3 STUDY RATIONALE Based upon the above rationale, the investigators propose a phase I study
combining Pazopanib with TH-302 in advanced solid tumors. Pazopanib is FDA approved at a dose
of 800mg per day. Using this dose ensures consistency with standard clinical use. It also
ensures using the dose most likely to induce maximal hypoxia, which in turn will help ensure
maximal local activation of TH-302 (a hypoxia activated prodrug). TH-302 can be given as
monotherapy at a weekly dose of 575 mg/m2. When TH-302 is combined with full doses of various
chemotherapeutics, the recommended dose of TH-302 has ranged from 240 to 480 mg/m2. Little
overlapping toxicity between TH-302 and pazopanib is expected. However to ensure patient
safety, the starting dose for the combination will be conservative and use the TH-302 dose
found safe with the majority of cytotoxic agents, 340 mg/m2 given days 1,8, 15 on an every 28
day cycle.
Using a standard 3+3 design, the investigators will add increasing doses of TH-302 (340
mg/m2, 480 mg/m2, 575 mg/m2 given weekly, 3 weeks on/1 week off (the standard TH-302 dosing
schedule) to the full monotherapy dose of pazopanib (800 mg p.o daily) with expected accrual
ranging from 12-18 subjects. Once the recommended phase II dose is identified, the
investigators will then enroll an expanded cohort of approximately 12-18 (i.e. total of 30
subjects overall) patients to better define the tolerability of this study drug combination.
4 STUDY OBJECTIVES 4.1 Primary
- To define the maximal tolerated dose (if any) and the recommended phase II doses for the
combination of pazopanib plus TH-302 in patients with advanced solid tumors 4.2
Secondary
- To describe any dose limiting and non dose-limiting toxicities of this drug combination
Phase:
Phase 1
Details
Lead Sponsor:
Herbert Hurwitz, MD
Collaborators:
GlaxoSmithKline National Comprehensive Cancer Network Threshold Pharmaceuticals