Dual HDAC, PI3K Inhibitor Active in Lymphoma, Myeloma

A first-in-man, phase I study of CUDC-907, which targets both histone deacetylase (HDAC) and PI3K enzymes, has shown promise in patients with relapsed or refractory multiple myeloma or lymphoma. Results of the study were published in Lancet Oncology.

“Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited,” wrote researchers led by Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York. “We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy.”

The drug was administered to patients using different dosing schedules-daily, intermittently (two or three times per week), and 5 days on with 2 days off-and antitumor activity was seen in 14% of evaluable patients across the different schedules.

To confirm the drug’s activity, the dose-expansion portion of this trial is ongoing at the recommended phase II dose-60 mg at the 5 days on, 2 days off dosing schedule in patients with relapsed or refractory multiple myeloma, diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, and T-cell lymphoma.

The study was an open-label trial that included 44 patients aged 18 or older with lymphoma or multiple myeloma that was refractory to or had relapsed after two or more prior regimens. Dosing of CUDC-907 was started at 30 mg for the once-daily schedule and 60 mg for the other schedules, and was increased in 30 mg increments.

Ten patients were assigned to the once daily schedule; 12 to twice-weekly; 13 to three times weekly; and seven to the 5 days on, 2 days off schedule. The maximum tolerated dose for each schedule was 60 mg, 150 mg, 150 mg, and 60 mg, respectively.

Five of 37 patients evaluable for response achieved an objective response to CUDC-907. There were two complete responses and three partial responses. According to the researchers, all five of these responses were in patients with DLBCL, three of which were in patients with transformed follicular lymphoma DLBCL. Fifty-seven percent of patients had stable disease, including patients with Hodgkin lymphoma and multiple myeloma.

The majority of patients (84%) had to stop taking the study drug either due to disease progression or clinical signs of progressive disease. Forty patients were evaluable for dose-limiting toxicities, of which four occurred in three patients. Dose-limiting toxicities included diarrhea and hyperglycemia in a patient assigned 60 mg CUDC-907 daily, hyperglycemia in one patient assigned 150 mg twice weekly, and diarrhea in one patient assigned 150 mg three times weekly.

Grade 3 adverse events occurred in about half of patients (43%) and one-quarter had a serious adverse event. Adverse events forced a dose reduction in 14% of patients and treatment discontinuation in 16%.

In an editorial that accompanied the study, Paul G. Richardson, MD, of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, wrote that the researchers’ rationale for conducting this trial was strong, given that both targets are members of common oncogenic pathways.

“In this trial, the investigators were able to identify best responses in a cluster of patients diagnosed with transformed follicular DLBCL, an area of particular unmet medical need,” Richardson wrote. “In the patients with myeloma, stable disease was reported, which, given their relapsed or refractory characteristics and previous exposure to HDAC inhibitors, suggests that this particular oral agent in combination with other drugs might be of particular interest in relapsed or refractory myeloma.”