Open-Label, Phase 2 Study to Evaluate the Efficacy and Safety of CUDC-907 in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma, Including Patients with MYC Alterations

Patients (pts) with relapsed and/or refractory (RR) MYC-altered diffuse large B-Cell lymphoma (DLBCL) respond poorly to available therapeutic options. Due to acquired chemoresistance, these patients are often ineligible for or relapse following autologous stem cell transplantation (ASCT), and do not respond well to additional cytotoxic therapy. Our previous translational studies have demonstrated that combined pharmacologic inhibition of HDAC and PI3K signaling, via CUDC-907, effectively suppresses MYC activity through transcriptional and translational mechanisms. In MYC-dependent DLBCL and NUT midline carcinoma cell lines, CUDC-907 treatment has demonstrated dose-dependent decreases in MYC protein expression and a more potent inhibition of MYC expression than various HDAC and PI3K inhibitors, either alone or in combination. CUDC-907 has also shown greater in vitro and in vivo activity than single-target HDAC or PI3K inhibitors, especially in MYC-altered DLBCL models. In a phase 1 study, RR MYC-altered DLBCL pts achieved objective, durable responses while treated with CUDC-907, including complete responses (CRs). As of 15 March 2016, among the 5 response evaluable pts with RR MYC-altered DLBCL, 4 (80%) achieved objective responses (3 CRs and 1 partial response [PR]). All 3 CRs observed occurred in subjects with MYC gene copy number gain. In addition, to support our diagnostic plan, we evaluated MYC in a panel of DLBCL samples to better understand the prevalence of alterations. This ongoing phase 2 study is designed to further examine the efficacy of CUDC-907 in RR DLBCL pts with MYC-altered disease.

Up to 200 pts with RR DLBCL, including those who have MYC-altered disease per central testing, will be enrolled to receive either CUDC-907 alone or in combination with rituximab. Within each treatment cohort (n= ~60), pts will be stratified based on MYC status as determined by central testing: MYC translocation by FISH (Groups A and D) versus MYC copy number gain by FISH or ≥40% of cells scored as MYC protein expression positive by immunohistochemistry (Groups B and E). Pts with negative testing for MYC-altered disease will still be eligible for treatment (Groups C and F). Other key eligibility criteria include: Age ≥ 18 years, ECOG performance status score ≤ 2, measurable disease on CT imaging, at least 2 but no more than 4 prior lines of therapy for DLBCL which may include ASCT, and confirmed availability of adequate viable tissue (fresh or most recent archival) for central testing. Pts with transformed follicular lymphoma will be eligible. However, other B-cell lymphomas including B- cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma and Burkitt lymphoma are not eligible.

All pts will take 60 mg of CUDC-907 orally once a day on a 5 days on/2 days off schedule in 21-day cycles. Pts assigned to the combination arm will also receive rituximab 375 mg/m² IV on Day 1 of each cycle for the first 6 cycles. Response will be evaluated every other cycle per Cheson criteria by central review and survival assessments will occur every 12 weeks.

The primary endpoint is objective response rate (ORR); secondary endpoints include duration of response (DOR), disease control rate (DCR), progression free survival (PFS), median and 6-month PFS, and overall survival (OS). Other disease associated biomarkers, including BCL-2 and BCL-6, will also be evaluated. Clinical trial information: NCT02674750.