Lauren M. Green
Jacob Laubach, MD
The addition of the investigational hypoxia-targeted drug TH-302 to dexamethasone has demonstrated beneficial activity and a manageable adverse event profile in the treatment of patients with relapsed/refractory multiple myeloma, according to findings of a phase I/II multicenter study presented at the 2014 ASCO Annual Meeting.
TH-302 is activated under tumor hypoxic conditions, a hallmark of many cancers including hematologic malignancies, representing a new therapeutic target for multiple myeloma where the bone marrow of patients has been shown in some cases to be severely devoid of oxygen. The agent is a member of the class of alkylating drugs with “a half-century, proven track record in multiple myeloma,” noted lead trial investigator Jacob Laubach, MD, but “what’s unique about TH-302 is that it is essentially a smart alkylator, in this case targeting cells that reside in a hypoxic environment.”
Laubach is clinical director of the Jerome Lipper Multiple Myeloma Center at the Dana Farber Cancer Institute. He spoke with Targeted Oncology
following an ASCO poster highlights session where the trial’s phase I dose-escalation and ongoing phase II dose-expansion findings were presented.
Patients with relapsed/refractory myeloma and an ECOG performance status of 0-2 who had received at least two prior therapies were eligible for the study. Findings presented at ASCO were from 24 patients with a median age of 62.5 years who had received a median of 6.5 prior therapies (range: 3-13). Four of the 24 patients remained in treatment at the May 19 cutoff.
The study’s primary objectives were to assess the safety and tolerability of TH-302 in combination with dexamethasone, identify any dose-limiting toxicities, and determine the maximum tolerated dose (MTD).
A dose of 340 mg/m2
emerged from the study as the MTD for TH-302, which is administered intravenously biweekly in combination with 40 mg of oral dexamethasone. The clinical benefit rate (based on partial response [PR] + minimal response [MR]) was 31%, with three patients experiencing PR and two, MR. Objective responses were also observed in patients who had failed multiple immunomodulatory therapies including pomalidomide or multiple proteasome inhibitor therapies, including carfilzomib.
At the MTD, grade 3/4 hematologic adverse events (leukopenia, thrombocytopenia, and anemia) were experienced by 12% of patients, and neutropenia by one patient (6%). All grade leukopenia occurred in 41% of patients and 29% of patients experienced neutropenia.
“We were expecting bone marrow toxicity, and we saw some suppression, but certainly not of a proportion we would expect with this class of drugs,” Laubach explained. “Most patients are dropping their counts, but not to the point where they needed to have dose reduction or come off the trial because of bone marrow suppression.”
Laubach added that skin and mucosal toxicities were observed at the MTD and at the higher 480 mg/m2
dose, but not at the initial or lower doses of the drug. At the 480 mg/m2
dose, dose-limiting stomatitis was seen in three patients. Skin rash occurred at the MTD dose in about 25% of patients, he said, but none of these events were grade 3/4.