Abstract B77: Phase I study of TH-302, an investigational hypoxia-targeted drug, in combination with sunitinib.
Authors: Starodub Alexander , Vaena Daniel , Pennington Kenneth L. , Kio Ebenezer A. , Bruetman Daniel , Thorne Tracy , Kroll Stewart , Milhem Mohammed M. 
Published: August 2014

Abstract
Background: Tumors often consist of highly hypoxic subregions known to be resistant to chemotherapy and radiotherapy. TH-302 is an investigational hypoxia-targeted drug that selectively releases the DNA cross-linker bromo-isophosphoramide mustard under hypoxic conditions. Preclinical models demonstrate that treatment with antiangiogenic receptor tyrosine kinase inhibitor sunitinib increased the tumor hypoxic fraction, the therapeutic target of TH-302, in a dose dependent manner. Treatment with TH-302 following sunitinib significantly increased antitumor activity in these models. In this Phase I dose-escalation study, TH-302 was combined with standard dose sunitinib. Methods: Eligible patients (pts) for the study (NCT01381822) had advanced renal cell carcinoma (RCC), gastrointestinal stromal tumors (GIST) or pancreatic neuroendocrine tumors (PNET), evaluable disease by RECIST, ECOG ≤2 and acceptable hematologic, hepatic and renal function. Pts received TH-302 in combination with standard full doses of 50 mg PO sunitinib daily from Day 1 to Day 28 of a 6 week cycle. TH-302 was administered IV on Days 8, 15 and 22. TH-302 starting dose was 240 mg/m2. The study objectives were to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs) and the recommended Phase II dose (RP2D), and to evaluate the safety and preliminary efficacy of TH-302 when used in combination with sunitinib. Results: Twelve pts were enrolled. Median age: 51 (range 27-72); Female (4)/ Male (8); ECOG 0 (6); ECOG 1 (6); Primary tumor: RCC (8), GIST (4). Median prior systemic therapies: 2 (range: 0-6) including prior sunitinib in 8 pts. No DLTs were observed in the 3 pts at the 240 mg/m2 cohort and 1 pt of 6 DLT evaluable in the 340 mg/m2cohort had a DLT of stomatitis. Eleven pts discontinued [progressive disease (9), pursued other treatment options (1), adverse event unrelated to study drugs (1)]. Three pts had a study drug related SAE (neutropenic sepsis, anemia, hyperthyroidism). Common TH-302 related AEs were nausea and mucosal toxicity and were mostly grade 1 or 2. Grade 3/4 thrombocytopenia and neutropenia were reported in 3 pts and 5 pts, respectively. One of 4 (25%) pts with GIST had a confirmed PR and 3 of 6 (50%) pts with RCC had PRs including 2 with confirmed PRs. All 4 pts with PRs had received prior sunitinib. Conclusions: TH-302 can be administered in combination with full dose sunitinib. Stomatitis was dose limiting. These preliminary data suggest activity of TH-302 in combination with sunitinib in patients with RCC who had progressed on prior sunitinib.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B77.
Citation Format: Alexander Starodub, Daniel Vaena, Kenneth L. Pennington, Ebenezer A. Kio, Daniel Bruetman, Tracy Thorne, Stewart Kroll, Mohammed M. Milhem. Phase I study of TH-302, an investigational hypoxia-targeted drug, in combination with sunitinib. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B77.