Novel Dual HDAC/PI3K Inhibitor Assessed in Lymphoma, Myeloma

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CUDC-907 had an acceptable safety profile and demonstrated promising preliminary evidence of response in patients with diffuse large B-cell lymphoma.
CUDC-907 had an acceptable safety profile and demonstrated promising preliminary evidence of response in patients with diffuse large B-cell lymphoma.

CUDC-907, an oral, first-in-class, small molecule inhibitor designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, had an acceptable safety profile and demonstrated promising preliminary evidence of response in patients with diffuse large B-cell lymphoma, a study published in the journal The Lancet Oncology has shown.1

Because treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited, researchers developed CUDC-907, which inhibits enzymes that are members of common oncogenic pathways in hematologic malignancies. In this phase 1 dose-escalation study, researchers assessed the overall safety and preliminary activity of CUDC-907 monotherapy in this patient population.

For the multicenter study, researchers enrolled 44 adult patients with lymphoma or multiple myeloma who were refractory to or had relapsed after 2 or more previous regimens. Patients received CUDC-907 orally once daily, twice weekly, 3 times weekly, or daily for 5 days followed by a 2-day break (5/2) in 21-day cycles.

Patients in the once-daily group received the drug starting at doses of 30 mg, while others were initiated at 60 mg doses, with dose escalations in 30 mg increments. Participants were treated until disease progression or until discontinuation.

At the time of data cutoff, 84% of patients had discontinued treatment due to progressive disease or clinical signs of progressive disease.

Results showed that no dose-limiting toxicities had been reported in patients on the 5/2 schedule. A total of 19 patients developed grade 3 or worse adverse events, the most common of which were thrombocytopenia, neutropenia, and hyperglycemia. Of note, 3 patients experienced a serious treatment-related adverse event.

In terms of efficacy, 5 patients achieved a response, of which 2 were complete responses and 3 were partial responses. All 5 occurred in patients with diffuse large B-cell lymphoma and 3 occurred in patients with diffuse large B-cell lymphoma that transformed from follicular lymphoma.

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More than half of the 37 evaluable patients had stable disease, including those with diffuse large B-cell lymphoma, Hodgkin lymphoma, and multiple myeloma.

Researchers ultimately selected the 60 mg dose on the 5/2 dosing schedule as the recommended phase 2 dose. The findings support further development of CUDC-907 alone and in combination with other therapies in patients with hematologic malignancies, particularly diffuse large B-cell lymphoma.

Reference

  1. Younes A, Berdeja JG, Patel MR, et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial [published online ahead of print March 31, 2016]. Lancet Oncol. doi: 10.1016/S1470-2045(15)00584-7.

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