SOURCE: Threshold Pharmaceuticals

Threshold Pharmaceuticals

December 06, 2014 12:00 ET

Encouraging Initial Data From Ongoing Phase 1/2 Trial of TH-302 Plus Bortezomib (Velcade®) Plus Dexamethasone ("TBorD") in Patients With Relapsed/Refractory Multiple Myeloma Presented at ASH Annual Meeting

SAN FRANCISCO, CA--(Marketwired - Dec 6, 2014) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced new preliminary data from the Phase 2 component of an ongoing Company-sponsored Phase 1/2 trial of TH-302, the Company's lead investigational anticancer drug, in combination with the proteasome inhibitor bortezomib (Velcade®) and low-dose dexamethasone ("TBorD") for the treatment of patients with relapsed/refractory multiple myeloma (MM). The median number of prior therapies was 8 (range, 4-12). The recommended phase 2 dose of TH-302 was determined to be 340 mg/m2 and no dose limiting toxicities were observed at this dose level. Partial responses (one very good partial response and one partial response) were observed in 2 of 7 (29%) evaluable patients overall and 2 of 4 (50%) evaluable patients at the recommended phase 2 dose of TH-302. These data are being presented today at the 56th ASH Annual Meeting and Exposition in San Francisco, California (Abstract #2142). 

"These initial responses to TBorD therapy are encouraging given that these patients had progressive disease despite having received multiple types of treatment prior to enrollment in this study," said Irene Ghobrial, M.D., Medical Oncologist at Dana-Farber/Brigham and Women's Cancer Center and Principal Investigator of the Phase 1/2 trial. "I am also pleased with the initial safety and tolerability assessments of the TBorD regimen. In collaboration with the Blood Cancer Research Partnership, we are continuing to accrue patients to the study. Potential new treatment options for patients who have developed resistance to currently available therapies would be an important and welcome advancement in the multiple myeloma community."

"TH-302 is currently the subject of multiple clinical trials in various solid tumors, including a pivotal phase 3 trial in patients with advanced soft tissue sarcoma and another pivotal phase 3 trial in patients with advanced pancreatic cancer," said Barry Selick, Ph.D., Chief Executive Officer of Threshold. "We are pleased to see that these early clinical data in relapsed/refractory multiple myeloma are consistent with preclinical models of multiple myeloma, which demonstrated synergistic activity of combination therapy with TH-302 and bortezomib in vitro. The clinical data continue to provide support for further investigation of TH-302 in hematological malignancies, such as multiple myeloma, where hypoxia is believed to play a key role in treatment resistance."

About the Phase 1/2 Trial
The ongoing Phase 1/2 trial is investigating TH-302 and dexamethasone with or without bortezomib with respect to safety and tolerability, dose-limiting toxicities and the maximum-tolerated dose of TH-302, and preliminary efficacy in patients with relapsed/refractory MM.

A total of 18 patients with relapsed/refractory MM have been enrolled in the Phase 2 TBorD component of the study as of November 17, 2014. For the ASH presentation, preliminary safety and efficacy analyses are being presented from 9 patients (7 of whom were evaluable) who initiated therapy prior to September 12, 2014, with presented analyses reflecting data in the clinical database as of November 25, 2014.

Key data from TBorD dosing cohorts being presented at ASH include:

Preliminary assessment of safety and tolerability
No dose limiting toxicities were reported during Cycle 1 at TH-302 doses of 240 mg/m² or 340 mg/m². The maximum tolerated dose of TH-302 with dexamethasone had previously been established at 340 mg/m2, and dose escalation above that dose of TH-302 with dexamethasone plus bortezomib was not allowed.1 Therefore, after 6 patients had been treated at 340 mg/m2 without a dose limiting toxicity, the recommended Phase 2 dose of TH-302 in TBorD was established at 340 mg/m2

Safety data were available for 8 of 9 patients. The most common Grade 3/4 hematological adverse events were thrombocytopenia (reported in 4 patients), anemia (reported in 2 patients), and lymphopenia (reported in 2 patients). Fatigue (reported in 5 patients; one Grade 3/4) and nausea (reported in 4 patients; one Grade 3/4) were the most common non-hematological adverse events. Five serious adverse events (SAEs) were reported in 4 patients. One SAE of thrombocytopenia was considered related to TH-302. Skin toxicity, an adverse event of interest with TH-302, was limited: a Grade 2 rash resulting in treatment delay was reported at the 240 mg/m2 dose of TH-302, and one Grade 2 skin lesion with no impact on treatment was reported at the 340 mg/m2 dose of TH-302. There were no deaths related to the study drug.

Preliminary assessment of clinical activity
Of the 9 patients included in the ASH presentation, 7 were evaluable for response. According to modified International Myeloma Working Group (IMWG) criteria,2,3 responses included one very good partial response (VGPR), one partial response (PR), and 4 stable disease (SD) assessments; one patient had progressive disease (PD). The patients with PR and VGPR had both previously undergone two autologous transplantations and had received prior current standard treatment including IMiDs, proteasome inhibitors, dexamethasone, and at least one conventional alkylating agent.

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 2 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 expected continued accrual of patients into the Phase 2 component of the ongoing Phase 1/2 trial. 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 and Merck KGaA, Darmstadt, Germany, to 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 preclinical studies in animal models of disease may not accurately predict the results of human clinical trials of TH-302; the risk that the final data from the ongoing Phase 1/2 trial of TH-302 may be materially different from the preliminary data that Threshold has reported, particularly as patient treatment and enrollment continue and additional and updated patient data becomes available; 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. Ghobrial IM, et al. Phase 1 study of TH-302, an investigational hypoxia-targeted drug, and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood 122:1948, 2013.
2. Durie B, et al. International uniform response criteria for multiple myeloma. Leukemia 1-7, 2006.
3. Rajkumar SV, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 117: 4691-4695, 2010.

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