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.
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. The Company is currently evaluating fimepinostat in a Phase 1 combination study with venetoclax, a BCL2 inhibitor, in diffuse large B-cell lymphoma (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).
In May 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 DLBCL after two or more lines of systemic therapy. In April 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).
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.
For more information on current trials click here.
Posters and Presentations
1Clin Cancer Res 2012; 18:4104-4113
2Lancet Oncology 2016; 17(5):622-631
