SOURCE: Threshold Pharmaceuticals

Threshold Pharmaceuticals

November 17, 2014 07:00 ET

Threshold Pharmaceuticals Announces Phase 1/2 Interim Data Signaling Activity of TH-302 Plus Bevacizumab (Avastin®) in Patients With Glioblastoma

64% of Patients Achieved Stable Disease or Tumor Shrinkage on Combination Therapy Following Progression on Single-Agent Bevacizumab; U.S. FDA Set to Fund Phase 2 Investigator-Sponsored Trial

SOUTH SAN FRANCISCO, CA--(Marketwired - Nov 17, 2014) -  Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced interim data from a U.S. investigator-sponsored Phase 1/2 clinical trial of the investigational anticancer drug TH-302 in combination with bevacizumab (Avastin®) for the treatment of glioblastoma (GBM), the most lethal form of brain cancer. All patients in the study had previously progressed on single-agent bevacizumab, the only U.S. Food and Drug Administration (FDA)-approved therapy for GBM patients with progressive disease following prior therapy. As reported by the investigator, in a total of 22 evaluable patients, best responses included one complete response and three partial responses for a response rate of 18%, and ten stable disease assessments for a clinical benefit rate of 64%; eight patients had progressive disease. Median progression-free survival was 2.8 months, and median overall survival was 4.6 months.

The data were presented on November 14, 2014, at the 19th Annual 2014 Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO) by Andrew J. Brenner, M.D., Ph.D., 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, and Principal Investigator of the ongoing Phase 1/2 clinical trial.

"When bevacizumab fails in the second-line (recurrent disease) setting, patients often continue to receive bevacizumab and another cytotoxic agent. Historically, however, patients experience disease progression in about a month and survive approximately three months on average," said Dr. Brenner.

"The responses observed in this study are encouraging because they signal activity of TH-302 in combination with bevacizumab in a significant percentage of patients with GBM whose tumors have grown despite prior treatment with single-agent bevacizumab," said Dr. Brenner. "Of particular note were the responses of those patients with very large tumor burdens, which are historically associated with worse outcomes, who experienced stable disease on the combination therapy for some time before their tumors grew again. Based on these data, our next step is to conduct a larger Phase 2 study to see if these encouraging preliminary findings hold up and whether TH-302 can make a difference for patients with advanced-stage GBM."

In addition, the FDA, through its Office of Orphan Product Development, recently awarded Dr. Brenner a grant for a Phase 2 clinical trial of TH-302 for the treatment of GBM. His is one of 15 grants the FDA awarded in 2014 in order to boost the development of medical device, drug, and biological products for patients with rare diseases.1 According to the FDA, the grants are for clinical studies on safety and/or effectiveness of products that could either result in, or substantially contribute to, approval of the products.

Phase 1/2 Interim Data Presented at SNO

As reported at SNO, a total of 23 patients in the Phase 1/2 study were 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. No grade 4 adverse events (AEs) were observed. Three grade 3 AEs in three patients were observed: skin ulceration at 340 mg/m2, thrombocytopenia at 670 mg/m2, and oral mucositis at 670 mg/m2. Primary TH-302-related toxicities were mucosal, but were not dose limiting: rectal mucositis in one of four (1/4) patients at 480 mg/m2 and all patients (13/13) at 670 mg/m2 (all grade 1 or 2). Oral mucositis was less frequent. Best tumor responses in 22 patients evaluable by RANO criteria included one complete response and three partial responses for a response rate of 18%, and ten stable disease assessments for a clinical benefit rate of 64%; eight patients had progressive disease. Median progression-free survival was 2.8 months (95% confidential interval (CI): 1.9 to 3.9 months) and 4-month progression-free survival was 22% (95% CI: 3.2% to 41%). Median overall survival was 4.6 months (95% CI: 3.4 to 6.2 months).

