A Phase I/Ib Study of Paclitaxel in Combination With VS-6063, a Focal Adhesion Kinase Inhibitor, in Subjects With Advanced Ovarian Cancer
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Verastem, Inc.
- Enrollment
- 22
- Locations
- 3
- Primary Endpoint
- Determine the recommended phase 2 dose (RP2D) based on a combination of maximum tolerated dosed (MTD), review of adverse event data and review of AUC, Tmax and t1/2 obtained from PK data during the dose escalation phase of the study.
Study Overview
Brief Summary
This is a Phase I/Ib, open-label, multicenter, dose-escalation trial of paclitaxel in combination with defactinib (VS-6063), a focal adhesion kinase inhibitor, in patients with advanced ovarian cancer. This clinical study is comprised of 2 parts: Phase I (Dose Escalation) and Phase Ib (Expansion). The purpose of this study is to assess assess the safety (including the recommended phase 2 dose), the pharmacokinetics, and the anti-cancer activity of defactinib (VS-6063) when administered in combination with paclitaxel. Pharmacodynamic effects will also be examined in tumor biopsies.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Able to provide signed and dated informed consent prior to initiation of any study procedures.
- •Female subjects aged ≥ 18 years.
- •Advanced or refractory ovarian cancer, confirmed histologically.
- •Subjects may have received up to 4 prior lines of chemotherapy for their metastatic disease.
- •All persistent clinically significant toxicities from prior chemotherapy must be ≤ Grade
- •ECOG performance status of 0 or 1 (refer to Appendix A), 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 x109cells/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 females of child-bearing potential; must be surgically sterile, postmenopausal, or willing and able to be compliant with a contraceptive regimen (double barrier birth control) during and for 3 months after the treatment period.
- •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 Gilbert's Syndrome.
- •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 Hepatitis A, B or C (testing not required).
- •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.
- •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.
- •Uncontrolled intercurrent illness including symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Arms & Interventions
defactinib (VS-6063) plus paclitaxel
Oral defactinib (VS-6063) administered twice daily, in combination with intravenous paclitaxel administered on Days 1, 8, and 15 of a 28 day cycle.
Intervention: defactinib (Drug)
defactinib (VS-6063) plus paclitaxel
Oral defactinib (VS-6063) administered twice daily, in combination with intravenous paclitaxel administered on Days 1, 8, and 15 of a 28 day cycle.
Intervention: Paclitaxel (Drug)
Outcomes
Primary Outcomes
Determine the recommended phase 2 dose (RP2D) based on a combination of maximum tolerated dosed (MTD), review of adverse event data and review of AUC, Tmax and t1/2 obtained from PK data during the dose escalation phase of the study.
Time Frame: From start of treatment to end of cycle 1 (4 week cycles)
The RP2D will be determined based on the maximum tolerated dose (MTD) of defactinib (VS-6063) in combination with paclitaxel as determined by number of participants with dose limiting toxicities (DLTs) related to defactinib in combination with paclitaxel
Number of patients experiencing treatment-related adverse events as assessed by CTCAE v4.03 (Common Toxicity Criteria for Adverse Effects)during the study (safety and tolerability).
Time Frame: From start of treatment to end of treatment, an expected average of 12 weeks
Adverse events and their frequency, duration and severity, as determined based on CTCAE 4.03
Secondary Outcomes
- Proportion of patients treated with paclitaxel and defactinib (VS-6063) with progression-free survival using Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1(Every 2 cycles up to end of treatment, an expected average of 12 weeks)
- Pharmacokinetics (PK) estimates of defactinib (VS-6063) when co-administered with paclitaxel, AUC (Area Under Curve) 0-t.(Time points at Day 1 and Day 15 in Cycle 1)
- Pharmacokinetics (PK) estimates of defactinib (VS-6063) when co-administered with paclitaxel, maximum concentrations (Cmax)(Time points at Day 1 and Day 15 in Cycle 1)
- Pharmacokinetics (PK) estimates of defactinib (VS-6063) when co-administered with paclitaxel, Time to maximum concentrations (Tmax)(Time points at Day 1 and Day 15 in Cycle 1)
- Pharmacokinetics (PK) estimates of defactinib (VS-6063) when co-administered with paclitaxel, , estimates of concentration 1/2 life (T1/2)(Time points at Day 1 and Day 15 in Cycle 1)