Vorinostat, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVES:

I. To find a safe dose of vorinostat to be used in combination with R-CHOP (rituximab,
cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone)
(vorinostat-R-CHOP). (Phase I) II. To estimate the 2-year progression-free survival (PFS)
rate in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with
vorinostat and R-CHOP therapy (vorinostat-R-CHOP). (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 vorinostat-R-CHOP in patients with newly diagnosed DLBCL. (Phase II) V. To assess
whether pre-treatment acetylation status of histones, expression of major histocompatibility
complex (MHC) class II genes, and/or percentage of cluster of differentiation (CD)8+ tumor
infiltrating lymphocytes correlate with progression-free survival. (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+, forkhead box P3
[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,
progression-free or overall survival. (Phase II)

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

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

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

Inclusion Criteria:

- Patients must have biopsy proven, newly diagnosed DLBCL with stage II bulky, stage III
or stage IV disease, with an International Prognostic Index (IPI) or revised (R)-IPI
score greater than 0; a report providing confirmation of CD20 expression must be
submitted

- Adequate sections from the original diagnostic specimen must be available for
submission for review by the Southwest Oncology Group (SWOG) Lymphoma Pathology
Laboratory; an adequate biopsy requires sufficient tissue to establish the
architecture and World Health Organization (WHO) histologic subtype with certainty;
fine needle aspiration or cytology is not adequate

- Patients must be offered the opportunity to consent to the correlative science
studies; patients are encouraged to submit specimens for correlative studies; however,
specimen submission is not a requirement for participation in the study

- Patients must have measurable disease; measurable disease must be determined by
computed tomography (CT) scan of chest, abdomen and pelvis performed within 28 days
prior to registration; positron emission tomography (PET)/CT may be substituted for CT
scan only if CT scan is of diagnostic quality and is contrast enhanced

- Patients must have a unilateral bone marrow aspirate and biopsy for staging performed
within 42 days prior to registration

- Patients must not have clinical evidence of central nervous system involvement by
lymphoma; any laboratory or radiographic tests performed within 42 days prior to
registration to assess central nervous system (CNS) involvement must be negative

- Patients must not have received prior chemotherapy, radiation, or antibody therapy for
lymphoma; steroid pre-medication for IV contrast allergy is allowed

- Patients must have Zubrod performance status of 0-2

- Patients must have serum lactate dehydrogenase (LDH) measured within 28 days prior to
registration

- Absolute neutrophil count (ANC) > 1,000/mcL within 28 days prior to registration,
unless due to bone marrow infiltration by lymphoma

- Platelets > 100,000/mcL within 28 days prior to registration, unless due to bone
marrow infiltration by lymphoma

- Cardiac ejection fraction ≥ institutional lower limit of normal (ILLN) by multigated
acquisition (MUGA) scan or 2-dimensional (2-D) echocardiogram (ECHO) with no
significant abnormalities within 42 days prior to registration

- Patients must not have received valproic acid (a histone deacetylase [HDAC] inhibitor)
within 28 days prior to registration

- Patients must have no known hypersensitivity to the components of treatment

- Patients must be willing to discontinue taking any medications that are generally
accepted to have a risk of causing Torsades de Pointes while on study

- Patients known to be human immunodeficiency virus (HIV) positive are not eligible;
existing therapeutic options are effective and study design does not support assessing
the efficacy of treatment on those with HIV

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for five years

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines

- At the time of patient registration, the treating institution's name and
identification (ID) number must be provided to the Data Operations Center in Seattle
in order to ensure that the current (within 365 days) date of institutional review
board approval for this study has been entered into the data base