Addition of â€˜Smartâ€™ Alkylator TH-302 to Dexamethasone Shows Benefit in Myeloma
Lauren M. Green
Published Online: 10:09 AM, Fri June 6, 2014
Jacob Laubach, MD
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.
“Nobody came off the trial because of skin toxicity, but it is an issue. It can be uncomfortable for the patients, and the distribution of the rash is somewhat unique and tends to occur in areas of the skin where the cells may be hypoxic. We see it in the groin and in the axilla, for example, where mechanistically, there is a rationale for it.” Laubach said preemptive, proactive steps can be taken to minimize that toxicity as the drug is developed further.
“In the short run, what we’re doing currently is utilizing topical steroids and antihistamines. We’ve also noticed that the skin rash can be transient. It can come and go. In some patients, it is self-limiting. It will occur, we will hold a dose, the rash resolves, and we can go on dosing, similar to what we see with other chemotherapeutic agents that cause rash.”
The 340 mg/m2 plus dexamethasone expansion arm of the trial is ongoing, and the next step in the development of the drug is to combine TH-302 with bortezomib (NCT01522872).
“This will be the first-of-its-kind study of a hypoxia-inducible drug with a proteasome inhibitor, so in that context, we step back and deescalate the dose to a 240 mg/m2 dose in combination with bortezomib and then subsequently we will dose-escalate again to identify the maximum tolerated dose of the combination,” said Laubach.
The FDA and the European Commission have granted TH-302 Orphan Drug Designation for the treatment of soft tissue sarcoma and pancreatic cancer. The drug is being developed by San Francisco–based Threshold Pharmaceuticals and is currently under evaluation 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 (MAESTRO). The agent also is being studied in an ongoing phase I/II trial in combination with bevacizumab in recurrent glioblastoma.
Laubach J, Noopur S, Raje PA, et al. Preliminary safety and efficacy of TH-302, an investigational hypoxia-targeted drug, and dexamethasone in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2014;32:5s (suppl; abstr 8534).