Πέμπτη, 21 Απριλίου 2016

FIRST DUAL PI3K/HDAC INHIBITOR FOR HAEMATOLOGICAL MALIGNANCIES

In a phase I trial reported in The Lancet Oncology, Younes et al found that a first-in-class oral dual HDAC-PI3K inhibitor (CUDC-907) showed activity in patients with relapsed or refractory lymphoma or multiple myeloma.
Toxicity
In the study, 44 patients from four U.S. sites were treated with CUDC-907 once daily, two or three times a week, or for 5 days with 2 days off (5/2 schedule) in 21-day cycles. Dosing started at 30 mg in the once-daily schedule and 60 mg in the other schedules and was escalated in 30-mg increments. Four dose-limiting toxicities occurred in 3 of 40 evaluable patients, consisting of diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 on 150 mg twice weekly, and diarrhea in 1 on 150 mg three times weekly. No dose-limiting toxicities were reported in patients on the 5/2 schedule. Grade ≥ 3 adverse events occurred in 19 (43%) of 44 patients, with the most common being thrombocytopenia (20%), neutropenia (7%), and hyperglycemia (7%). Adverse events led to dose reduction in six patients (14%) and to drug discontinuation in seven (16%).
Responses
Objective response, consisting of 2 complete and 3 partial responses, occurred in 5 (14%) of 37 evaluable patients. The five responses were observed in the subgroup of nine patients with diffuse large B-cell lymphoma (DLBCL), including three of five with transformed follicular lymphoma DLBCL. Stable disease was observed in 21 patients (57%), including those with DLBCL, Hodgkin lymphoma, and multiple myeloma.
The investigators concluded: “The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular is ongoing.”
The study was supported by Curis, Inc, and the Leukemia and Lymphoma Society.

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