Targeting the epigenome: A phase I/II study of vorinostat (SAHA), cladribine (2-CdA), and rituximab in relapsed B-cell malignancies.

Abstract

TPS301 Background: Epigenetic modifications are important to cancer pathogenesis. Thus, better defining the role of epigenetic therapeutic approaches in B-cell malignancies is paramount. Cladribine combined with rituximab is an effective treatment for many B-cell malignancies. In addition to its cytotoxic effects, recent evidence suggests that cladribine has DNA hypomethylating activity. Vorinostat is a histone deacetylase inhibitor and has clinical activity in some lymphomas and is FDA approved for use in cutaneous T cell lymphoma. To explore epigenetic modifications as a means for improving therapeutic efficacy, while defining potential epigenetic targets, we have initiated a phase I/II trial combining vorinostat, cladribine, and rituximab for the treatment of relapsed B-cell malignancies. Methods: A standard 3x3 dose escalation phase I trial is used to determine the vorinostat MTD. Vorinostat is administered orally on days 1-14 (200 mg, 300 mg, or 400 mg) in combination with 2-CdA 5 mg/m2 IV on days 1-5, and rituximab 375 mg/m2 IV on days 3, 10, 17, and 24 with cycle 1 and then on Day 3 with subsequent cycles. Cycles are repeated every 28 days for up to 6 cycles. Patients with relapsed/refractory B-cell malignancies including non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL) are eligible for phase I. After vorinostat MTD determination, phase II will enroll an additional 40 patients including patients with 1) newly diagnosed mantle cell lymphoma or 2) newly diagnosed CLL. Primary outcome is response rate. Secondary outcomes include overall survival (OS) and progression-free survival (PFS). Currently, 8 patients have been enrolled on study. Blood and/or tumor samples are collected prior to, during, and after therapy for correlative studies and include: global DNA methylation, quantitative analysis of CD20 expression, histone acetylation, total gene microarray analysis, and Q- PCR of potential target genes. Chi-square testing will be used to compare objective response and DNA methylation and/or histone deacetylation status and the log-rank test will be used to compare PFS and OS and DNA methylation and/or histone deacetylation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck