SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 11/22/13 -- Threshold Pharmaceuticals, Inc. (NASDAQ: THLD), today announced early data from the Phase 1 portion of an investigator-sponsored Phase 1/2 trial of its investigational hypoxia-targeted drug TH-302 in combination with Avastin® (bevacizumab) in patients with recurrent glioblastoma following bevacizumab failure (Study 4003). No dose-limiting toxicity has been reported to date at doses of TH-302 up to 670 mg/m2 plus bevacizumab at 10 mg/m2 every two weeks. Preliminary data in 14 patients showed TH-302 in combination with bevacizumab was associated with a median time to progression of 2.8 months. One patient achieved a complete response and two patients achieved partial responses. The data will be presented this evening from 7 p.m. to 9 p.m. at the 4th Quadrennial World Federation of Neuro-Oncology (WFNO) meeting held in conjunction with the 18th annual 2013 Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO), San Francisco, CA.
Chemotherapy with radiotherapy is standard care for newly diagnosed glioblastoma. Bevacizumab is approved in the U.S. for progressive disease following prior therapy. After disease progression on bevacizumab, patients may start a subsequent bevacizumab-containing regimen. These patients typically progress in 5 to 8 weeks.(1,2) Three-month progression-free survival is approximately 15%.(1)
"There is a critical unmet need for new medicines to treat patients with glioblastoma who experience recurrence of their disease," said Andrew J. Brenner, M.D., Ph.D., Principal Investigator of the study and Clinical Investigator with the Institute for Drug Development at the Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio, Texas. "These preliminary data signal that TH-302 in combination with bevacizumab may have activity in patients with glioblastoma following single-agent bevacizumab failure. We are looking forward to further evaluation of TH-302 as this study continues to enroll patients."
A total of 19 patients have been enrolled in the ongoing trial. Of 14 patients evaluable for tumor response, the median time to progression was 86 days. Forty-six percent (95% CI: 18% - 74%) of patients were alive without disease progression after three months of treatment. Best tumor responses were one patient achieving a complete response, two patients achieving a partial response, and seven patients demonstrating stable disease; four patients experienced progressive disease. The longest disease stabilization is currently ongoing in one patient who achieved a partial response and is currently receiving cycle 26 at 22 months.
No grade 4 adverse events were observed at any dose. Two grade 3 adverse events were observed at 340 mg/m2 and 670 mg/m2 of skin ulceration and thrombocytopenia, respectively. The primary TH-302 related toxicities were mucosal, with rectal mucositis in two of four patients at 480 mg/m2 and four of four patients at 670 mg/m2. Limited oral mucositis was observed. Mucositis was treated conservatively and was not dose limiting.
About the Phase 1/2 Trial (Study 4003)
The ongoing phase 1/2 trial is a single-center, dose-escalation trial in patients with recurrent glioblastoma whose disease has progressed following initial combined modality treatment with radiotherapy and temozolomide and subsequent treatment with bevacizumab. The presentation at WFNO/SNO will include data from a total of 14 evaluable patients who received combination therapy of bevacizumab (10 mg/m2) and TH-302 (240 to 670 mg/m2) every two weeks. Best response was assessed by Response Assessment in Neuro-Oncology (RANO) criteria. Enrollment continues at 670 mg/m2 TH-302.
About Glioblastoma and Hypoxia
Glioblastoma is the most common and most aggressive of the primary malignant brain tumors in adults (also known as Grade IV astrocytoma). Median survival is approximately 15 months; the five-year survival rate is approximately three percent. There are an estimated 30,000 new cases of glioblastoma per annum in the U.S. and Europe.
Hypoxia, a predominant characteristic of glioblastoma and most solid tumors, is associated with tumor growth, progression and resistance to conventional radiation and chemotherapies, as well as poor patient survival. Bevacizumab is a biologic antibody designed to interfere with the tumor blood supply by directly binding to a protein called VEGF. Preclinical data suggest that antiangiogenic agents, such as bevacizumab, may increase tumor hypoxia, which supports the rationale for combination therapy with a hypoxia-targeted agent in glioblastoma.
TH-302 is an investigational hypoxia-targeted drug that is designed to be activated under tumor hypoxic conditions, a hallmark of many cancers. Areas of low oxygen levels (hypoxia) in solid tumors are due to insufficient blood supply as a result of aberrant vasculature. Similarly, the bone marrow of patients with hematological malignancies has also been shown, in some cases, to be severely hypoxic.
TH-302 is currently under evaluation in two Phase 3 trials: one in combination with doxorubicin versus doxorubicin alone in patients with soft tissue sarcoma, and the other in combination with gemcitabine versus gemcitabine and placebo in patients with advanced pancreatic cancer (MAESTRO). Both Phase 3 trials are being conducted under Special Protocol Agreements with the U.S. Food and Drug Administration (FDA). The FDA and the European Commission have granted TH-302 Orphan Drug Designation for the treatment of soft tissue sarcoma and pancreatic cancer. TH-302 is also being investigated in hematological malignancies and in combination with other therapies in a variety of solid tumors.
Threshold has a global license and co-development agreement for TH-302 with Merck KGaA, Darmstadt, Germany, which includes an option for Threshold to co-commercialize in the U.S.
About Threshold Pharmaceuticals
Threshold is a biotechnology company focused on the discovery and development of drugs targeting tumor hypoxia, the low oxygen condition found in microenvironments of most solid tumors as well as the bone marrows of some hematologic malignancies. This approach offers broad potential to treat a variety of cancers. By selectively targeting tumor cells, we are building a pipeline of drugs that hold promise to be more effective and less toxic to healthy tissues than conventional anticancer drugs. For additional information, please visit our website (www.thresholdpharm.com).
Except for statements of historical fact, the statements in this press release are forward-looking statements, including statements regarding the potential therapeutic uses and benefits of TH-302 to treat patients with glioblastoma or other cancers. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Potential risks and uncertainties include, but are not limited to, whether additional trials are conducted to evaluate TH-302 in combination with bevacizumab or other chemotherapy agents to treat glioblastoma and whether such trials confirm the results of the initial trial reported here, and issues arising in the regulatory or manufacturing process and the results of such clinical trials (including product safety issues and efficacy results). Further information regarding these and other risks is included under the heading "Risk Factors" in Threshold's Quarterly Report on Form 10-Q, which has been filed with the Securities and Exchange Commission on November 4, 2013 and is available from the SEC's website (www.sec.gov) and on our website (www.thresholdpharm.com) under the heading "Investors". We undertake no duty to update any forward-looking statement made in this news release.
1. Quant EC, et al. Neuro-Oncology 11, 550-555, 2009
2. Iwamoto FM, et al. Neurology 73, 1200-1206, 2009