Planned Phase 2 Study

Dr. Brenner's planned investigator-sponsored Phase 2 trial, which is designed to assess safety and efficacy of 670 mg/m2 TH-302 in combination with bevacizumab for the treatment of recurrent GBM following prior bevacizumab failure, is expected to enroll up to 33 patients. PET imaging will also be conducted in an effort to predict which patients may benefit from TH-302 combination therapy. Dana Farber Cancer Institute and The University of Texas at Austin will participate in the trial. Threshold and Merck KGaA, Darmstadt, Germany, will provide TH-302 for the trial.

About GBM

GBM is the most common and most aggressive of the primary malignant brain tumors in adults with a 5-year survival rate of less than 5%.2 Standard of care for patients with GBM is surgery, radiation, and concurrent temozolomide (TMZ), followed by adjuvant TMZ. Despite chemoradiation, tumor regrowth inevitably occurs.3 Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) currently approved in the U.S. for treating recurrent GBM; however, responses are rarely durable.4 Continuation of bevacizumab in combination with another chemotherapeutic agent has been associated with median progression-free survival of 37.5 days and median overall survival of 2.7 months.5

About TH-302

TH-302, an investigational hypoxia-activated prodrug, 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 locally advanced unresectable or metastatic STS, and the other in combination with gemcitabine versus gemcitabine and placebo in patients with advanced pancreatic cancer (the MAESTRO trial). Both Phase 3 trials are being conducted under Special Protocol Assessment (SPA) agreements with the FDA. The FDA and the European Commission have granted TH-302 Orphan Drug Designation for the treatment of STS and pancreatic cancer. TH-302 is also being investigated in a Phase 2b trial designed to support registration for the treatment of non-squamous non-small cell lung cancer, and in earlier-stage clinical trials of other solid tumors and hematological malignancies.

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 Pharmaceuticals, Inc. 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).

Forward-Looking Statements

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 and statements regarding the TH-302 development plan, including the planned investigator-sponsored Phase 2 trial of TH-302 in combination with bevacizumab for the treatment of recurrent GBM following prior bevacizumab failure, or the planned Phase 2 Investigator Sponsored Trial (IST). 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: the ability of Threshold, Merck KGaA, Darmstadt, Germany, and third-party investigators to initiate, enroll or complete TH-302 clinical trials; the time and expense required to conduct such clinical trials and analyze data; issues arising in the regulatory or manufacturing process and the results of such clinical trials (including product safety issues and efficacy results); the risk that the final data from ongoing trials may be materially different from any interim or preliminary data that Threshold or third-party investigators have reported; the risk that later trials may not confirm the results of earlier trials; the risk that the design of, or data collected from, clinical trials of TH-302 may be inadequate to demonstrate safety and efficacy, or otherwise may be insufficient to support regulatory submissions and/or approvals, and therefore, significant uncertainty remains regarding the regulatory approval process for TH-302; the risk that the FDA's decision to award the grant for the planned Phase 2 IST is not an indication of the approvability of TH-302 and does not increase the likelihood that TH-302 will receive any regulatory approval; Threshold's and Merck KGaA's (Darmstadt, Germany) dependence on single source suppliers, including the risk that these single source suppliers may be unable to meet clinical supply demands for TH-302 which could significantly delay the development of TH-302; risks related to Threshold's dependence on its collaborative relationship with Merck KGaA, Darmstadt, Germany, including its dependence on decisions by Merck KGaA, Darmstadt, Germany regarding the amount and timing of resource expenditures for the development of TH-302; and Threshold's need for and the availability of resources to develop TH-302 and to support Threshold's operations. 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 3, 2014 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.

References
1. U.S. Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm416738.htm (accessed November 14, 2014)
2. Dolecek TA, et al. Neuro-Oncology 14:v1-v49, 2012
3. Piccioni DE, et al. Neuro-Oncology 16:815-822, 2014
4. Weathers S-P and Gilbert MR. F1000Prime Reports 6:46, 2014
5. Quant EC, et al. Neuro-Oncology 11:550-555, 2009

Contact Information