Recurrent KRAS-Mutant (KRAS-MT) Non-Small Cell Lung Cancer (NSCLC) MedDRA version: 21.1 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Defactinib
Product Code: [VS-6063]
Pharmaceutical Form: Tablet
INN or Proposed INN: Defactinib
CAS Number: 1073160-26-5
Current Sponsor code: VS-6063
Concentration unit: mg milligram(s)
Sponsors
Verastem, INC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female subjects = 18 years of age. 2. Histologic or cytologic evidence of NSCLC without histologicalevidence of a small cell component that is either metastatic (Stage 4) or locally advanced (Stage 3B-C) and unresectable (IASLC 8th edition). The Sponsor's Medical Monitor must review the pathology report prior to start of treatment. 3. Subjects must have a known KRAS mutation determined using a validated next-generation sequencing (NGS) and/or polymerase chain reaction (PCR) testing method prior to enrollment. Adequate material (as defined in the lab manual) must be available prior to study therapy to be used for central confirmation of KRAS mutation status. Central confirmation does not need to be completed prior to enrollment. a. In Part A of the study, subjects must have either a KRAS-G12V mutation or ANY other KRAS mutation (KRAS-other, including KRASG12C). b. In Part B of the study, subjects must have either a KRAS-G12V mutation or another specific type(s) of KRAS mutation(s) (KRASselected),to be determined at the end of Part A. 4. The subject has received appropriate therapy for an activating mutation of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or other activating mutation in which a therapeutic has been approved. 5. The subject has received appropriate platinum-based therapy for a non-activating mutation, such as those mentioned in inclusion criterion #3, and has received appropriate treatment with a monoclonal antibody to PD-1 or PD-L1 unless contraindicated. 6. The subject must have received appropriate treatment with at least one prior systemic regimen, but no more than 2 prior regimens, for Stage 3B-C or 4 NSCLC. 7. The subject may have previously received adjuvant chemotherapy for earlier stage disease. Adjuvant chemotherapy in early stages will not count as a prior regimen unless disease progression occurred during or within 3 months following adjuvant therapy. 8. Measurable disease according to RECIST 1.1. All radiology studies must be performed within 28 days prior to randomization (Part A) or start of study-directed therapy in Part B. 9. An Eastern Cooperative Group (ECOG) performance status = 1. 10. Must have adequate organ function defined by the following laboratory parameters: a. Adequate hematologic function including: hemoglobin (Hb) = 9.0 g/dL; platelets =100,000/mm3 ; and absolute neutrophil count (ANC) = 1500/mm3 ) with no transfusion or growth factor support at least 14 days before first dose of study therapy. b. Adequate hepatic function: (i) total bilirubin = 1.5 × upper limit of normal (ULN) for the institution; subjects with Gilbert syndrome may enroll if total bilirubin =65 years) yes F.1.3.1 Number of subjects for this age range 172
Exclusion criteria
Exclusion criteria: 1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy. 2. History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression. 3. Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study therapy. 4. Treatment with warfarin. Subjects on warfarin for DVT/PE can be converted to low-molecularweight heparin (LMWH). 5. History of treatment with a direct and specific inhibitor of MEK. 6. History of treatment with a direct and specific inhibitor of KRAS 7. Exposure to strong CYP2C9 and CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy. For additional guidance see https://www.fda.gov/drugs/drug-interactions labeling/drug-development-and-druginteractionstable-substrates-inhibitors-and-inducers. 8. Exposure to P-glycoprotein (P-gp) inhibitors or inducers within 14 days prior to the first dose and during the course of therapy. 9. Symptomatic brain metastases requiring steroids or other local interventions. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 2 weeks prior to first dose of study therapy, and are neurologically stable. 10. Known SARS-Cov2 infection =28 days prior to first dose of study therapy. 11. Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that is active and/or requires therapy. 12. Active skin disorder that has required systemic therapy within the past 1 year. 13. History of rhabdomyolysis. 14. Concurrent ocular disorders: a. Subjects with history of glaucoma, history of retinal vein occlusion (RVO),predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes. b. Subject 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. c. Subjects with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. 15. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease. 16. Subjects with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease. 17. Subjects with a history of hypersensitivity to any of the inactive ingredients (hydroxypropylmethylcellulose, mannitol, magnesium stearate) of the investigational product. 18. Female subjects who are pregnant or breastfeeding. 19. Any other medical condition (e.g. cardiac, gastrointestinal,pulmonary, psychiatric, neurological, genetic, etc.) that in the opinion of the investigator would places the subject at unacceptably high risk for toxicity.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A: To determine the optimal regimen, either VS-6766 monotherapy or VS-6766 in combination with defactinib, for subsequent evaluation for efficacy in the expansion phase (Part B) Part B: To determine the efficacy of the optimal regimen identified from Part A;Secondary Objective: To characterize the safety and toxicity profile of VS-6766 as a monotherapy and in combination with defactinib in KRAS-MT NSCLC To characterize the pharmacokinetics (PK) of VS-6766,defactinib, and relevant metabolites Part A: To evaluate additional efficacy parameters for VS-6766 monotherapy and in combination with defactinib Part B: To evaluate additional efficacy parameters for the optimal regimen identified in Part A;Primary end point(s): Part A: Confirmed overall response rate (ORR; partial response [PR] + complete response [CR] defined according to RECIST 1.1) as assessed by the independent radiology review committee (IRC) Part B: Confirmed ORR defined according to RECIST 1.1 as assessed by the IRC;Timepoint(s) of evaluation of this end point: Throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Adverse events (AEs), serious AEs (SAEs), vital signs, physical examinations, clinical laboratory values, and tolerability (dose interruptions/reductions) Duration of response (DOR) as assessed by the IRC ORR as assessed by the Investigator (Part B) Disease control rate (DCR), defined as CR+PR+ stable disease (SD), as assessed by the IRC Progression free survival (PFS), defined as the time from first dose of study treatment to the first documentation of PD, or death from any cause Overall survival (OS) PK parameters derived from blood concentrations of VS-6766, defactinib, and relevant metabolites;Timepoint(s) of evaluation of this end point: Throughout the study | — |
Countries
Belgium, France, Germany, Italy, Spain, United States
Contacts
Public ContactGloria Patrick
Verastem, Inc.
Outcome results
None listed