Phase 1 safety and dose escalation of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K in relapsed or refractory lymphoma and multiple myeloma

Summary

Background

Current treatment options for patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM) are limited, highlighting the unmet need for effective therapies in these disease settings. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes, which are members of common oncogenic pathways in hematologic malignancies. This study examines CUDC-907 monotherapy in patients with RR lymphoma and MM.

Methods

This open-label, non-randomized, first-in-man, phase 1 multi-center trial enrolled adult patients with lymphoma or MM who were refractory to or relapsed after ≥2 prior regimens. CUDC-907 was orally administered in a standard 3+3 dose escalation design using three different dosing schedules which enrolled sequentially as follows: once daily (QD), then intermittent twice (BIW) or thrice weekly (TIW) that enrolled simultaneously, and finally five days on/two days off (5/2) in 21-day cycles. Dosing started at 30 mg for QD and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum-tolerated dose and recommended phase 2 dose (RP2D); secondary objectives were to assess the safety and tolerability, and preliminary anti-cancer activity. Results from the completed dose escalation phase are presented. Safety analyses were conducted in all patients who received at least one dose of study medication; efficacy analyses were conducted in all patients who received at least one dose of study drug and underwent at least one post-baseline response assessment. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988.

Findings

Forty-four heavily pretreated patients received CUDC-907 up to a maximum of 60 mg for the QD and 5/2 schedules, and 150 mg for the intermittent schedules in the dose escalation phase. The most common Grade ≥3 adverse events were thrombocytopenia (n=9, 20%), neutropenia (n=3, 7%), and hyperglycemia (n=3, 7%). Dose limiting toxicities (DLTs) were diarrhea and hyperglycemia; no DLTs were observed on the 5/2 schedule. Eleven of 44 patients reported serious AEs, 3 of which were considered treatment-related: epistaxis and the DLTs of diarrhea and hyperglycemia. AEs led to dose reductions in 6 patients and treatment discontinuation in 7 patients. Thirty-seven patients were evaluable for response. Five out of 9 patients with diffuse large B-cell lymphoma (DLBCL) achieved objective responses (2 complete responses [CR], 3 partial responses [PR]). Three of these objective responses (1 CR, 2PR) occurred in patients with transformed follicular (t-FL) DLBCL. Stable disease (SD) has been observed in 21 (57%) of 37 response-evaluable patients including DLBCL, Hodgkin lymphoma (HL), and MM. On the basis of the response and tolerability profile, the RP2D of CUDC-907 was determined to be 60 mg on the 5/2 schedule.

Interpretation

CUDC-907 has demonstrated tolerability and anti-tumor activity across all dosing schedules studied, including multiple objective responses and disease control in heavily pre-treated patients with DLBCL. These results support continued development of CUDC-907, alone and in combination with other therapies, for the treatment of DLBCL in refractory and relapsed settings.

Funding

Curis, Inc. with support from the Leukemia and Lymphoma Society.