Clinical Trial: Vorinostat and Combination Chemotherapy With Rituximab in Treating Patients With HIV-Related Diffuse Large B-Cell Non-Hodgkin Lymphoma or Other Aggressive B-Cell Lymphomas
Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional
Official Title: 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
Brief Summary: This partially randomized phase I/II trial studies the side effects and the best dose of vorinostat when given together with combination chemotherapy and rituximab to see how well it works compared to combination chemotherapy alone in treating patients with human immunodeficiency virus-related diffuse large B-cell non-Hodgkin lymphoma or other aggressive B-cell lymphomas. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving vorinostat together with combination chemotherapy and rituximab may kill more cancer cells.
Detailed Summary:
PRIMARY OBJECTIVES:
I. Determine the recommended phase II dose (RPTD) of vorinostat that may be used in combination with dose-adjusted etoposide, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride and rituximab (R-DA-EPOCH) (in high-risk disease) in participants with human immunodeficiency virus (HIV)-associated aggressive cluster of differentiation (CD)20 positive non-Hodgkin lymphoma (NHL). (Phase I) II. Determine the overall toxicity rates of 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, Epstein-Barr virus (EBV), 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 (doxorubicin hydrochloride), and vincristine (vincristine sulfate) (on Phase I only).
VI. Perform wide human gene expression profiling and methylation studies in tumors banked at baseline.
Original Primary Outcome:
- Maximum-tolerated dose and recommended phase II dose of vorinostat and risk-adapted chemotherapy with rituximab (Phase I)
- Toxicity (Phase II)
- Complete response (Phase II)
Current Secondary Outcome:
- Change in CD8 cell counts (Phase I) [ Time Frame: Baseline up to 12 months ]Evaluated using analyses of variance.
- Changes in CD4 cell counts (Phase I) [ Time Frame: Baseline up to 12 months ]Evaluated using analyses of variance. For each dose group and for all groups combined, the Wilcoxon signed rank test will be used to evaluate the changes in HIV viral load and CD4 count. If there is sufficient number of patients in each dose group, the Kruskal-Wallis test will be used to compare dose groups with respect to changes in HIV viral load and CD4 count.
- Changes in EBV viral load [ Time Frame: Baseline up to 12 months ]Descriptive statistics such as frequencies and percentages will be used to aid in the evaluation of EBV and HHV-8 gene expression patterns.
- Changes in HHV-8 viral load [ Time Frame: Baseline up to 12 months ]Descriptive statistics such as frequencies and percentages will be used to aid in the evaluation of EBV and HHV-8 gene expression patterns.
- Changes in HIV viral load [ Time Frame: Baseline up to 12 months ]A repeated measures analysis of variance will be used to assess the effect across time points.
- Event-free survival (EFS) (Phase II) [ Time Frame: 1 year ]Binomial proportions and their 95% confidence intervals will be used to determine the 1-year EFS rate.
- Overall survival (OS) (Phase II) [ Time Frame: 1 year ]Binomial proportions and their 95% confidence intervals will be used to determine the 1-year OS rates.
- Percentage of plasma associated HIV-1 RNA (Phase I) [ Time Frame: Baseline up to 12 months ]Evaluated using analyses of variance. For each dose group and for all groups combined, the Wilcoxon signed rank test will be used to evaluate the changes in HIV viral load and CD4 count. If there is sufficient number of patients in each dose group, the Kruskal-Wallis test will be used to compare dose groups with respect to changes in HIV viral load and CD4 count.
- Pharmacokinetic profile and the parameters of clearance and the AUC (area under the curve) (Phase I) [ Time Frame: Up to 12 months ]Summary statistics will be used to describe pharmacokinetic results by dose level. Comparisons across dose levels will be made to assess proportionality or variability of the different parameters.
- Tumor response rate (Phase I) [ Time Frame: Up to 5 years ]The tumor response rate will be estimated for each dose group and for all groups combined. The 95% confidence intervals will be constructed for tumor response rates.
Original Secondary Outcome:
- 1-year event-free survival
- 1-year overall survival
- Effect of treatment on HIV, HBV, and HHV-8 viral load
- Effect of treatment on T-cell subsets (CD4 and CD8) and plasma immunoglobulin levels
- Gene expression profiling
- EBV gene expression
Information By: National Cancer Institute (NCI)
Dates:
Date Received: September 1, 2010
Date Started: October 2010
Date Completion:
Last Updated: May 12, 2017
Last Verified: May 2017
