A Phase 1 Dose Escalation Study of VS-5584 Administered in Combination With VS-6063, in Subjects With Relapsed Malignant Mesothelioma
- Registration Number
- NCT02372227
- Lead Sponsor
- Verastem, Inc.
- Brief Summary
The purpose of this study is to evaluate rising dose levels of VS-5584 administered in combination with a fixed dose of VS-6063 in subjects with relapsed malignant mesothelioma to determine a recommended Phase 2 dose (RP2D) for further development of this combination in this indication.
- Detailed Description
This study is comprised of 2 sequential parts: Part 1 (Dose Escalation of VS-5584) and Part 2 (Expansion). Up to 56 evaluable subjects (i.e., subjects who complete at least 1 cycle \[21 days\] of therapy) will be enrolled, assuming that:
* Up to 6 dose levels of VS-5584 are studied in Part 1 (Dose Escalation of VS-5584) in combination with a fixed dose of VS-6063 at 400 mg twice daily (BID) with a maximum of 6 subjects enrolled per VS-5584 dose level, for a total of up to 36 subjects (exclusive of replacement subjects).
* Up to an additional 20 evaluable subjects may be enrolled in Part 2, the expansion portion of the study. Subjects will be treated with VS-5584 at the RP2D and schedule determined in the dose escalation portion of the study in combination with a fixed dose of VS-6063.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 21
- Histopathologically-confirmed diagnosis of malignant mesothelioma (pleural or peritoneal). Must have disease that has relapsed following at least one prior line of chemotherapy.
- Must have received at least 3 cycles of first-line chemotherapy.
- Evaluable or measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST).
- Must have archival tumor tissue available for biomarker analysis. A study-specific tumor core biopsy, pleural effusion or ascites sample must be obtained prior to treatment if archival tissue is not available.
- Performance status according to the Karnofsky Performance Scale ≥70%.
- Fasting blood glucose of ≤ 140 mg/dL (7.8 mmol/L).
- Adequate renal function (creatinine ≤ 1.5x upper limit of normal [ULN]) and/or glomerular filtration rate (GFR) of ≥50 mL/min.
- Adequate hepatic function (total bilirubin ≤ 1.5x ULN; AST and ALT ≤ 3x ULN).
- Adequate bone marrow function (hemoglobin ≥9.0 g/dL; platelets ≥100 x10^9 cells/L; absolute neutrophil count ≥1.5x10^9 cells/L) without the use of hematopoietic growth factors.
- Have had a previous extra pleural pneumonectomy (EPP).
- Gastrointestinal condition which could interfere with the swallowing or absorption of study drug.
- Uncontrolled or severe concurrent medical condition (including uncontrolled brain metastases).
- Known history of stroke or cerebrovascular accident within 6 months prior to the first dose of study drug.
- Any evidence of serious active infection.
- Undergoing active treatment for a secondary malignancy.
- Cancer-directed therapy (chemotherapy, radiotherapy) within 21 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.
- Acute or chronic pancreatitis.
- Diabetes mellitus requiring insulin treatment or subjects with a hemoglobin A1C (HbA1C) >7%.
- History or evidence of cardiac risk.
- Known history of malignant hypertension.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description VS-5584 and VS-6063 VS-5584 and VS-6063 -
- Primary Outcome Measures
Name Time Method Incidence of dose-limiting toxicities (DLTs) 6 months Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of VS-5584 and VS-6063 in a 21 day cycle
Safety and tolerability of the combination of VS-5584 and VS-6063 16 months Dose Escalation Phase and Expansion Phase: A composite by dose level to include incidence of AEs, SAEs (overall and severity), laboratory abnormalities, ECGs, vital signs, Karnofsky Performance Status, dose interruptions and dose reductions as a measure of safety and tolerability
- Secondary Outcome Measures
Name Time Method Pharmacokinetics of VS-5584 & VS-6063 plasma area under the curve from time zero to last quantifiable concentration (AUClast) 0-48 hours per patient Pharmacokinetics of VS-5584 & VS-6063 time to reach maximum observed concentration (Tmax) 0-48 hours per patient Pharmacokinetics of VS-5584 & VS-6063 maximum observed plasma concentration (Cmax) 0-48 hours per patient Pharmacokinetics of VS-5584 & VS-6063 apparent oral clearance (CL/F) 0-48 hours per patient Pharmacokinetics of VS-5584 & VS-6063 apparent volume of distribution (Vz/F) 0-48 hours per patient Pharmacokinetics of VS-5584 & VS-6063 trough plasma concentration 0-48 hours per patient Pharmacokinetics of VS-5584 & VS-6063 area under the curve from time zero to extrapolated infinite time (AUCO-inf) 0-48 hours per patient
Trial Locations
- Locations (4)
University of Leicester
🇬🇧Leicester, United Kingdom
Memorial Sloane Kettering Cancer Center
🇺🇸New York, New York, United States
The University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
The Institute of Cancer Research
🇬🇧Sutton Surrey, United Kingdom