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

May 26, 2010

BlankTargeting the epigenome: A phase I/II study of vorinostat (SAHA),

cladribine (2-CdA), and rituximab in relapsed B-cell malignancies.

Sub-category: Lymphoma

Category: Lymphoma and Plasma Cell Disorders

Meeting: 2010 ASCO Annual Meeting

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr TPS301)

Abstract No: TPS301

Author(s): S. E. Spurgeon, C. Y. Okada, J. Huang, J. , E. E. Epner;

Oregon Health & Science University, Portland, OR; Oregon Health & Science

University/Portland Veterans Affairs Medical Center, Portland, OR; University of

Utah, Salt Lake City, UT; Penn State Hershey Cancer Institute, Hershey, PA

Abstract:

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.

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