Threshold Pharmaceuticals Announces Update on Its Phase 3 Trial in Soft Tissue Sarcoma

Threshold Pharmaceuticals Announces Update on Its Phase 3 Trial in Soft Tissue 
Sarcoma 
Company to Host Conference Call and Webcast Today, July 1, 2013 at
8:30 AM ET 
SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 07/01/13 --  Threshold
Pharmaceuticals, Inc. (NASDAQ: THLD) today announced a protocol
amendment to the company's pivotal Phase 3 trial of TH-302, an
investigational hypoxia-targeted drug, in patients with advanced soft
tissue sarcoma (STS). The changes to the protocol are based on new
assumptions related to the performance of current standard of care in
STS, as well as a higher than anticipated rate of enrollment, and are
intended to strengthen the ability of the study to detect a
clinically meaningful and statistically significant effect of TH-302
on overall survival. The U.S. Food and Drug Administration (FDA) has
agreed to the amendment under the existing Special Protocol
Agreement.  
The first change to the protocol is an increase in the number of
patients (from 450 to 620). This increase is intended to adjust for
new assumptions about the primary endpoint overall survival, based on
the latest medical findings in STS clinical research. According to
recently published data, patients who receive standard of care
treatment being used in the control arm of Threshold's study may live
longer than has historically been observed.(1) The addition of
patients to the trial is required to maintain the power of the study
and the ability to detect a clinically meaningful effect of TH-302
with a robust level of statistical significance.  
The second change to the protocol comprises the removal of an interim
futility analysis of the secondary endpoint progression-free survival
(PFS). Given the study's high rate of enrollment, an interim futility
analysis would no longer serve its original purpose as the trial
would be largely through its enrollment phase by the time the
analysis would be completed. Safety will remain under regular review
by an Independent Data Monitoring Committee (IDMC). 
Though Threshold will remain blinded to the data from its ongoing
Phase 3 trial, an IDMC, which monitors patient safety on an ongoing
basis, will conduct an interim analysis for survival after 235 events
are reached and data are ready for analysis. Although the tim
ing is
event-based, the interim analysis is projected to occur in the first
half of 2014. The interim efficacy analysis is designed to allow for
the early termination of the study based on achieving a pre-specified
statistical outcome and recommendation of the IDMC. If the IDMC
recommends that the study continue as planned, Threshold will remain
blinded to the data until the company conducts the final analysis on
overall survival when 434 events will have been reached. Unless the
IDMC recommends that the study end early, Threshold expects to report
top-line results following the final efficacy analysis on overall
survival in the first half of 2015. 
"We are pleased with the FDA's agreement on the protocol amendment,
which is intended to strengthen our Phase 3 study," said Barry
Selick, Ph.D., Chief Executive Officer of Threshold. "Importantly, at
our current enrollment rate, we should be able to accommodate the
increase in sample size while still completing enrollment of the
study around the end of this year." 
"The scientific and clinical data provide rationale for evaluating
TH-302 as a potential new therapy for patients with STS," said
William D. Tap, M.D., Section Chief, Sarcoma Oncology at Memorial
Sloan-Kettering Cancer Center and Principle Investigator of the Phase
3 study. "TH-302 is activated under hypoxic conditions, a common
feature of many solid tumors, which may be associated with worse
outcomes in patients with soft tissue sarcoma. Importantly, the
critical need remains for new therapies to improve outcomes for
patients with soft tissue sarcoma, and we are looking forward to the
outcome of this Phase 3 study."  
About the Clinical Development Program for TH-302 in Patients with
Soft Tissue Sarcoma 
Threshold is conducting this international, randomized, pivotal Phase
3 trial in partnership with the Sarcoma Alliance for Research through
Collaboration (SARC). The trial is enrolling patients with metastatic
or locally advanced unresectable soft tissue sarcoma and is designed
to evaluate the efficacy and safety of TH-302 in combination with
doxorubicin, compared to doxorubicin alone. The Phase 3 trial for
TH-302 was initiated following results from a multi-center,
dose-escalation, single arm, uncontrolled Phase 1/2 trial of TH-302
in 91 patients with soft tissue sarcoma.(2) The most commonly
reported adverse events were nausea and fatigue, which were reported
in 70% and 67% of patients, respectively. Skin rash and
hyperpigmentation were reported in 32% and 18% of patients,
respectively; stomatitis, an inflammation of the mucous lining in the
mouth and throat, was reported in 41% of patients. These events were
all grade 1 or grade 2 and reversible. Frequency of grade 3/4
neutropenia and thrombocytopenia was 20% and 25%, respectively.
