Threshold Pharmaceuticals Reports TH-302 Data at the 55th Annual Meeting of the
American Society of Hematology (ASH)
38 Percent Clinical Benefit Rate Reported for Combination Therapy
With TH-302 and Dexamethasone in Heavily Pretreated Patients With
Relapsed/Refractory Multiple Myeloma; Responses to TH-302 Monotherapy
Observed in Patients With Advanced Leukemias
SOUTH SAN FRANCISCO, CA -- (Marketwired) -- 12/07/13 -- Threshold
Pharmaceuticals, Inc. (NASDAQ: THLD), today announced that clinical
data from two early-stage trials of TH-302, its investigational
hypoxia-targeted drug, will be presented at the 55th Annual Meeting
of the American Society of Hematology (ASH), taking place December 7
- 10, 2013, New Orleans, LA.
Results from the dose escalation component of a Phase 1/2 clinical
trial of TH-302 in combination with dexamethasone in patients with
relapsed and/or refractory multiple myeloma will be presented in a
poster session on Saturday evening (Abstract #1948). Fourteen
patients initiated therapy, all having received 3 to 11 prior
treatments (median of 6.5) and all having received a regimen
containing Velcade(R) (bortezomib, a first-in-class proteasome
inhibitor), an immunomodulatory agent [Revlimid(R) (lenalidomide)
and/or Thalomid(R) (thalidomide)], and an alkylating agent.
"There are few treatment options for patients with advanced multiple
myeloma who stop responding to bortezomib and lenalidomide, and
responses to subsequent salvage therapy have historically been
extremely low," said Irene Ghobrial, M.D., Associate Professor of
Medicine at Dana-Farber Cancer Institute, who led the study and will
present the results at ASH. "The preliminary results suggest that the
combination of TH-302 with dexamethasone is active in some heavily
pretreated patients who stop responding to conventional therapy."
Thirteen patients were evaluable for response. Two patients achieved
a partial response and three patients achieved a minimal response,
with the combination of the two types of responses comprising a
clinical benefit rate of 38 percent. Seven patients had stable
disease and one patient had progressive disease. One patient with a
minimal response continues to receive therapy after approximately six
months. Two patients, one with a partial response and one with stable
disease, remained on the study for more than one year (13 to 15
months) before discontinuing.
"We are encouraged by these preliminary results obtained thus far at
Dana-Farber Cancer Institute and are expanding the number of clinical
trial sites to help accelerate enrollment," said Tillman Pearce,
M.D., Chief Medical Officer at Threshold. "Our next steps are to
better characterize the efficacy and safety at the maximum tolerated
dose of TH-302 in combination with dexamethasone and then to evaluate
the addition of a proteasome inhibitor to the therapeutic regimen."
TH-302 is designed to be selectively activated under conditions of
tumor hypoxia. In mouse models of multiple myeloma, diseased animals
showed a marked expansion of hypoxia in the bone marrow, suggesting
that hypoxia may be a therapeutically meaningful target in this
disease. TH-302 has shown antimyeloma activity in cell culture and in
mouse models of multiple myeloma as well as synergistic activity with
the proteasome inhibitor bortezomib in cell culture.
The dose of TH-302 administered in the dose escalation portion of the
study was 240, 340, or 480 mg/m2 (depending on the dose cohort into
which a patient enrolled) given on days 1, 4, 8, and 11 of a 21-day
cycle, with 40 mg dexamethasone given on the same days as TH-302.
Patients received one to 19 cycles (median of 4 cycles) 3-week cycles
of therapy with TH-302 and dexamethasone. No dose-limiting toxicities
were reported during Cycle 1 at TH-302 doses of 240 or 340 mg/m2. Two
dose-limiting toxicities of grade 3 stomatitis were reported during
Cycle 1 for the two patients treated at 480 mg/m2. Therefore, the
maximum tolerated dose was determined to be 340 mg/m2 TH-302. The
most frequent grade 3/4 side effects were thrombocytopenia,
leukopenia, anemia, and neutropenia.
Data on TH-302 Monotherapy in Advanced Leukemias to be Presented on
Results from a Phase 1 clinical trial of TH-302 administered as
single-agent monotherapy will be presented in a poster session on
Monday evening (Abstract #3920). As reported in the abstract, a total
of 49 patients with previously treated AML (n=39), ALL (n=9) or CML
in blast phase (n=1) initiated therapy with TH-302.
"This trial has provided useful information on TH-302 dosing in
patients with advanced leukemias, and the responses observed in these
very difficult to treat patients are consistent with the monotherapy
activity that we have previously observed in a variety of solid
tumors," said Dr. Pearce. "Further evaluation of TH-302 in
combination with other chemotherapies for the treatment of advanced
leukemias is warranted."
In the first part of the trial, a total of 38 patients received
30-minute bolus administration of TH-302 at escalating doses of 120 -
550 mg/m2 (depending on the dose cohort) daily on days 1-5 of a
21-day cycle. Two of three evaluable patients treated with bolus
TH-302 (550 mg/m2) experienced dose-limiting toxicities of grade 3
esophagitis and the maximum-tolerated dose for the daily 30-minute
bolus administration was established at 460 mg/m2.
In the second part of the trial, a total of 11 patients received
TH-302 as a continuous infusion on days 1-5 of a 21-day cycle. Two of
three patients treated with continuous infusion of TH-302 (460
mg/m2/day) experienced dose-limiting toxicities of grade 3 mucositis
or grade 3 hyperbilirubinemia; continuous administration
maximum-tolerated dose was established at 330 mg/m2/day.
Generally, a significant rapid cytoreduction was documented early in
Cycle 1, but was not maintained prior to initiation of the next
cycle. Two AML patients who received 550 mg/m2 bolus TH-302 had
complete resolution of leukemia cutis. One AML patient at 550 mg/m2
bolus TH-302 had a complete response with incomplete platelet
recovery (CRp), and one AML patient at 440 mg/m2 bolus TH-302 had a
Abstract #1948: Phase 1 Study of TH-302, an Investigational
Hypoxia-Targeted Drug, and Dexamethasone in Patients with
Relapsed/Refractory Multiple Myeloma; 5:30 PM - 7:30 PM Central Time
on Saturday, December 7, 2013, in Hall G.
Abstract #3920: A Phase 1 Study of TH-302, an Investigational
Hypoxia-Targeted Drug, In Patients With Advanced Leukemias; 6:00 PM -
8:00 PM Central Time on Monday, December 9, 2013, in Hall E.
Abstracts are now available on the ASH website at www.hematology.org.
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
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 multiple myeloma, advanced leukemias 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 dexamethasone or
other targeted agents to treat multiple myeloma, or whether
additional trials are conducted to evaluate TH-302 in advanced
leukemias, 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.
Laura Hansen, Ph.D.
Senior Director, Corporate Communications
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