The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.
In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).
And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.
However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.
These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.
“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.
CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.
Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).
Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).
Treatment
CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.
Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.
Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).
Safety
Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.
The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).
Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.
AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).
Efficacy
Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.
Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.
The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.
Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.
Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.
