Abstract B174: Complementary activity of the vascular disruption agent BNC105 and the hypoxia-activated prodrug evofosfamide (TH-302) in suppressing the growth of preclinical renal and breast solid tumors

• Published in: Molecular cancer therapeutics Vol. 14; no. 12_Supplement_2; p. B174
• Main Authors: Lavranos, Tina C., Inglis, Daniel, Beaumont, Donna, Leske, Annabell F., Hawkins, Chloe, Scherer, Michaela, Hart, Charles, Sun, Jessica, Elenbaas, Brian, Kremmidiotis, Gabriel
• Format: Journal Article
• Language: English
• Published: 01-12-2015
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-15-B174

BNC105 is a vascular disruption agent that selectively disrupts tumor blood vessels resulting in hypoxia and necrosis. Evofosfamide (previously known as TH-302, Evo) is a nitroimidazole-triggered prodrug of bromo-isophosphoramide mustard (Br-IPM), an alkylating agent with DNA cross-linking ability. Evo is reduced by intracellular reductases, and under hypoxic conditions selectively releases Br-IPM. Evo has little activity under normoxic conditions, but is highly cytotoxic under hypoxic conditions. Both BNC105 and Evo are currently being evaluated in Phase 1-3 clinical trials. Our studies sought to establish the potential therapeutic combination of BNC105 and Evo. It was reasoned that tumor hypoxia caused by BNC105 will result in increased intratumoral activation of Evo. A greater localized conversion of Evo to Br-IPM would increase the tumor kill achieved. A dose range-finding study was conducted to define the dose level and administration schedule for the BNC105 + Evo combination. The study assessed the safety of administering these two drugs in combination in three different dosing sequences whereby Evo was administered 1hr prior to, immediately following (concurrently) or 1 hr after BNC105. Each of the drugs was administered weekly for 2 weeks. Evo dose levels examined were 50, 75, 100, and 150 mg/kg, and. BNC105 doses investigated were 10 and 16 mg/kg. The combination was well-tolerated at all dose levels evaluated when the drugs were administered concurrently or when Evo was administered 1hr before BNC105. The anti-tumor efficacy of the combination was assessed in the orthotopic syngeneic RENCA renal cancer model and in the MDA-MB-231 breast cancer xenograft model. BNC105 was used at 10 or 16 mg/kg and Evo at 75 mg/kg. RENCA kidney cancer cells were inoculated under the kidney capsule and tumors were allowed to grow for 11 days prior to commencement of dosing (Day 1). BNC105 and Evo were dosed concurrently on Days 1 and 8. Treatment groups included: vehicle control; BNC105; Evo and BNC105 + Evo. The growth of tumors implanted in the kidneys of mice was significantly impeded by the monotherapies and considerably more pronounced when these two drugs were used as a combination treatment. Mice bearing subcutaneous MDA-MB-231 xenografts were treated with BNC105, Evo, or the BNC105 + Evo combination administered concurrently with the same schedule (dosing on Days 1 and 8 of a 21-day cycle). A total of 3 treatment cycles were administered. Based on tumor growth inhibition, there was a clear advantage in treating MDA-MB-231 tumors with the BNC105 + Evo combination compared to either monotherapy. The combination of 16 mg/kg BNC105 + 75 mg/kg Evo substantially inhibited tumor growth as early as the 1st cycle of treatment (Day 1, 8 treatment). This effect continued through the 2nd and 3rd cycles of treatment with the tumor growth curve remaining relatively static. In both models tested the combination of BNC105 with Evo was found to be more efficacious than either therapy alone. Based on these encouraging data the combination is currently being evaluated in additional models including pancreatic cancer and soft tissue sarcoma.
Citation Format: Tina C. Lavranos, Daniel Inglis, Donna Beaumont, Annabell F. Leske, Chloe Hawkins, Michaela Scherer, Charles Hart, Jessica Sun, Brian Elenbaas, Gabriel Kremmidiotis. Complementary activity of the vascular disruption agent BNC105 and the hypoxia-activated prodrug evofosfamide (TH-302) in suppressing the growth of preclinical renal and breast solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B174.