, 2026

Completion date

Sep 17, 2029

Anticipated

Primary completion date

Mar 17, 2029

Anticipated

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

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
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
Patients must have the ability to ingest oral medications
The effects of defactinib and avutometinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry,for the duration of study participation, for 3 months following the last dose of study therapy for male patients, and 1 month following the last dose of study therapy for female patients. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
Patients must be able to understand and be willing to sign a written informed consent document
Baseline corrected QT (QTc) interval < 460 ms for women and ≤ 450 ms for men (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

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
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
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
Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease
Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism should be converted to low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs). Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with defactinib within 14 days prior to the first dose of avutometinib or defactinib and during the course of therapy, including:

Strong CYP3A4 inhibitors or inducers, strong CYP2C9 inhibitors or inducers, strong P-glycoprotein (P-gp) inhibitors or inducers
Patients with a known "treatable driver mutation" with FDA approved targeted therapy (such as EGFR, ALK, ROS1, NTRK, BRAF, RET, MET exon 14, HER2). The exception is KRAS as listed in the inclusion section
History of prior malignancy within past 2 years prior to study entry, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression
Female patients who are pregnant or breastfeeding

Study Design

Enrollment

50 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (defactinib, avutometinib, nivolumab)

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.

Interventions

Avutometinib

Given PO

Biopsy

Undergo biopsy

Biospecimen Collection

Undergo blood sample collection

Computed Tomography

Undergo CT

Defactinib

Given PO

Nivolumab

Given IV

Positron Emission Tomography

Undergo PET

Primary outcome measure

Progression free survival (PFS) [ Time Frame: At 6 months ]

Central Contacts and Locations

Central contacts

Conor Steuer, MD

404-778-5378 csteuer@emory.edu

Mashunte Holmes, PhD

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

Locations

Emory University Hospital/Winship Cancer Institute

Recruiting

Atlanta, Georgia, United States, 30322

Contacts

Conor E. Steuer

404-778-5378 csteuer@emory.edu

Principal Investigator:

Conor E. Steuer

Emory Saint Joseph's Hospital

Recruiting

Atlanta, Georgia, United States, 30342

Contacts

Conor Steuer, MD

csteuer@emory.edu

More Information

Sponsor

Emory University

Last update posted

Apr 6, 2026

Last verified

Mar, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Emory University on 2026-04-06.