Abstract
Phase I study of TH-302, investigational hypoxia-targeted drug, in combination with sunitinib
Journal of clinical oncology, Vol.31(15_suppl), pp.e15557-e15557
05/20/2013
DOI: 10.1200/jco.2013.31.15_suppl.e15557
Abstract
e15557
Background: Tumors often consist of highly hypoxic subregions known to be resistant to chemotherapy and radiotherapy. TH-302 is an investigational hypoxia-targeted drug with a 2-nitroimidazole trigger designed to release the DNA alkylator bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. Preclinical models demonstrate that treatment with sunitinib increased the tumor hypoxic fraction, the therapeutic target of TH-302. Initiating TH-302 following sunitinib significantly increased the efficacy of sunitinib in these models. In this phase 1 dose escalation study, TH-302 was combined with standard dose sunitinib. Methods: Eligible patients (pts) for the study (NCT01381822) had advanced RCC, GIST or PNET tumors, 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/m
2
. The study objectives were to determine the MTD, DLTs and RP2D and to evaluate the safety and preliminary efficacy of TH-302 when used in combination with sunitinib. Results: Ten pts were enrolled. Median age: 63 (range 27-72); Female (5)/ Male (5); ECOG 0 (5); ECOG 1 (5); Primary tumor: RCC (6), GIST (4). Median prior chemotherapies: 3 (range: 0-3) including prior sunitinib in 7 pts. No DLTs were observed in the 3 pts at the 240 mg/m
2
cohort and 1 pt of 5 DLT evaluable in the 340 mg/m
2
cohort had a DLT of stomatitis. Eight pts discontinued (progressive disease (6), pursued other treatment options, adverse event unrelated to study drugs). 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 4 pts and 3 pts, respectively. One of 4 (25%) pts with GIST had a confirmed PR and 3 of 4 (75%) pts with RCC had PRs including 2 with confirmed PRs. Conclusions: TH-302 can be administered in combination with full dose sunitinib. Mucositis was dose limiting. There is preliminary evidence of activity of TH-302 in combination with sunitinib in RCC. Clinical trial information: NCT01381822.
Details
- Title: Subtitle
- Phase I study of TH-302, investigational hypoxia-targeted drug, in combination with sunitinib
- Creators
- Alexander Starodub - Goshen HealthMohammed M. Milhem - University of IowaKenneth Lee Pennington - Goshen HealthEbenezer A. Kio - Goshen HealthDaniel Bruetman - Goshen HealthTracy Thorne - Goshen HealthBarbara Hickingbottom - Threshold PharmaceuticalsStew Kroll - Threshold Pharmaceuticals
- Resource Type
- Abstract
- Publication Details
- Journal of clinical oncology, Vol.31(15_suppl), pp.e15557-e15557
- DOI
- 10.1200/jco.2013.31.15_suppl.e15557
- ISSN
- 0732-183X
- eISSN
- 1527-7755
- Language
- English
- Date published
- 05/20/2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984363181002771
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