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

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.

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 phase II study.

PHASE I: Patients receive vorinostat orally (PO) once daily (QD) on days 1-5; rituximab
intravenously (IV) on day 1; etoposide IV over 24 hours, doxorubicin hydrochloride IV over 24
hours, and vincristine sulfate IV over 24 hours on days 1-4; prednisone PO daily on days 1-5;
and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for 6 courses
in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM A (VR-DA-EPOCH): Patients receive vorinostat, rituximab, etoposide, doxorubicin
hydrochloride, vincristine sulfate, prednisone, and cyclophosphamide as in Phase I.

ARM B (DA-R-EPOCH): Patients receive rituximab, etoposide, doxorubicin hydrochloride,
vincristine sulfate, prednisone, and cyclophosphamide as in Arm A.

In all arms, treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity.

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

Inclusion Criteria:

- Participants with histologically or cytologically documented diffuse large B-cell
lymphoma (DLBCL) must meet at least 1 of the following risk criteria:

- Age-adjusted International Prognostic Index (IPI) score: 2-3

- Ki-67 >= 80%

- Histologically, or cytologically documented activated B-cell-like (ABC, also
known as post-GCB) subtype

- Double hit variant, defined as having v-myc avian myelocytomatosis viral oncogene
homolog (MYC) gene rearrangement in the presence of B-cell chronic lymphocytic
leukemia (CLL)/lymphoma (BCL) 2 or BCL6 gene rearrangement

- Other aggressive non-DLBCL non-Burkitt non-Hodgkin B-cell lymphoma variants
as defined by the 2008 World Health Organization (WHO) classification,
including rare CD20 negative B-cell lymphomas (i.e. plasmablastic lymphoma,
and primary effusion lymphoma) are also eligible; grade 3B follicular
lymphoma is also eligible as long as one the above risk criteria is met

- Participants who are untreated or who received a maximum of one (1) cycle of
combination chemotherapy, including rituximab-containing regimens, prior are eligible;
the start of previous chemotherapy cycle must occur at least 21 days prior to
beginning treatment under this protocol, and such cycle will count towards the total
maximum of 6 cycles under this study

- Documentation of HIV infection at any time prior to study entry; documentation may be
molecular (detectable viral ribonucleic acid [RNA] by polymerase chain reaction
[PCR]), serologic (positive enzyme-linked immunosorbent assay [ELISA] and positive
Western blot), or other federally approved licensed HIV test; prior documentation of
HIV seropositivity is acceptable

- All stages of disease

- Measurable or non-measurable tumor parameter(s); non-measurable tumor parameters are
defined as not having bidimensional measurements (e.g., gastric or marrow
involvement), but can be followed for response by other diagnostic tests such as
gallium, positron emission tomography (PET) imaging, and/or bone marrow biopsy

- Performance status (PS) 0, 1, or 2 per the Eastern Cooperative Oncology Group (ECOG)
performance status scale (Karnofsky performance score >= 50%)

- Able to provide informed consent

- Total bilirubin =< 1.5 institutional upper limit of normal (ULN), unless elevated
secondary to lymphomatous involvement of liver or biliary system, or due to other HIV
medications (e.g., indinavir, tenofovir, or atazanavir); for direct bilirubin > 1.2
due to hepatic involvement by tumor for the initial dose of EPOCH drug adjustment

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times ULN
(unless elevated due to secondary lymphomatous involvement of the liver)

- Negative for hepatitis B, or if infected with hepatitis B, receiving anti-hepatitis B
therapy; all participants will be required to be screened for hepatitis B and C; per
Infectious Disease Society of America (IDSA) and American Association for the Study of
Liver Diseases (AASD) guidelines, those participants that show no immunity, defined by
the lack of hepatitis B surface antibody, and show evidence of chronic infection (i.e.
hepatitis B surface antigen positive [HBsAg+], hepatitis B core antibody positive
[HBcore+], hepatitis surface antibody negative [HBsAB-]) will be required to be on
anti-hepatitis B therapy, during the study, in order to be eligible; participants will
be permitted to enroll in the study provided liver function tests meet criteria, and
there is no evidence of cirrhosis; the exact hepatitis B therapy will be at the
discretion of the infection disease specialist or investigator; however all
participants who present with acute hepatitis B or show normal transaminases and are
HBsAg+ and immunoglobulin (Ig)M+ for hepatitis core antigen will not be eligible for
trial enrollment; participants who are hepatitis C antibody positive, with or without
a positive hepatitis C RNA level, will be permitted to enroll in the study provided
liver function tests meet criteria, and have no evidence of cirrhosis; participants
diagnosed with hepatitis C less than 6 months from trial enrollment, will be
considered to have acute hepatitis C and will be excluded from study unless hepatitis
(hep) C viral load is undetectable

- Creatinine clearance >= 60 mL/min, unless secondary to renal involvement by lymphoma;
for creatinine clearance < 50 mL/min due to kidney involvement by tumor

- Granulocytes/absolute neutrophil count (ANC) >= 1,000/mm^3

- Platelets >= 75,000/mm^3 (unless these parameters are abnormal secondary to
lymphomatous involvement of bone marrow); all participants must cease
colony-stimulating factor therapy at least 24 hours prior to institution of cycle 1
chemotherapy

