A Pooled Analysis of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients Treated with the Dual PI3K and HDAC Inhibitor Fimepinostat (CUDC-907), Including Patients with MYC-Altered Disease
Authors: Landsburg Daniel J. , Ramchandren Radhakrishnan , Lugtenburg Petronella J , Kelly Kevin R. , Younes Anas , Gharavi Robert , Tuck David P. , Barta Stefan Klaus 
Published: October 2019

Abstract
Introduction
Patients with relapsed or refractory (R/R) MYC-altered DLBCL have poor outcomes, and other than for a subset of patients who may benefit from chimeric antigen receptor T cell therapy, no treatment has shown a significant durable benefit or impact on survival outcomes. Fimepinostat is a first-in-class, well-tolerated, oral small molecule inhibitor of HDAC and PI3K enzymes. There is particular interest in evaluating fimepinostat in patients with MYC-dependent tumors as nonclinical studies demonstrated that fimepinostat inhibits transcription of MYC and a subset of MYC-associated genes. Additionally, MYC protein levels were downregulated by fimepinostat in part through inhibition of PI3K-mediated ubiquitination. Pharmacodynamic inhibition of HDAC and PI3K has also been demonstrated in human studies. Here we report the outcome of R/R DBLCL patients treated with fimepinostat in a Phase 1 and Phase 2 study, with an emphasis on outcomes for patients with MYC-altered disease.
Patients and Methods
A total of 105 R/R DLBCL patients were enrolled on the Phase 1 study CUDC-907-101 (n = 37) and the Phase 2 study CUDC-907-201 (n = 68). In CUDC-907-101, 14 patients were found to have MYC-altered disease, defined as presence of MYC rearrangement by either central or local testing by fluorescent in situ hybridization or MYC protein expression ≥40%) by immunohistochemistry (IHC). In CUDC-907-201, 46 patients had confirmed MYC-altered disease by central IHC testing. Across both studies, patients without available tissue or prior test results were deemed as MYC-status unknown (n = 23).
Results
A total of 19 responses (9 CR, 10 partial responses [PR]) were reported across both studies. The objective response rate (ORR) in MYC altered patients was 23.3% (14/60). Responses showed encouraging durability with a median duration of response of 13.6 months (range: 2.8 to Not Calculable [NC]). Five MYC-altered responses were ongoing as of the data-cut. Two MYC-altered patients achieving CR discontinued treatment early to pursue stem cell transplantation.
Responses associated with fimepinostat often require multiple cycles of treatment to manifest (median time to first response = 2.5 months for MYC-altered patients), and of patients who were treated for ≥2 months, a large proportion (17/33; 52%) achieved a response. Patients with low disease burden at screening (tumor lesions diameters ≤ 5 cm and lactate dehydrogenase [LDH] < 1.5 x upper limit of normal [ULN]) generally continued treatment longer and were most likely to derive clinical benefit (Table 2).
Conclusions
The biologic rationale, tolerable safety profile, and evidence of durable anti-tumor activity in MYC-altered R/R DLBCL support the continued development of fimepinostat in this poor-prognosis patient population. Patients with low disease burden features may be more likely to have sufficient duration of drug exposure to allow clinical benefit. Future enrollment will focus on patients with screening characteristics most likely to derive the greatest benefit from fimepinostat treatment.

Disclosures
Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Ramchandren:Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Lugtenburg:Millennium/Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Roche: Consultancy; BMS: Consultancy; Sandoz: Consultancy; Genmab: Consultancy. Younes:Takeda: Honoraria; Abbvie: Honoraria; BMS: Honoraria, Research Funding; Novartis: Research Funding; Curis: Research Funding; Incyte: Honoraria; Seattle Genetics: Honoraria; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; J&J: Research Funding; Pharmacyclics: Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Genentech: Research Funding. Tuck:Curis, Inc: Employment, Equity Ownership. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding.