Abstract
PI3K and HDAC inhibitors have demonstrated single agent clinical activity in patients (pts) with a variety of B-cell malignancies, including lymphoma and multiple myeloma (MM). Preclinical experiments indicated synergistic effects between HDAC and PI3K pathway inhibitors. CUDC-907 is a chemically-designed small molecule that combines the active hydroxamate moiety of HDAC inhibitors with a PI3K inhibitor morpholinopyrimidine pharmacophore. CUDC-907 potently inhibits class I PI3K (alpha, beta, and delta) as well as HDACs class I and II enzymes. Preclinical experiments demonstrated that CUDC-907 inhibits the PI3K-AKT-mTOR pathway and compensatory MEK/ERK and STAT3 signaling pathways. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells, including human B-cell tumor xenograft models. Here we present the preliminary results of a First-In-Human Phase 1 study of CUDC-907.
This is a Phase 1 study using a standard 3+3 dose escalation design. CUDC-907 was orally administered to pts with lymphoma and MM. Patients were eligible if they had relapsed or refractory disease after at least 2 prior regimens and adequate bone marrow and organ functions. The starting dose was 30mg given continuously once daily in 21-day cycles without rest, with planned escalations until the maximum tolerated dose was reached. In the absence of dose limiting toxicities (DLTs), pts were allowed to continue treatment until disease progression. DLTs were defined so as to include ≥ Grade 3 adverse events (AE) or any Grade AE resulting in dose delay ≥7 days. Tumor response was assessed every 2 cycles using standard criteria appropriate for the disease type. Blood samples for pharmacokinetic (PK) and pharmacodynamic analyses were collected during Cycle 1.
At the time of this abstract, 6 pts were treated on study: 3 each at 30 and 60 mg/day dose. The median age was 70 years (range 61-77) and 2 pts had MM, 3 Non-Hodgkin’s lymphoma and 1 Hodgkin's lymphoma. The median number of prior regimens was 3 (range 2-8) and 3 pts had prior bone marrow transplant. The most common treatment-related AEs were diarrhea (6 pts, Grade 1-3) and thrombocytopenia (5 pts, Grade 1-4). The severity and time to onset of these events appear to be dose-related. In general, thrombocytopenia recovered quickly by withholding treatment and diarrhea was well controlled with loperamide co-administration. However, 1 pt at the 60 mg/day dose level with a history of diabetes and poor co-medication compliance (i.e., loperamide and insulin) developed multiple DLTs including diarrhea (Grade 3), thrombocytopenia (Grade 4) and hyperglycemia (Grade 4). Of the 6 pts, 2 remain on treatment at ≥ 5 cycles with stable disease. CUDC-907 was rapidly transformed to 2 metabolites, M1 and M2, with M2 retaining potent PI3K inhibition activity. While CUDC-907 had low plasma exposure and a short half-life, M2 levels increased during the 24 hour PK sampling period.
To address AEs and further dose escalate, with consideration of the PK profile of the parent and M2 metabolite, the protocol was modified to include 2 additional dosing schedules: 2x/week and 3x/week administration. In addition, the 30mg continuous daily dose cohort was expanded to further assess the tolerability of this schedule. Updated results from pts treated with the 3 schedules will be presented.
Younes:Gilead: Honoraria; Seattle Genetics: Honoraria; Millenium: Honoraria; Celgene: Honoraria; Johnson & Johnson: Honoraria; Pharmacyclics: Honoraria. Fattaey:Curis, Inc.: Employment. Lai:Curis, Inc.: Employment. Laliberte:Curis, Inc.: Employment. Voi:Curis, Inc.: Employment.
Author notes
Asterisk with author names denotes non-ASH members.
