Trial Title:
Defactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer
NCT ID:
NCT06495125
Condition:
Advanced Lung Adenocarcinoma
Refractory Lung Adenocarcinoma
Stage III Lung Cancer AJCC v8
Stage IV Lung Cancer AJCC v8
Conditions: Official terms:
Lung Neoplasms
Adenocarcinoma
Adenocarcinoma of Lung
Nivolumab
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Avutometinib
Description:
Given PO
Arm group label:
Treatment (defactinib, avutometinib, nivolumab)
Other name:
CH-5126766
Other name:
CH5126766
Other name:
CKI-27
Other name:
R-7304
Other name:
Raf/MEK Inhibitor VS-6766
Other name:
RG 7304
Other name:
RG-7304
Other name:
RG7304
Other name:
RO5126766
Other name:
VS 6766
Other name:
VS-6766
Other name:
VS6766
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Treatment (defactinib, avutometinib, nivolumab)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (defactinib, avutometinib, nivolumab)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (defactinib, avutometinib, nivolumab)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Drug
Intervention name:
Defactinib
Description:
Given PO
Arm group label:
Treatment (defactinib, avutometinib, nivolumab)
Other name:
PF-04554878
Other name:
VS-6063
Intervention type:
Biological
Intervention name:
Nivolumab
Description:
Given IV
Arm group label:
Treatment (defactinib, avutometinib, nivolumab)
Other name:
ABP 206
Other name:
BCD-263
Other name:
BMS-936558
Other name:
CMAB819
Other name:
MDX-1106
Other name:
NIVO
Other name:
Nivolumab Biosimilar ABP 206
Other name:
Nivolumab Biosimilar BCD-263
Other name:
Nivolumab Biosimilar CMAB819
Other name:
ONO-4538
Other name:
Opdivo
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET
Arm group label:
Treatment (defactinib, avutometinib, nivolumab)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron emission tomography (procedure)
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
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.
Criteria for eligibility:
Criteria:
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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Emory University Hospital Midtown
Address:
City:
Atlanta
Zip:
30308
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Conor Steuer, MD
Email:
csteuer@emory.edu
Facility:
Name:
Emory University Hospital/Winship Cancer Institute
Address:
City:
Atlanta
Zip:
30322
Country:
United States
Status:
Recruiting
Contact:
Last name:
Conor E. Steuer
Phone:
404-778-5378
Email:
csteuer@emory.edu
Investigator:
Last name:
Conor E. Steuer
Email:
Principal Investigator
Facility:
Name:
Emory Saint Joseph's Hospital
Address:
City:
Atlanta
Zip:
30342
Country:
United States
Status:
Recruiting
Contact:
Last name:
Conor Steuer, MD
Email:
csteuer@emory.edu
Start date:
July 31, 2024
Completion date:
June 30, 2026
Lead sponsor:
Agency:
Emory University
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
Emory University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06495125
