MC# 21-03 - A Phase II study of VS-6766 (dual RAF/MEK inhibitor) as a single agent and in combination with defactinib (FAK inhibitor) in recurrent KRAS-mutant (KRAS-MT) non-small cell lung cancer (NSCLC)

  • Agent(s): VS-6766 & Defactinib
  • Disease Type(s): Lung-NSCLC
  • Phase(s): II
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): MEK, RAF, PYK, FAK

Mechanism of Action

VS 6766 is an orally active, small-molecule, dual inhibitor of Raf kinase and mitogen-activated protein-kinase.

Defactinib is a small molecule, reversible inhibitor of Focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk-2).  FAK is a non-receptor protein tyrosine kinase that integrates signals from integrin and growth factor receptors to regulate cells.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of VS-6766 alone or in combination with defactinib
  • If VS-6766, alone or in combination with defactinib, prevents or delays tumor growth or shrinks existing tumors
  • How much of VS-6766 and defactinib are absorbed into the blood and how fast they are removed
  • If research tests can be used in the future to predict who will benefit from VS-6766 and defactinib
Inclusion Criteria
  1. Male or female subjects ≥ 18 years of age
  2. Histologic or cytologic evidence of NSCLC without histological evidence 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.
    1. In Part A of the study, subjects must have either a KRAS-G12V mutation or ANY other KRAS mutation (KRAS-other, including KRAS-G12C)
    2. In Part B of the study, subjects must have either a KRAS-G12V mutation or another specific type(s) of KRAS mutation(s) (KRAS-selected), 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:
    1. 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
    2. 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 < 3.0 mg/dL (51 μmole/L).  (ii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or < 5x ULN in subjects with liver metastases).
    3. Adequate renal function with a creatinine clearance rate of ≥ 60 mL/min as calculated by the Cockcroft-Gault formula)
    4. International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation
    5. Albumin ≥ 3.0 g/dL (451 μmole/L)
    6. Creatine phosphokinase (CPK) ≤ 2.5 x ULN
    7. Adequate cardiac function with left ventricular ejection fraction ≥ 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan
  11. Baseline 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 subjects with a right or left bundle branch block.
  12. Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v 5.0.  Exceptions include alopecia and peripheral neuropathy grade ≤ 2.  Subjects with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the Sponsor.
  13. Females with reproductive potential and their male partners agree to use highly effective method of contraceptive during the trial and for 3 months following the last dose of study drug
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- molecular-weight 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
  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:
    1. Subjects with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes
    2. 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
    3. 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

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://www.clinicaltrials.gov/ct2/show/NCT04620330

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Re: MC# 21-03