Ph 1 Study of VS-4718, a FAK Inhibitor, in Combination With Nab-paclitaxel and Gemcitabine in Advanced Cancer Subjects

Study Overview
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Brief Summary
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The purpose of this study is to evaluate increasing dose levels of VS-4718 administered in combination with gemcitabine and nab-paclitaxel in subjects with advanced cancer and to determine a recommended Phase 2 dose (RP2D) for further development of this combination in subjects with untreated advanced pancreatic cancer.

Detailed Description
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The study is comprised of 2 sequential parts: Part A (Dose Escalation of VS-4718) in subjects with advanced cancer and Part B (Expansion) in subjects with untreated advanced pancreatic cancer. Up to 60 evaluable subjects (i.e., subjects who complete at least 1 cycle (28 days) of therapy) will be enrolled, assuming that: Part A: The maximum sample size will be 6 subjects up to 4 dose levels (exclusive of replacement subjects). However, additional subjects may be added if exploration of intermediate dose level(s) of VS 4718 is warranted. The starting dose of VS-4718 will be 200mg BID. Part B: Up to 36 additional subjects may be enrolled at the RP2D. These subjects will be randomized at a 1:1 ratio to 1 of 2 treatment cohorts: Cohort 1: IV treatment in 28-day cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15) and oral VS 4718 BID continuously starting on Day 1 of Cycle 1 Cohort 2: IV treatment for the first 2 cycles, followed by IV treatment and oral VS-4718 BID continuously starting on Day 1 of Cycle 3

Official Title
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A Phase 1 Study of VS-4718, a Focal Adhesion Kinase Inhibitor, in Combination With Nab-paclitaxel and Gemcitabine in Subjects With Advanced Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Part B, Cohort 1- VS-4718, nab-paclitaxel, gemcitabine
* Drug: Part B, Cohort 2- VS4718, nab-paclitaxel, gemcitabine
* Drug: Part A- VS-4718, nab-paclitaxel, gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Histologically or cytologically confirmed diagnosis of an advanced nonhematological malignancy (Part A) or advanced pancreatic adenocarcinoma (Part B) that is not surgically resectable Eligible for treatment with nab-paclitaxel and gemcitabine on Days 1, 8, and 15 in 28-day cycles as standard therapy Evaluable or measurable disease, as assessed by RECIST v1.1 ECOG performance status of ≤ 1 Adequate renal function (creatinine ≤ 1.5×ULN [upper limit of normal]) or glomerular filtration rate of ≥ 60 mL/min Adequate hepatic function (total bilirubin ≤ 1.5×ULN for the institution; aspartate transaminase and alanine transaminase ≤ 2.5×ULN, or ≤ 5×ULN if due to liver involvement by tumor; albumin ≥ 3 g/dL) Adequate bone marrow function (hemoglobin ≥ 9.0 g/dL; unsupported platelets ≥ 100×109 cells/L; absolute neutrophil count [ANC] ≥ 1.5×109 cells/L without the use of hematopoietic growth factors) Corrected QT interval (QTc) < 470 ms Willing and able to participate in the trial and comply with all trial requirements Exclusion Criteria: Gastrointestinal (GI) condition that could interfere with the swallowing or absorption of study medication Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases). History of upper gastrointestinal bleeding, ulceration, or perforation within 6 months prior to the first dose of protocol therapy Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of protocol therapy. Part B only: Prior therapy (including investigational agents) for pancreatic cancer Chemotherapy or radiotherapy within 14 days prior to first dose of protocol therapy Active treatment for a secondary malignancy

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part B, Cohort 1- VS-4718, nab-paclitaxel, gemcitabine<br>Part B, Cohort 1- IV treatment in 28-day cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15) and oral VS 4718 BID continuously starting on Day 1 of Cycle 1 | Drug: Part B, Cohort 1- VS-4718, nab-paclitaxel, gemcitabine<br>* IV treatment in 28-day cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15) and oral VS 4718 BID continuously starting on Day 1 of Cycle 1<br>|
| Experimental: Part B, Cohort 2- VS-4718, nab-paclitaxel, gemcitabine<br>Part B, Cohort 2- IV treatment for the first 2 cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15), followed by IV treatment and oral VS-4718 BID continuously starting on Day 1 of Cycle 3 | Drug: Part B, Cohort 2- VS4718, nab-paclitaxel, gemcitabine<br>* IV treatment for the first 2 cycles, followed by IV treatment and oral VS-4718 BID continuously starting on Day 1 of Cycle 3<br>|
| Experimental: Part A- VS-4718, nab-paclitaxel, gemcitabine<br>Part A- intravenous (IV) treatment in 28-day cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15) and oral VS 4718 twice-daily (BID) continuously starting on Cycle 1 Day 2. The starting dose of VS-4718 will be 200 mg BID. | Drug: Part A- VS-4718, nab-paclitaxel, gemcitabine<br>* Part A- intravenous (IV) treatment in 28-day cycles (nab-paclitaxel 125 mg/m2 over 30 minutes on Days 1, 8, and 15 and gemcitabine at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15) and oral VS 4718 twice-daily (BID) continuously starting on Cycle 1 Day 2. The starting dose of VS-4718 will be 200 mg BID.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) | Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of VS-4718 in combination with gemcitabine and nab-paclitaxel | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival |  | From the date of first treatment to the date of progression including death from any cause, expected average at least 5 months | 
| Response rate (RR) | RR is measured as the best overall response using Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1. | Every 8 weeks from baseline through the end of treatment, an expected average of 5 months] | 
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Clearance |  | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | 
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Plasma concentration |  | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | 
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Area under the plasma concentration versus time curve (AUC) |  | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | 
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Maximum observed plasma concentration (Cmax) |  | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | 
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Time to reach maximum observed concentration (Tmax) |  | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle | 
| Pharmacokinetics of VS-4718 in combination with nab-paclitaxel and gemcitabine: Half life (T1/2) |  | Time points on Day 1, 2,15, 16, and 22 in Cycle 1; Day 1 of each subsequent cycle |