Febrile neutropenia or neutropenic sepsis were reported in 10% of
patients. There was no evidence of renal, hepatic or cardiotoxicity.
Updated efficacy results showed that patients treated with TH-302 and
doxorubicin had a median overall survival of 21.5 months and an
overall best response (partial and complete responses, unconfirmed)
of 36%.(3) 
About Soft Tissue Sarcoma 
Sarcomas are a group of aggressive cancers of connective tissues of
the body for which there are currently limited treatment options.
Soft tissue sarcomas are treated with surgery, chemotherapy and
radiation. Usually a combination of these modalities offers the best
chance to treat the disease successfully. Doxorubicin and ifosfamide
are the most commonly used chemotherapeutic agents in patients with
advanced soft tissue sarcoma, but response rates are generally low
and toxicity can be significant. The American Cancer Society
estimates about 11,410 new soft tissue sarcomas will be diagnosed in
2013 and 4,390 Americans are expected to die from these cancers. 
About TH-302 
TH-302 is an investigational hypoxia-targeted drug that is designed
to be activated under severe 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 (STS), and the other in combination with
gemcitabine versus gemcitabine and placebo in patients with advanced
pancreatic cancer. Both Phase 3 trials are being conducted under a
Special Protocol Assessment 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 STS.
TH-302 is also being investigated in hematological malignancies and
combination trials in solid tumors. 
Threshold signed a global license and co-development agreement for
TH-302 with Merck KGaA, Darmstadt, Germany, in February 2012, which
includes an option for Threshold to co-commercialize in the U.S. 
Conference Call and Webcast  
At 8:30 a.m. Eastern Time today, Threshold's management will host a
conference call and a simultaneous webcast to discuss the Phase 3 STS
study update. The
 webcast can be accessed on the company's website in
the Investors/Webcasts section
http://investor.thresholdpharm.com/events.cfm. Alternatively, please
call 1-866-748-8653 (U.S) or 1-678-825-8234 (international). The
conference ID number is 13817932. The webcast will be archived on
Threshold's website though August 1, 2013.  
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 the microenvironments of most solid
tumors as well as the bone marrows of some patients with 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 timing and potential results of the Phase 3 trial of
TH-302 in patients with advanced soft tissue sarcoma, including a
potential interim analysis, rate of patient enrollment in the Phase 3
trial of TH-302 in patients with advanced soft tissue sarcoma, and
potential therapeutic uses and benefits of TH-302 to treat patients
with soft tissue sarcoma, pancreatic cancer 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, the ability to enroll or complete anticipated clinical
trials, the time and expense required to conduct such clinical trials
and analyze data, whether later trials confirm the results of earlier
trials, whether the Phase 3 trial data is sufficient to support
regulatory approval to market TH-302, 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 May 2, 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. 
References 
1. Judson I, et al. Results of a randomised phase III trial (EORTC
62012) of single agent doxorubicin versus doxorubicin plus ifosfamide
as first line chemotherapy for patients with advanced or metastatic
soft tissue sarcoma: a survival study by the EORTC Soft Tissue and
Bone Sarcoma Group. Presented at the 37th European Society for
Medical Oncology Congress; September 28-October 2, 2012; Vienna,
Austria. Abstract LBA7.  
2. Chawla SP, et al. A Phase 2 Study of TH-302 in combination with
doxorubicin in advanced soft tissue sarcoma. Presented at the 16th
Annual Meeting of the Connective Tissue Oncology Society; October
26-29, 2011; Chicago, Illinois. 
3. Ganjoo KN, et al. TH-302 maintenance following TH-302 plus
doxorubicin induction: the results of a phase 2 study of TH-302 in
combination with doxorubicin in soft tissue sarcoma. Presented at the
17th annual meeting of the Connective Tissue Oncology Society;
November 14-17, 2012; Prague, Czech Republic. 
Contact 
Laura Hansen, Ph.D.
Senior Director, Corporate Communications
Threshold Pharmaceuticals
Phone: 650-474-8206
E-mail: lhansen@thresholdpharm.com 
 
 
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