A Sequential Phase I/Randomized Phase II Trial of Vorinostat and Risk-Adapted Chemotherapy With Rituximab in HIV-Related B-cell Non-Hodgkin's Lymphoma
PRIMARY OBJECTIVES:
I. Determine the recommended phase II dose (RPTD) of vorinostat that may be used in
combination with cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate,
prednisone, and etoposide and rituximab (R-CHOP) (in high-risk disease) in subjects with
HIV-associated aggressive cluster of differentiation (CD)20 positive non-Hodgkin lymphoma
(NHL). (Phase I) II. Determine the overall toxicity rates of dose-adjusted etoposide,
prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (R-DA-EPOCH) (in
high-risk disease) with and without vorinostat. (Phase II) III. Determine the efficacy of
the combinations of R-DA-EPOCH (in high-risk disease) with and without vorinostat in
HIV-associated aggressive CD20 positive NHL using complete response (CR) rates as study
endpoints. (Phase II)
SECONDARY OBJECTIVES:
I. Determine 1-year event-free survival (EFS) and 1 year overall survival (OS). II. Assess
the effect of vorinostat and chemotherapy on latent HIV in memory T cells.
III. Assess the effect of vorinostat and/or chemotherapy on HIV, hepatitis B virus (HBV),
and human herpes virus 8 (HHV-8) viral loads on banked specimens.
IV. Assess the effect of vorinostat and/or chemotherapy on T-cell subsets (CD4 and CD8) and
plasma immunoglobulin levels.
V. Assess the effect of concurrent vorinostat and rituximab on plasma steady-state
concentrations of etoposide, doxorubicin, and vincristine (on Phase I only).
VI. Perform wide human gene expression profiling in tumors banked at baseline. VII. Evaluate
EBV and HHV-8 gene expression patterns in positive tumors banked at baseline.
OUTLINE: This is a phase I dose-escalation study of vorinostat followed by a randomized,
open label phase II study. Patients are randomized to 1 of 2 treatment arms.
PHASE I:
Patients receive vorinostat orally (PO) once daily (QD) on days 1-5, and rituximab
intravenously (IV) on day 1, etoposide IV, doxorubicin hydrochloride IV, and vincristine
sulfate IV on days 1-4, prednisone PO daily on days 1-5, and cyclophosphamide IV over 1 hour
on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity.
PHASE II:
ARM A (VR-DA-EPOCH): Patients receive vorinostat PO QD, rituximab IV , etoposide IV,
doxorubicin hydrochloride IV, and vincristine sulfate IV , prednisone PO daily, and
cyclophosphamide IV over 1 hour as in Phase I.
ARM B (DA-R-EPOCH): Patients receive rituximab IV, etoposide IV, doxorubicin hydrochloride
IV, and vincristine sulfate IV , prednisone PO daily, and cyclophosphamide IV over 1 hour as
in Arm A.
In all arms, treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity
In all arms, treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity.
Blood samples are collected periodically for correlative studies. Archived tumor tissue
samples may also be analyzed for gene expression profile.
After completion of study therapy, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.
Interventional
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Recommended phase II dose of vorinostat determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (Phase I)
21 days
Yes
Juan Ramos
Principal Investigator
AIDS Associated Malignancies Clinical Trials Consortium
United States: Food and Drug Administration
NCI-2011-02508
NCT01193842
October 2010
Name | Location |
---|---|
Johns Hopkins University | Baltimore, Maryland 21205 |