Date: 2014-05-30
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 50th American Society of Clinical Oncology (ASCO) Annual Meeting, May 30 to June 3, 2014, in Chicago
Company: Threshold Pharmaceuticals (USA - CA)
Product: TH-302
Action
mechanism: TH-302 is a hypoxia-activated prodrug consisting of a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. The product has been discovered by Threshold scientists. It is designed as a prodrug that is selectively activated under the extreme hypoxic conditions commonly found in tumors, but not typically in healthy tissues. Within regions of tumor hypoxia, TH-302 is converted to its active form, bromo isophoramide mustard (Br-IPM). Variants of IPM are clinically validated potent DNA alkylating agents, which kill tumor cells by causing DNA to crosslink thereby rendering cells unable to replicate their DNA and divide. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect”.
In February 2012, Merck KGaA signed a global agreement to co-develop and commercialize TH-302 with Threshold. Under the terms of the agreement, Merck KGaA received co-development rights, exclusive global commercialization rights with Threshold retaining an option to co-commercialize the therapeutic in the United States.
Disease: recurrent glioblastoma
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On May 30, 2014, Threshold Pharmaceuticals announced new clinical data from an ongoing investigator-sponsored Phase 1/2 trial of its investigational hypoxia-activated prodrug, TH-302, in combination with bevacizumab (Avastin®) in patients with recurrent glioblastoma following progression on single-agent bevacizumab. The results are being presented as part of the poster highlights session on Central Nervous System Tumors at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago [Abstract #2029 (Poster #20)]. The objectives of the ongoing Phase 1/2 investigator-sponsored trial include evaluating the safety and tolerability of TH-302, determining thedose-limiting toxicities and the maximum-tolerated dose of TH-302, and assessing preliminary signals of clinical activity in patients with bevacizumab-refractory recurrent glioblastoma. The ASCO poster reports on a total of 17 patients treated with bevacizumab 10 mg/kg every two weeks and TH-302 dose escalated 240-670 mg/m2 every two weeks (four-week cycle) until disease progression. Patients had received a median of three prior systemic anticancer regimens including both chemoradiation and bevacizumab. Preliminary assessment of safety and tolerability: No Grade 4 adverse events were observed at any dose. Three Grade 3 adverse events were observed: skin ulceration at 340 mg/m2, oral mucositis at 670 mg/m2, and thrombocytopenia at 670 mg/m2. The primary TH-302 related toxicities were mucosal: rectal/anal mucositis in one of four patients at 480 mg/m2 (Grade 2) and six of seven patients at 670 mg/m2 (all Grade 1 or 2). Limited oral mucositis was observed. Preliminary assessment of clinical activity: In 17 patients evaluable for response according to Response Assessment in Neuro-Oncology (RANO) criteria, best responses included one complete response (1CR) and three partial responses (3PR) for a response rate of 24%, and eight stable disease (8 SD) assessments for a clinical benefit rate of 65%; five patients had progressive disease (5 PD). The longest disease stabilization is ongoing at 30 months. The median progression-free survival (PFS) for patients treated with TH-302 plus bevacizumab was 3.1 months, while these patients experienced PFS of 2.4 months on their first bevacizumab regimen. The 4-month PFS rate was 26%. Median overall survival of patients treated with TH-302 plus bevacizumab was 4.9 months.
