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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
21
Starting dose of VS-5584 will be 20mg taken once daily, 3x/week of each 21 day cycle. All subjects will also receive 2x/day treatment with 400mg VS-6063 in 21 day cycles. Number of Cycles: until progression or unacceptable toxicity develops.
The University of Chicago Medical Center
Chicago, Illinois, United States
Memorial Sloane Kettering Cancer Center
New York, New York, United States
University of Leicester
Leicester, United Kingdom
The Institute of Cancer Research
Sutton Surrey, United Kingdom
Incidence of dose-limiting toxicities (DLTs)
Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of VS-5584 and VS-6063 in a 21 day cycle
Time frame: 6 months
Safety and tolerability of the combination of VS-5584 and VS-6063
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
Time frame: 16 months
Pharmacokinetics of VS-5584 & VS-6063 maximum observed plasma concentration (Cmax)
Time frame: 0-48 hours per patient
Pharmacokinetics of VS-5584 & VS-6063 plasma area under the curve from time zero to last quantifiable concentration (AUClast)
Time frame: 0-48 hours per patient
Pharmacokinetics of VS-5584 & VS-6063 time to reach maximum observed concentration (Tmax)
Time frame: 0-48 hours per patient
Pharmacokinetics of VS-5584 & VS-6063 area under the curve from time zero to extrapolated infinite time (AUCO-inf)
Time frame: 0-48 hours per patient
Pharmacokinetics of VS-5584 & VS-6063 apparent oral clearance (CL/F)
Time frame: 0-48 hours per patient
Pharmacokinetics of VS-5584 & VS-6063 apparent volume of distribution (Vz/F)
Time frame: 0-48 hours per patient
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Pharmacokinetics of VS-5584 & VS-6063 trough plasma concentration
Time frame: 0-48 hours per patient