Objective Responses Achieved in Patients with MYC-Altered Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated with the Dual PI3K and HDAC Inhibitor CUDC-907

Introduction

Patients with relapsed/refractory (RR) diffuse large B-cell lymphoma (DLBCL) characterized by translocation or amplification of MYC or increased expression of MYC protein (MYC-altered) are reported to have a dismal prognosis (Blood. 2012 May 17;119(20):4619-24. and Haematologica. 2013 Oct;98(10):1554-62.). CUDC-907, a first-in-class oral dual inhibitor of HDAC and PI3K enzymes, has demonstrated downregulation of MYC mRNA and protein levels in MYC-altered DLBCL cell lines, as well as anti-tumor activity in multiple MYC-driven animal cancer models. In a Phase 1 study, objective responses were reported in a number of patients with MYC-altered RR DLBCL treated with CUDC-907. This Phase 2 study is designed to further explore the efficacy of CUDC-907 in this population. Clinical trial information: NCT02674750.

Patients and Methods

Up to 200 RR DLBCL patients may be enrolled to enrich for a total of 100 patients with confirmed MYC-altered disease by central immunohistochemistry (IHC) testing. Following central testing, patients are placed into one of three groups; Group A consists of patients with MYC translocation and/or amplification by fluorescent in situ hybridization (FISH) without MYC protein expression ≥40% by IHC, Group B (n = 100) of patients with MYC protein expression ≥40% by IHC (regardless of FISH results), and Group C of patients that do not qualify for Group A or B. Central testing of BCL2 and BCL6 gene and protein expression status are also being performed. Key eligibility criteria include confirmed availability of viable biopsy tissue (fresh or archival) for central testing, ECOG score ≤1, 2-4 prior lines of therapy for DLBCL, and ineligible for/failed prior autologous stem cell transplantation. Transformed follicular lymphoma patients are also eligible. All patients receive 60 mg of CUDC-907 orally once a day on a 5 days on/2 days off schedule in 21-day cycles. The primary endpoint is to assess the objective response rate (ORR) in Group B. The evaluable population in this analysis are defined as any patient who received at least one dose of CUDC-907 and had a post-baseline disease assessment.

Results

As of 29 June 2017, 68 patients received CUDC-907; 5 in Group A, 44 in Group B, and 19 in Group C. All patients with MYC translocations also had MYC protein expression ≥40% by IHC (n = 16). There were 17 patients with MYC amplifications, 12 of which also had MYC protein expression ≥40% by IHC, making all 5 Group A patients MYC amplifications only.

The most frequently reported adverse events were diarrhea (64.1%), nausea (42.2%), thrombocytopenia (35.9%), fatigue (31.3%), hypokalemia (29.7%), and vomiting (25%). The most frequently reported Grade ≥3 treatment-related adverse events were thrombocytopenia (18.8%), neutropenia (14.1%), diarrhea (14.1%), anemia (6.3%), and hypokalemia (6.3%).

Seven objective responses (3 CR and 4 PR) were reported in Group B and none in Groups A or C. The ORR in evaluable Group B patients was 19.4% (7/36). One of the PRs was reported in a double-hit lymphoma patient (both MYC and BCL2 translocations present). Responses showed encouraging durability considering the follow-up time with a range of 0.8 to 6.9+ months. Four of the responses were ongoing as of the data-cut, including 2 CRs. One of the CR patients discontinued study treatment early to pursue a stem cell transplant. The median duration of treatment for responders was not reached (95% confidence interval, 4.7 months to not reached).

Conclusions

The biologic rationale, tolerable safety profile, and evidence of anti-tumor activity in MYC-altered RR DLBCL support the continued development of CUDC-907 in this poor-prognosis patient population.