9 November 2009 - US-based biotechnology company Threshold Pharmaceuticals Inc (NASDAQ: THLD) reported on 6 November interim data from a Phase I/II study of its clinical stage hypoxia-activated prodrug, TH-302.
Data were presented at the 15th Annual Connective Tissue Oncology Society (CTOS) Meeting taking place in Miami Beach, Florida.
The presentation focused on the 403 trial, which is investigating TH-302 in combination with doxorubicin in patients with soft tissue sarcoma who have not received prior doxorubicin. Twelve patients have had at least one evaluable post-treatment tumour assessment, including 3 (25%) with a partial response (PR) as measured by RECIST (Response Evaluation Criteria In Solid Tumours). Two of the PRs are confirmed, including one patient who has remained on study for 33 weeks. One of the PRs was unconfirmed due to progression at the subsequent assessment. Five of the 12 patients continue to receive TH-302 after receiving TH-302 for 3 to 13 three-week cycles. Seven (58%) patients achieved stable disease while 2 (17%) had progressive disease. Additional patients are being enrolled to better define the extent of the tumour response activity.
Chief medical officer, John Curd, said the company believes that TH-302 may "complement" doxorubicin, the standard of care in sarcoma, and treat that portion of the tumour that typically does not respond to this traditional chemotherapy agent. This clinical trial has thus far established that TH-302 can be safely combined with full doses of doxorubicin, and the preliminary data suggests that TH-302 may add to the activity and durability of doxorubicin, added Curd.
TH-302 continues to be tolerated and there have been no new unexpected adverse events in the 14 patients assessed for safety. Nausea was the most commonly reported adverse event and was reported in 8 (57%) patients. After observing significant, but not dose limiting toxicity at a TH-302 dose of 240 mg/m2, prophylactic growth factor support was initiated. Two dose limiting toxicities, grade 3 cellulitis with grade 4 neutropenia and grade 4 thrombocytopenia, were observed in 2 of 4 patients treated at a TH-302 dose of 340 mg/m2. The maximum tolerated dose (MTD) was then established at 300 mg/m2. Skin toxicity is common with 9 of 14 (64%) patients having at least one skin adverse event. All were grade 1 or 2 with the exception of the one patient with grade 3 cellulitis. Eight (57%) patients had a mucosal adverse event; all were grade 1 or 2.
The 403 trial is a Phase I/II, multi-centre, dose escalation trial to determine the safety, efficacy and pharmacokinetics of TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. The trial was initiated in September 2008. The study will enroll up to 36 patients including 12 patients treated at the MTD as part of the dose expansion component of the trial. TH-302 is administered intravenously on days 1 and 8 of a 21 day cycle. Doxorubicin is dosed according to its package insert (75 mg/m2 on day 1 of the 21 day cycle). The Phase I/II clinical trial has completed the dose escalation component, reached the MTD and is currently enrolling patients in the dose expansion cohort.
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