Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302.
Authors: Meadows Kellen L. , Lee Paula H. , Riedel Richard F. , Morse Michael A. , Uronis Hope E. , Blobe Gerard C. , George Daniel J. , Crawford Jeffrey , Hurwitz Herbert I. 
Published: August 2014

Background: Preclinical data demonstrate anti-VEGF agents can induce hypoxia, which may mediate resistance and induce increased tumor invasiveness. TH-302 is an investigational hypoxia-targeted drug; under hypoxic conditions, TH-302 releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). In several preclinical models, TH-302 plus an anti-VEGF therapy has greater anti-tumor activity than either treatment alone and this activity was associated with anti-VEGF induced hypoxia. Thus, we evaluated the multi-receptor tyrosine kinase VEGFR inhibitor, pazopanib (Paz) in combination with TH-302 in a phase I dose-escalation study, followed by an expanded cohort to better define the safety, tolerability and preliminary activity of the combination.

Methods: Eligible patients (pts) had advanced solid tumors. TH-302 was given intravenously, and Paz was orally administered; cycle length was 28 days. TH-302 was dosed at 340 mg/m2 in cohort 1 and 480 mg/m2 in cohort 2 on days 1, 8 and 15; Paz was dosed at the approved dose of 800 mg daily in all cohorts. Dose limiting toxicity (DLT) was assessed in cycle 1.

Results: To date, 29 pts have been enrolled; median age 55 years (26-79), median prior treatments =1 (range 0-8). Tumor types include colorectal, ovarian, sarcoma, neuroendocrine, pancreatic, lung, gastric, hurthle cell, and bladder/urothelial cancer. Eleven pts were evaluable for toxicity following dose escalation of TH-302. Initially, 3 pts were enrolled in cohort, one with no DLTs. In cohort 2, two DLTs were observed out of 5 evaluable pts: grade 3 thrombocytopenia and neutropenia lasting over 7 days (n=1) and grade 3 vaginitis (n=1). A total of six evaluable pts were enrolled in cohort 1 with one DLT: grade 2 intolerable esophagitis. Possible grade ≥ 3 treatment-related adverse events (AEs) at any point on study include GI-related toxicities (diarrhea, vomiting), lab abnormalities (hyponatremia, AST elevation), hematologic suppression (anemia, ANC, thrombocytopenia), fatigue, headache, stroke, extremity pain and proctitis. Among 26 treated pts with at least one radiographic restaging, 3 pts experienced a PR: 1 pt each with extraskeletal myxoid chondrosarcoma, ovarian cancer and neuroendocrine cancer; all 3 pts had previously received at least one VEGFR inhibitor. Fifteen additional pts have had stable disease as best response, for a clinical benefit rate (PR +SD) of 69%. Four pts have had sustained disease control ≥6 months.

Conclusion: The recommended phase II dose for this combination is the standard dose of Paz at 800 mg daily and TH-302 at 340 mg/m2 on days 1, 8 and 15 of each cycle. At this dose, Paz in combination with TH-302 has shown promising preliminary activity in several treatment-refractory cancers. If confirmed, these preliminary data support the potential value of co-targeting tumor angiogenesis and tumor hypoxia.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C61.

Citation Format: Kellen L. Meadows, Paula H. Lee, Richard F. Riedel, Michael A. Morse, Hope E. Uronis, Gerard C. Blobe, Daniel J. George, Jeffrey Crawford, Herbert I. Hurwitz. Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302. [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 C61.