First-in-Class Suppressor of MYC
(Oral, Small Molecule HDAC/PI3K Inhibitor)
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 2018, the U.S. Food and Drug Administration (FDA) granted Fast Track designation for the development of fimepinostat in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. In 2015, the FDA granted fimepinostat orphan drug designation for the treatment of patients with DLBCL.
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. 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. 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 (RP2D) was determined to be once-daily oral administration of 60 mg dose using a 5 days “on” and 2 days “off” schedule, in 21-day cycles. The most common drug-related adverse events (AEs) reported in the study were low grade (Grade 1 and 2) diarrhea, fatigue and nausea. Dose limiting toxicities (DLTs) 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).
The Company also previously evaluated fimepinostat in a Phase 1 combination study with venetoclax, a BCL2 inhibitor, in DLBCL patients, including patients with translocations in both MYC and the BCL2 gene, also referred to as double-hit lymphoma, or high-grade B-cell lymphoma (HGBL), but discontinued the study in March 2020 due to lack of efficacy.
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Posters and Presentations
1 Qian C, et al., Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling. Clin Cancer Res (2012) 18 (15): 4104–4113. https://doi.org/10.1158/1078-0432.CCR-12-0055
2 Younes A, et al., Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. The Lancet. Oncology, 31 Mar 2016, 17(5):622-631. https://doi.org/10.1016/s1470-2045(15)00584-7
