Phase I Dose Escalation Study of VS-6063 in Japanese Subjects With Non-Hematologic Malignancies

Study Overview
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Brief Summary
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This is a phase I, open-label, dose-escalation trial of defactinib (VS-6063), a focal adhesion kinase inhibitor, in Japanese patients with non-hematologic malignancies. The purpose of this study is to assess the safety (including the recommended phase 2 dose), the pharmacokinetics, and the anti-cancer activity of defactinib (VS-6063).

Official Title
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A Phase I Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of VS-6063, a Focal Adhesion Kinase Inhibitor, in Japanese Subjects With Non-Hematologic Malignancies

Conditions
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Non Hematologic Cancers

Intervention / Treatment
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* Drug: Defactinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide signed and dated informed consent prior to initiation of any study procedures. Age ≥ 20 years. Subject must be of Japanese descent. Subjects must have a histopathologically confirmed diagnosis of a non-hematologic malignancy. Subjects must have no further standard of care options or have refused standard therapy. All persistent clinically significant toxicities from prior chemotherapy must be ≤ Grade 1. ECOG performance status of 0 or 1, measured within 72 hours before the start of treatment. Predicted life expectancy of ≥ 3 months. Adequate renal function [creatinine ≤ 1.5x ULN (upper limit of normal)] or GFR of ≥ 50mL/min. Adequate hepatic function (total bilirubin ≤ 1.5x ULN for the institution; AST [aspartate transaminase] and ALT [alanine transaminase] ≤ 3x ULN, or ≤ 5x ULN if due to liver involvement by tumor). Adequate bone marrow function (hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x109 cells/L; absolute neutrophil count ≥ 1.5x109 cells/L). Corrected QT interval (QTc) < 470 ms (as calculated by the Fridericia correction formula). Negative pregnancy test for women of child-bearing potential. (A woman of childbearing potential is defined as one who is biologically capable of becoming pregnant except for women who have undergone permanent contraceptive surgery or are postmenopausal (defined as the absence of menstruation for at least 12 months without other medical reasons). Men and women of child bearing potential must agree to use adequate birth control throughout their participation in the study and for 90 days following the last study treatment. Willing and able to participate in the trial and comply with all trial requirements. Exclusion Criteria: Gastrointestinal (GI) condition which could interfere with the swallowing or absorption of study medication. Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases). Stable brain metastases either treated or being treated with a stable dose of steroids/ anticonvulsants, with no dose change within 28 days prior to the first dose of study drug, will be allowed. History of upper gastrointestinal bleeding, ulceration, or perforation within 12 months prior to the first dose of study drug. Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of study drug. Subjects with known infection with human immunodeficiency virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS) (testing not required). Subjects with known Hepatitis B or C (Including known seropositivity Hepatitis B virus surface antigen (HBsAg), hepatitis C virus antibody (HCV antibody). Subjects being actively treated for a secondary malignancy. Cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, etc.) within 28 days of the first dose of study drug or 5 half-lives, whichever is shorter. Major surgery within 28 days prior to the first dose of study drug. Use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. A minimum of 10 days between termination of the investigational drug and administration of the study treatment is required. In addition, any drug-related toxicity except alopecia should have recovered to grade 1 or less. Women who are pregnant or breastfeeding. Any evidence of serious active infections. Uncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis. Known history of malignant hypertension Uncontrolled intercurrent illness including symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Defactinib<br>Oral defactinib (VS-6063) administered twice a day (BID) during a 21 day cycle. | Drug: Defactinib<br> <br> * Other names: VS-6063;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Safety and Tolerability of Defactinib (VS-6063) in Japanese Subjects With Non-hematologic Malignancies | A composite by dose level to include incidence of AEs, SAEs, dose interruptions and dose reductions as a measure of safety and tolerability. Abnormal Clinical significant laboratory results, ECG measurements, vital signs measurement, physical examination findings, and ECOG performance status were captured as adverse events. The severity of AEs were evaluated according to CTCAE (Common Toxicity Criteria for Adverse Effects) 4.03 | From start of treatment to end of treatment, an expected average of 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Define the Maximum Tolerated Dose (MTD), if Achieved, and Establish the Recommended Phase 2 Dose (RP2D) of Defactinib (VS-6063) in Japanese Subjects. | The RP2D will be determined based on the MTD of defactinib (VS-6063) as determined by number of participants with dose limiting toxicities (DLTs) related to defactinib. | From start of treatment to end of cycle 1 (21 day cycles) | 
| Assess the Pharmacokinetics, Metabolism and Elimination of Defactinib (VS-6063) in Plasma and Urine. | PK parameters, including but not limited to plasma concentration, AUC (Area Under Curve) 0-t, Cmax, Tmax, and T1/2. Total 24-hour urine output will be collected in conjunction with PK sampling to assess the elimination of defactinib (VS-6063) and its potential metabolites. | Time points at Day 1 and Day 15 in Cycle 1 | 
| Evaluate the Efficacy (Response Rate and Progression-free Survival) of Subjects Treated With Defactinib (VS-6063). | Response rate and progression-free survival, as determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1 | Every 8 weeks up to end of treatment, an expected average of 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CSC, Focal Adhesion Kinase inhibitor, FAK inhibitor, Cancer Stem Cells