Threshold Pharma (ThLD) Doses First Patient in TH-302 Phase 1/2
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Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced that the first patient has been dosed in its Phase 1/2 clinical trial of TH-302 as monotherapy and in combination with bortezomib in patients with relapsed/refractory multiple myeloma who have received at least two prior lines of therapy. TH-302 is a hypoxia-targeted drug. Bortezomib (Velcade) is approved for the treatment of multiple myeloma, a hematologic cancer that develops in the bone marrow.
The primary objectives of the Phase 1/2 open label study are to evaluate the safety and tolerability of TH-302 as monotherapy and in combination with bortezomib in subjects with relapsed/refractory multiple myeloma, to identify potential dose-limiting toxicities, and to determine the maximum tolerated dose (MTD) and a recommended Phase 2 dose. Up to 60 patients will be enrolled at the Dana-Farber Cancer Institute in Boston, Massachusetts.
The initial dose escalation phase of the trial will investigate TH-302 as a single agent and enroll cohorts of up to 6 patients per dose. TH-302 will be administered on Days 1, 4, 8 and 11 of a 21 day cycle with a starting TH-302 dose of 240 mg/m2. Once the MTD is established a Simon two-stage design will be used. If there is sufficient activity at the MTD, the expansion phase of the study will allow an additional 15 subjects to be enrolled for a total of 24 subjects treated at the MTD. If the cumulative safety data from the dose escalation and expansion phases of the study confirm that monotherapy is well-tolerated, patients will then be enrolled into a separate dose escalation study investigating TH-302 in combination with bortezomib using the same dosing schedule.
Clinical Rationale TH-302 is thought to be selectively activated in the hypoxic microenvironment of tumors. Preclinical data support the hypothesis that TH-302 targets hypoxic regions of both solid tumors and hematologic malignancies. In multiple myeloma, hypoxia appears to be an important component of the microenvironment and TH-302 has shown significant activity in preclinical models. Additionally, an in vivo study presented at the 2011 International Myeloma Workshop demonstrated that the combination of TH-302 and bortezomib synergistically induced apoptosis (programmed cell death), and that the combination of TH-302 and bortezomib showed improvements in multiple disease parameters, including decreased tumor burden, when compared to TH-302 or bortezomib alone.
The primary objectives of the Phase 1/2 open label study are to evaluate the safety and tolerability of TH-302 as monotherapy and in combination with bortezomib in subjects with relapsed/refractory multiple myeloma, to identify potential dose-limiting toxicities, and to determine the maximum tolerated dose (MTD) and a recommended Phase 2 dose. Up to 60 patients will be enrolled at the Dana-Farber Cancer Institute in Boston, Massachusetts.
The initial dose escalation phase of the trial will investigate TH-302 as a single agent and enroll cohorts of up to 6 patients per dose. TH-302 will be administered on Days 1, 4, 8 and 11 of a 21 day cycle with a starting TH-302 dose of 240 mg/m2. Once the MTD is established a Simon two-stage design will be used. If there is sufficient activity at the MTD, the expansion phase of the study will allow an additional 15 subjects to be enrolled for a total of 24 subjects treated at the MTD. If the cumulative safety data from the dose escalation and expansion phases of the study confirm that monotherapy is well-tolerated, patients will then be enrolled into a separate dose escalation study investigating TH-302 in combination with bortezomib using the same dosing schedule.
Clinical Rationale TH-302 is thought to be selectively activated in the hypoxic microenvironment of tumors. Preclinical data support the hypothesis that TH-302 targets hypoxic regions of both solid tumors and hematologic malignancies. In multiple myeloma, hypoxia appears to be an important component of the microenvironment and TH-302 has shown significant activity in preclinical models. Additionally, an in vivo study presented at the 2011 International Myeloma Workshop demonstrated that the combination of TH-302 and bortezomib synergistically induced apoptosis (programmed cell death), and that the combination of TH-302 and bortezomib showed improvements in multiple disease parameters, including decreased tumor burden, when compared to TH-302 or bortezomib alone.
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