Threshold Pharmaceuticals Inc., a biotechnology company focused on the discovery and development of drugs targeting tumour hypoxia, has dosed the first patient in its phase I/II 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.

“Our clinical investigation of TH-302 in patients with multiple myeloma follows extensive preclinical multiple myeloma models that identified hypoxia as an essential component of the diseased marrow and that demonstrated the significant activity of TH-302 in these models,” said Irene M Ghobrial, MD, of the Myeloma Programme at the Dana-Farber Cancer Institute and principal investigator of the study. “We are hopeful that the hypoxia targeting approach of TH-302 will expand our therapeutic options for patients with this difficult disease.”

“Similar to the growing body of scientific evidence defining the role of hypoxia in the progression and failure of solid tumours to adequately respond to chemotherapy and radiotherapy, there is growing support of a similar role of hypoxia in hematologic malignancies,” said Barry Selick, PhD, CEO of Threshold. “We are excited to work with Dr Ghobrial and the Dana-Farber Cancer Institute to investigate TH-302 as a monotherapy and in combination therapy in patients with multiple myeloma.”

The primary objectives of the phase I/II 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 II 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.

TH-302 is thought to be selectively activated in the hypoxic micro-environment of tumours. Preclinical data support the hypothesis that TH-302 targets hypoxic regions of both solid tumours and haematologic malignancies. In multiple myeloma, hypoxia appears to be an important component of the micro-environment 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.

Multiple myeloma is a cancer formed by malignant plasma cells in the bone marrow. The American Cancer Society estimates approximately 21,700 new cases of myeloma will be diagnosed in 2012 in the US and 10,710 will die from the disease. The 5-year relative survival rate for multiple myeloma is approximately 40 per cent. It is estimated that world-wide there are more than 102,000 cases of myeloma diagnosed every year (GLOBOCAN 2008).