Threshold
Pharmaceuticals, Inc. THLD today announced early clinical
data from two single-arm, open-label Phase 1 trials evaluating
TH-302, an investigational, hypoxia-targeted drug, in combination
with antiangiogenic agents for the treatment of advanced solid
tumors. New data from an investigator-sponsored trial (Study 4001) in
patients with advanced solid tumors showed that combination treatment
with TH-302 plus Votrient(R) (pazopanib) achieved a clinical benefit
rate of 76% (partial response rate of 12% plus stable disease rate of
64%). Updated data from a company-sponsored trial (Study 410) in
patients with renal cell carcinoma (RCC) and gastrointestinal stromal
tumors (GIST) showed partial responses to treatment with TH-302 plus
Sutent(R) (sunitinib). Detailed results for Studies 410 and 4001 will
be presented this Monday and Tuesday, respectively, at the 2013
AACR-NCI-EORTC International Conference on Molecular Targets and
Cancer Therapeutics in Boston, Massachusetts (Abstracts #B77 and
#C61, respectively).
"While antiangiogenics have proven to be an important new class of
targeted cancer therapy, essentially all tumors eventually become
resistant to these treatments. Novel therapeutic approaches that
address treatment resistance are greatly needed," said Herbert I.
Hurwitz, MD, Professor of Medicine at Duke Cancer Institute and
principal investigator of Study 4001. "Co-targeting tumor
angiogenesis and tumor hypoxia, which is believed to be a key driver
of treatment resistance, is one approach to potentially prevent or
reverse this mechanism of resistance. These early clinical data
combining pazopanib and TH-302 in refractory cancers demonstrate
preliminary signals of activity that warrant further investigation."
The combination study with TH-302 plus pazopanib was conducted in 30
patients with a variety of solid tumors for whom standard therapy or
palliative measures were nonexistent or no longer effective. The
clinical benefit rate was 76% (n=25 evaluable patients) with three
patients with partial responses (12%) and 16 patients with stable
disease (64%). The partial responses were observed in patients with
neuroendocrine cancer, ovarian cancer, and chondrosarcoma.
Treatment-related grade 3 hematological adverse events were reported
for neutropenia (7%), thrombocytopenia (7%), and anemia (13%).
Treatment-related, grade e 2 nonhematologic adverse events
included vomiting/nausea/diarrhea (7% grade 3), mucositis (7% grade
3), hand foot syndrome (all grade 2), and hypertension (all grade 2).
No grade 4 adverse events have been reported. The study has completed
enrollment and treatment is ongoing.
In addition, updated preliminary results from the combination study
with TH-302 plus sunitinib (n=12) showed that partial responses were
achieved by one of four (25%) evaluable GIST patients (confirmed) and
three of six (50%) evaluable RCC patients (two confirmed). All four
patients with partial responses had received prior sunitinib. Grade 3
thrombocytopenia and neutropenia were reported in 3 (25%) and 4 (33%)
patients, respectively; grade 4 neutropenia was reported in one
patient (8%). Fatigue, nausea, and vomiting were the most common
nonhematologic adverse events occurring in 83%, 75%, and 67% of
patients, respectively. All cases were grade 1 or 2 except for one
report of grade 3 nausea.
Preclinical Data on TH-302 in Pancreatic Cancer Also to be Presented
at Meeting
Preclinical data on the combination of TH-302 with
Gemzar(R) (gemcitabine) and Abraxane(R) (nab-paclitaxel) in models of
pancreatic cancer will be presented at the meeting on Tuesday October
22 (Abstract #C287) showing in xenograft models greater anti-tumor
activity associated with the "triplet" (TH-302 plus gemcitabine plus
nab-paclitaxel) compared with that of the doublet (gemcitabine plus
nab-paclitaxel), and without additive hematological toxicity or
peripheral neuropathy.
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