US-based Threshold Pharmaceuticals has started dosing patients in the final stage of an ongoing Phase I/II trial of its investigational hypoxia-activated prodrug, TH-302, in combination with the proteasome inhibitor bortezomib (Velcade) and low-dose dexamethasone (TBorD) to treat relapsed/refractory multiple myeloma.
In the dose-escalation and dose-expansion stages of the trial evaluating TH-302 and low-dose dexamethasone without bortezomib, patients were heavily-pretreated, and objective responses were observed in 5/16 patients treated at the maximum-tolerated dose of the prodrug.
Initial results from these stages of the trial were presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO).
Dana-Farber/Brigham and Women's Cancer Center medical oncologist and principal investigator of the Phase I/II trial Irene Ghobrial said: "Data seen thus far is encouraging using the combination of TH-302 and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma.
"I would like to acknowledge the Blood Cancer Research Partnership for their significant role in facilitating rapid accrual of patients to this study.
"We are excited to initiate this final stage in which patients will receive TH-302, bortezomib, and dexamethasone, particularly in light of preclinical research demonstrating synergistic cytotoxicity of TH-302 and bortezomib."
The objectives of the ongoing Phase I/II trial include evaluation of safety and tolerability, determination of dose-limiting toxicities and the maximum-tolerated dose of TH-302, as well as the evaluation of preliminary efficacy these patients.
Dana-Farber/Brigham and Women's Cancer Center clinical director of Jerome Lipper Multiple Myeloma Center and lead investigator on the Phase I/II trial Jacob Laubach said: "The presence of hypoxia in the diseased bone marrow may present a new therapeutic target for treating multiple myeloma and underscores my enthusiasm for further evaluation of TH-302 in this disease."
In patients with relapsed/refractory multiple myeloma, the most common adverse events related to TH-302 were nausea and fatigue that occurred in at least 25% of the patients, while the most common Grade 3/4 hematologic adverse events related to TH-302 were thrombocytopenia (29%) and leukopenia (25%).
TH-302 is currently being assessed in two Phase III 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 (the MAESTRO trial).
Image: Micrograph of a plasmacytoma, the histologic correlate of plasma cell myeloma. Photo: courtesy of Nephron.