Preliminary tolerability and pharmacokinetic (PK) data from an ongoing Phase I dose-finding study of fimepinostat (CUDC-907-101), a small molecule dual inhibitor of PI3K/HDAC and suppressor of MYC, in combination with venetoclax (Venclexta®; AbbVie and Genentech) , a BCL-2 inhibitor, for the treatment of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), including patients with double-hit/double-expressor (DH/DE) lymphoma, shows that the combination of the two agents has been generally well-tolerated.
The investigators did not find drug-drug PK interactiona that required dose modification of either agent.
The researchers noted that non-clinical studies, the combination with fimepinostat + venetoclax demonstrated striking synergistic anti-tumor effects in vitro and in vivo with nearly 100% tumor growth inhibition in a double-hit lymphoma mouse xenograft model.
A poster with study discussing fimepinostat, a drug being developed by Curis, will be presented at 61st Annual Meeting of the American Society of Hematology (ASH), being held December 7 – 10, 2019 in Orlando, Florida. 
“We are very pleased with the progress in our ongoing Phase I study, with the combination of fimepinostat and venetoclax demonstrating a favorable tolerability profile thus far,” noted James Dentzer, President and Chief Executive Officer of Curis.
“We believe demonstrating that this combination is generally well-tolerated for patients is a significant milestone, as both drugs have shown activity as monotherapies in this patient population and we believe activity will be improved by combining the two agents. Based on these data, we plan to initiate an expansion of the current study in 2020,” Dentzer added.
To date, the study has enrolled 11 patients, 6 patients in the first cohort and 5 patients in the second cohort. Patients in the first cohort received 30mg once-daily (QD) of fimepinostat and 400 mg QD of venetoclax, while the patients in the second cohort received 60 mg QD of fimepinostat and 400mg QD of venetoclax.
“There is an urgent need for therapies targeting MYC and BCL-2 alterations, particularly in DH/DE lymphoma, a disease defined by these alterations and one of the deadliest types of lymphoma,” said Robert Martell, MD, Ph.D, Head of R&D at Curis.
“We believe fimepinostat is unique in its ability to target MYC through simultaneous inhibition of both PI3K and HDAC. Venetoclax is a rapidly-acting inhibitor of BCL2, the other key abnormality in DH lymphoma. Supported by synergistic anti-cancer effects observed in preclinical models, we believe this is an ideal combination to target DLBCL and we look forward to gaining further insights on the combination from this study.
“The study was designed with initial patients undergoing a several-week run-in period allowing detailed PK interaction analysis and venetoclax ramp-up to be performed. In preliminary analyses, we found the combination to be generally well tolerated, with no dose-limiting toxicity (DLT) in the first cohort and one DLT of transient grade 3 diarrhea in the second cohort. Importantly, we found no drug-drug PK interaction that required dose modification of either agent. Drug-drug interactions are a major problem for many drugs combining with venetoclax, and we are encouraged that we have not seen such interaction to date with fimepinostat,” Martell continued.
Curis’ ongoing Phase I, open-label, multi-center, dose-finding 3+3 study is designed to evaluate the safety and tolerability, PK and pharmacodynamics, and preliminary activity of the fimepinostat and venetoclax combination in patients with DLBCL, including those with DH/DE lymphoma.
Patients are enrolled in two cohorts in the study, with fimepinostat administered on a 5-days-on-2-days-off schedule in combination with venetoclax in 21-day cycles.
Curis plans to initiate an expansion of the current study in 2020.
The poster presentation will be on Monday, December 9, 2019: 6:00 PM-8:00 PM in Hall B in the Orange County Convention Center.
Study to Assess the Safety, Tolerability and Pharmacokinetics of Fimepinostat (CUDC-907) in Patients With Lymphoma – NCT01742988.
 Younes A, Batlevi CL, Cohen JB, De Vos S, Landsburg DJ, Myint ZW, Patel K, Phillips TJ, et al. A Multi-Center Dose-Finding Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Fimepinostat (CUDC-907) in Combination with Venetoclax in Patients with Relapsed/Refractory (R/R) Lymphoma. Program: Oral and Poster Abstracts. Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster III. Hematology Disease Topics & Pathways: Diseases, Adult, Therapies, Combinations, Non-Hodgkin Lymphoma, DLBCL, Study Population, Lymphoid Malignancies. [Abstract]