Threshold Pharma Reports Early Clinical Data for Combining TH-302, Says Trial Achieved Partial Response Rate 12%, Stable Disease Rate 64%

Threshold Pharmaceuticals, Inc.

today announced early clinical data from two single-arm, open-label Phase 1 trials evaluating TH-302, an investigational, hypoxia-targeted drug, in combination with antiangiogenic agents for the treatment of advanced solid tumors. New data from an investigator-sponsored trial (Study 4001) in patients with advanced solid tumors showed that combination treatment with TH-302 plus Votrient(R) (pazopanib) achieved a clinical benefit rate of 76% (partial response rate of 12% plus stable disease rate of 64%). Updated data from a company-sponsored trial (Study 410) in patients with renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST) showed partial responses to treatment with TH-302 plus Sutent(R) (sunitinib). Detailed results for Studies 410 and 4001 will be presented this Monday and Tuesday, respectively, at the 2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts (Abstracts #B77 and #C61, respectively). "While antiangiogenics have proven to be an important new class of targeted cancer therapy, essentially all tumors eventually become resistant to these treatments. Novel therapeutic approaches that address treatment resistance are greatly needed," said Herbert I. Hurwitz, MD, Professor of Medicine at Duke Cancer Institute and principal investigator of Study 4001. "Co-targeting tumor angiogenesis and tumor hypoxia, which is believed to be a key driver of treatment resistance, is one approach to potentially prevent or reverse this mechanism of resistance. These early clinical data combining pazopanib and TH-302 in refractory cancers demonstrate preliminary signals of activity that warrant further investigation." The combination study with TH-302 plus pazopanib was conducted in 30 patients with a variety of solid tumors for whom standard therapy or palliative measures were nonexistent or no longer effective. The clinical benefit rate was 76% (n=25 evaluable patients) with three patients with partial responses (12%) and 16 patients with stable disease (64%). The partial responses were observed in patients with neuroendocrine cancer, ovarian cancer, and chondrosarcoma. Treatment-related grade 3 hematological adverse events were reported for neutropenia (7%), thrombocytopenia (7%), and anemia (13%). Treatment-related, grade e 2 nonhematologic adverse events included vomiting/nausea/diarrhea (7% grade 3), mucositis (7% grade 3), hand foot syndrome (all grade 2), and hypertension (all grade 2). No grade 4 adverse events have been reported. The study has completed enrollment and treatment is ongoing. In addition, updated preliminary results from the combination study with TH-302 plus sunitinib (n=12) showed that partial responses were achieved by one of four (25%) evaluable GIST patients (confirmed) and three of six (50%) evaluable RCC patients (two confirmed). All four patients with partial responses had received prior sunitinib. Grade 3 thrombocytopenia and neutropenia were reported in 3 (25%) and 4 (33%) patients, respectively; grade 4 neutropenia was reported in one patient (8%). Fatigue, nausea, and vomiting were the most common nonhematologic adverse events occurring in 83%, 75%, and 67% of patients, respectively. All cases were grade 1 or 2 except for one report of grade 3 nausea. Preclinical Data on TH-302 in Pancreatic Cancer Also to be Presented at Meeting Preclinical data on the combination of TH-302 with Gemzar(R) (gemcitabine) and Abraxane(R) (nab-paclitaxel) in models of pancreatic cancer will be presented at the meeting on Tuesday October 22 (Abstract #C287) showing in xenograft models greater anti-tumor activity associated with the "triplet" (TH-302 plus gemcitabine plus nab-paclitaxel) compared with that of the doublet (gemcitabine plus nab-paclitaxel), and without additive hematological toxicity or peripheral neuropathy.