Phase I/Ib Study of Paclitaxel in Combination With VS-6063 in Patients With Advanced Ovarian Cancer
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: defactinib
Other Names:
Drug: Paclitaxel
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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). [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
- 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. [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
Secondary Outcome Measures
- 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]
Response rate and progression-free survival, as determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1
- 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]
Plasma concentration of defactinib (VS-6063)
- 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]
Plasma concentration of defactinib (VS-6063)
- 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]
Plasma concentration of defactinib (VS-6063)
- 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]
Plasma concentration of defactinib (VS-6063)
Other Outcome Measures
- Evaluate biomarkers of defactinib (VS-6063) activity [Day 1 and Day 10 of treatment]
Pre and post dose biomarkers (including but not limited to FAK and phospho-FAK, as well as specific markers for cell cycle inhibition, apoptosis and cancer stem cells) in archival tumor tissue and new biopsy samples
- Examine if the tumor expression status correlates with response to defactinib (VS-6063) therapy [From start of treatment to end of treatment, an expected average of 12 weeks]
Tumor expression status (pFAK and other biomarkers) compared with response to defactinib, as determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1
Eligibility Criteria
Criteria
Inclusion Criteria:
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Able to provide signed and dated informed consent prior to initiation of any study procedures.
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Female subjects aged ≥ 18 years.
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Advanced or refractory ovarian cancer, confirmed histologically.
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Subjects may have received up to 4 prior lines of chemotherapy for their metastatic disease.
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All persistent clinically significant toxicities from prior chemotherapy must be ≤ Grade 1.
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ECOG performance status of 0 or 1 (refer to Appendix A), measured within 72 hours before the start of treatment.
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Predicted life expectancy of ≥ 3 months.
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Adequate renal function [creatinine ≤ 1.5x ULN (upper limit of normal)] or GFR of ≥ 50mL/min.
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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).
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Adequate bone marrow function (hemoglobin ≥ 9.0 g/dL; platelets≥ 100 x109cells/L; absolute neutrophil count ≥ 1.5x109 cells/L).
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Corrected QT interval (QTc) < 470 ms (as calculated by the Fridericia correction formula).
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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.
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Willing and able to participate in the trial and comply with all trial requirements.
Exclusion Criteria:
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Gastrointestinal (GI) condition which could interfere with the swallowing or absorption of study medication.
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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.
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History of upper gastrointestinal bleeding, ulceration, or perforation within 12 months prior to the first dose of study drug.
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Known history of Gilbert's Syndrome.
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Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of study drug.
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Subjects with known infection with human immunodeficiency virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS) (testing not required).
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Subjects with Hepatitis A, B or C (testing not required).
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Subjects being actively treated for a secondary malignancy.
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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.
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Major surgery within 28 days prior to the first dose of study drug.
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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.
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Pregnant or breastfeeding.
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Any evidence of serious active infections.
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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.
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Uncontrolled intercurrent illness including symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Florida Cancer Specialists | Sarasota | Florida | United States | |
| 2 | University of Oklahoma | Oklahoma City | Oklahoma | United States | |
| 3 | Sarah Cannon Research Institute | Nashville | Tennessee | United States | 37203 |
Sponsors and Collaborators
- Verastem, Inc.
Investigators
- Study Chair: Hagop Youssoufian, MD, Verastem, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VS-6063-101