A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in Combination With Rituximab-CHOP in Patients With Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL)

Status
Active
Cancer Type
Non-Hodgkin Lymphoma
Trial Phase
Phase I
Phase II
Eligibility
18 and over, Male and Female
Study Type
Biomarker/Laboratory analysis
Treatment
NCD ID
NCT00972478
Protocol IDs
NCI-2011-01964 (primary)
S0806
U10CA032102
CDR0000653803
SWOG-S0806
Study Sponsor
National Cancer Institute

Summary

This phase I/II trial is studying the side effects and best dose of vorinostat when given together with rituximab and combination chemotherapy and to see how well it works in treating patients with newly diagnosed stage II, stage III, or stage IV diffuse large B-cell lymphoma. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Monoclonal antibodies, such as rituximab, can block cancer cell growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cell-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with rituximab and combination chemotherapy may kill more cancer cells

Objectives

OBJECTIVES:

I. To find a safe dose of vorinostat to be used in combination with R-CHOP in patients with newly diagnosed stage II-IV diffuse large B-cell lymphoma. (Phase I) II. To estimate the 2-year progression-free survival (PFS) rate in patients treated with this regimen. (Phase II) III. To estimate the response rate (complete and partial) and 2-year overall survival rate. (Phase II) IV. To evaluate the toxicity of this regimen in these patients. (Phase II) V. To assess whether pre-treatment acetylation status of histones, expression of MHC Class II genes, and/or percentage of CD8+ tumor infiltrating lymphocytes correlate with PFS. (Phase II) VI. To explore whether treatment with vorinostat-R-CHOP increases histone acetylation, alters expression of MHC class II proteins, or alters percentage of T-cell subsets (CD8+, CD4+, FOXP3+) or infiltrating macrophages. (Phase II) VII. To explore whether histone acetylation status of tumor tissues correlates with MHC class II expression of peripheral blood B cells and lymphocyte subsets. (Phase II) VIII. To explore whether the change in systemic levels of immune cytokines with vorinostat-R-CHOP correlates with lymphoma symptoms, response, PFS, or overall survival. (Phase II)

OUTLINE: This is a multicenter, phase I dose escalation study of vorinostat followed by a phase II study.

Patients receive oral vorinostat once daily on days 1-5 or 1-9 (according to dose level), rituximab IV, cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV, and vincristine IV on day 3. Patients also receive oral prednisone once daily on days 3-7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

Paraffin block, core needle biopsy, and whole blood samples may be collected at baseline and during the first course of treatment for further analysis.

After completion of study treatment, patients are followed every 6 months for 2 years, and then annually for 3 years.