- Left ventricular ejection fraction (LVEF) that is at or above the lower institutional
limits of normal, as assessed by multiple gated acquisition (MUGA) scan or
echocardiogram within the 6 weeks prior to registration

- Concurrent radiation, with or without steroids, or steroids alone for emergency
conditions secondary to lymphoma (i.e. cord compression, etc.) will be permitted

- Female participants must have a negative pregnancy test within 7 days of entering into
the study; both men and women of child bearing potential must agree to use adequate
methods of contraception for the duration of the treatment; women must avoid
pregnancy, and men must avoid fathering children while in the study and for 6 months
following the last study drug treatment

- Participants on an antiretroviral regimen should be receiving treatment that is in
accordance with the current International acquired immune deficiency syndrome (AIDS)
Society guidelines; the specific agents are at the discretion of the investigator and
use of agents currently available on an expanded access basis is allowed but use of
experimental antiretroviral agents or those containing zidovudine (including Combivir
and Trizivir) are prohibited; changes to highly active anti-retroviral therapy (HAART)
therapy may be made if medically necessary (toxicity, failure of regimen, etc.);
antiretroviral naïve participants: participants who are not on HAART at study entry
MUST begin therapy (utilizing the above guidelines) AFTER one cycle of chemotherapy
has been completed under protocol; changes to HAART therapy may be made if medically
necessary (toxicity, failure of regimen, etc.); concurrent therapy with zidovudine or
a zidovudine-containing regimen (including Combivir and Trizivir) will be prohibited
until 2 months following the participant's completion of chemotherapy as part of this
protocol; the use of cobicistat (e.g., Tybost), or cobicistat containing single tablet
regimens (e.g., Stribild) is prohibited during concurrent chemotherapy under this
protocol; participants taking cobicistat or cobicistat-containing single table
regimens must switch to a different agent or regimen prior to enrollment, and will
remain on the regimen until at least 2 months following treatment discontinuation;
Cobicistat is a pure and potent cytochrome P450, family 3, subfamily A, polypeptide 4
(CYP3A4) inhibitor and has the potential to increase the area under the curve (AUC) of
CYP3A4 substrates; therefore, both vincristine and doxorubicin would have the
potential for drug drug interaction (DDI) with cobicistat since they are CYP3A4
substrates

- Participants already receiving erythropoietin or colony-stimulating factor therapy are
eligible for participation, although the latter must be discontinued at least 24 hours
prior to receiving chemotherapy

- Participants must be able to swallow oral medications

Exclusion Criteria:

- Participants who have received more than one (1) prior cycle of chemotherapy similar
to cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone
(CHOP) or EPOCH with or without rituximab

- Absolute CD4 count of < 50 cells/ mm^3

- Presence of second active tumor, other than non-melanoma skin cancer, carcinoma in
situ of the cervix, or Kaposi's sarcoma (KS) that requires systemic therapy

- Central nervous system (CNS) involvement by lymphoma including parenchymal brain or
spinal cord lymphoma or known presence of leptomeningeal disease prior to registration

- Participants with viral hepatitis who do not meet the criteria will not be eligible;
all participants who present with acute hepatitis B including those with normal
transaminases who are HBsAg+ and IgM + for hepatitis core antigen will not be
eligible; participants who are hepatitis B core antibody positive are eligible only if
they start or are on prophylactic therapy; a hepatitis B viral load should be
confirmed negative on all participants who are hepatitis B core antibody positive, but
hepatitis B antigen negative; participants refusing to take any anti-hepatitis B
therapy during study will also be excluded; participants diagnosed with hepatitis C
are eligible if they meet criteria

- Pregnant women or nursing mothers

- ECOG performance score >= 3 (Karnofsky performance status [KPS] < 50%)

- Expected survival < 2 months

- Unable to comply with the requirements of the protocol, or unable to provide adequate
informed consent in the opinion of the principal investigator

- Serious, ongoing, non-malignant disease or infection, which in the opinion of the
investigator and/or the sponsor would compromise other protocol objectives;
participants with active opportunistic infections are ineligible

- Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study entry;
splenectomy will not be considered an exclusionary major surgery

- Rituximab therapy within the 12 months prior to study entry; participants treated with
rituximab within 12 months prior to study registration are eligible only if it was
given for indications other than the treatment of aggressive lymphoma

- Prior cytotoxic chemotherapy or radiotherapy for this lymphoma

- History of cutaneous or mucocutaneous reactions, or diseases in the past, due to any
cause, severe enough to cause hospitalization or an inability to eat or drink for > 2
days; this exclusion relates to the long-term possibility of severe cutaneous or
mucocutaneous reactions to rituximab that might occur at increased frequency in
participants who have had severe skin disease or reactions in the past

- Use of zidovudine or cobicistat as part of the HAART regimen (a drug substitution at
the time of study entry is allowed)

- Any acute, inter-current infection that may interfere with planned protocol treatment;
participants with mycobacterium avium will not be excluded from study entry; chronic
therapy with potentially myelosuppressive agents is allowed provided that entry
hematologic criteria are met

- Myocardial infarction (MI) within 6 months prior to study entry, New York Heart
Association (NYHA) class II or greater heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or
electrocardiographic evidence of acute ischemic or active conduction system
abnormalities

- Participants should not have taken valproic acid or another histone deacetylase
inhibitor for at least 2 weeks prior to study enrollment