Fimepinostat (Oral, Small Molecule Dual HDAC & PI3K Inhibitor)

Fimepinostat (formerly known as CUDC-907) is an orally-available, small molecule drug candidate in Phase 2 clinical testing for treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) that harbor alteration of the MYC oncogene. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation and Fast Track designation to fimepinostat for the treatment of patients with DLBCL. Fimepinostat is also being developed in a Phase 1 clinical trial for treatment of patients with solid tumors, with a focus on tumors harboring MYC alterations.

About Fimepinostat's Clinical Program

Fimepinostat (formerly known as CUDC-907) is a synthetic, orally-available, small molecule that potently inhibits the activity of histone deacetylase, or HDAC, and phosphotidyl-inositol 3 kinase, or PI3 kinase enzymes1. In 2013, Curis initiated a Phase 1 clinical study to determine the maximum tolerated dose, recommended Phase 2 dose (RP2D) and preliminary anti-cancer activity of fimepinostat monotherapy in patients with relapsed or refractory lymphomas or multiple myeloma2. An analysis of the data from a total of 75 patients in this study was presented at the European Hematology Association's annual meeting in June 2016. In this Phase 1 trial, 9 objective responses (3 complete responses and 6 partial responses) were reported in 21 response-evaluable patients out of a total of 25 patients with relapsed/refractory DLBCL enrolled in the study.

In a retrospective post hoc analysis, 5 of the 9 patients who achieved objective responses had tumors with confirmed MYC oncogene alterations (defined as chromosome translocation involving MYC gene locus, gain in MYC gene copy number, or MYC protein over-expression in = 40% tumor cells). One of the 9 patients had tumors confirmed as MYC negative and 3 of the 9 patients had tumors whose MYC status could not be determined.

The recommended dose of fimepinostat for further Phase 2 development, or RP2D, was determined to be once daily oral administration of 60 mg dose using a 5 days “on”/2 days “off” schedule in 21-day cycles. The most common drug related adverse events (AEs) reported in the study have been low grade (Grade 1 and 2) diarrhea, fatigue and nausea. Dose limiting toxicities (DLTs) have consisted of diarrhea and hyperglycemia, however no DLTs occurred at the RP2D. Other drug-related Grade 3 or Grade 4 AEs reported in 3 or more patients included thrombocytopenia and neutrophil decrease (hematologic AEs) as well as diarrhea, hyperglycemia and fatigue (non-hematologic AEs).

Additionally, Curis investigated fimepinostat in conjunction with rituximab in patients with relapsed/refractory DLBCL in the expansion part of the Phase 1 clinical study in order to assess tolerability and preliminary efficacy of the combination regimen.

Based on the results of the Phase 1 trial in Q1 2016, Curis initiated a Phase 2 trial to examine the efficacy of fimepinostat in patients with MYC altered relapsed/refractory DLBCL.

In April 2015 the U.S. Food & Drug Administration, or FDA, granted fimepinostat orphan drug designation for the treatment of patients with DLBCL. The FDA's Orphan Drug Designation program grants orphan status to drugs and biologics that are intended for use in rare diseases/or disorders, defined as those that affect fewer than 200,000 people in the U.S. or that affect more than 200,000 people in the U.S. where there is no reasonable expectation that the cost of developing and making the drug or biological product for the specific disease or condition will be recovered from sales in the U.S.

In May 2018, the FDA granted Fast Track designation for the development of fimepinostat in adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapy. The FDA Fast Track process is designed to facilitate the development and expedite review of drugs used to treat serious conditions and fill an unmet medical need. Fast Track designation provides Curis with more frequent meetings and written communications with the FDA regarding fimepinostat's development plan, trial design and data collection to support the drug's approval. Fast Track designation also provides eligibility for Accelerated Approval and Priority Review, if the relevant criteria are met, as well as Rolling Review with regards to the submission of the completed sections of the NDA for review by the FDA.

Fimepinostat is also being investigated in a separate Phase 1 trial in patients with advanced solid tumors with a recent focus on patients with MYC-altered tumors including patients with NUT midline carcinoma, or NMC. The primary objective of this study is to determine the safety and tolerability of orally-administered fimepinostat in these disease settings. The secondary objectives are to assess the pharmacokinetics, establish the maximum tolerated dose/biologically effective dose, recommended Phase 2 dose, evaluate biomarkers of activity and identify any preliminary anti-cancer activity of fimepinostat.

1Clin Cancer Res 2012; 18:4104-4113
2Lancet Oncology 2016; 17(5):622-631