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Patients receive vorinostat PO QD on days 1-5; rituximab 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.

Patients receive rituximab, etoposide, doxorubicin hydrochloride, vincristine sulfate, prednisone, and cyclophosphamide as in Arm A. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Doxorubicin Hydrochloride

Laboratory Biomarker Analysis

Pharmacological Study

Vincristine Sulfate

Juan C Ramos

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.

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.

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

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

Percentage of participants with complete response as assessed by Response Evaluation Criteria in Solid Tumors (Phase II) according to treatment arm. Participants are planned to be treated for a total of 6 cycles (21 day cycle length). Participants with CR after Cycle 4 will receive two additional cycles of chemotherapy and complete 6 cycles of chemotherapy. Participants who achieve a partial response (PR) only after Cycle 4 may continue on protocol therapy or they may be removed from the study at the AMC discretion of the physician (local Principal Investigator). Participants with stable disease after 4 cycles (i.e., who did not achieve at least a PR) or progressive disease at any time will be removed from study.

In phase II, there are two arms: Vorinostat RPTD+rituximab-DA-EPOCH arm (VR-DA-EPOCH) and Rituximab-DA-EPOCH arm (DA-R-EPOCH).

The percentage of participants with AEs and their worst severity will be tabulated for each treatment arm. If a participant has more than one AE, the most severe AE is analyzed. All adverse events will be assessed by the investigator from the first dose of protocol therapy through the post-treatment discontinuation visit. Participants are planned to be treated for a total of 6 cycles (21 day cycle length), or roughly 4 months. After this evaluation, assessment and reporting of AEs will only be required for all grade 5 AEs and any serious AE (SAE) that the investigator considers related to protocol therapy.

Recommended phase II dose of vorinostat is defined as the dose level at which 0/6 or 1/6 subjects experience dose limiting toxicity (DLT) with the next higher dose having at least 2/3 or 2/6 subjects encountering DLT (Phase I). Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Using a 3+3 design, the recommended phase II dose is defined as the level at which 0/6 or 1/6 patients experiences at dose-limiting toxicity in the first cycle.

Differences from baseline (specified follow-up assessment minus baseline) in absolute CD8 counts.

Differences from baseline (specified follow-up assessment minus baseline) in absolute CD4 counts.

Differences from baseline (specified follow-up assessment minus baseline) in EBV viral load.

Differences from baseline (specified follow-up assessment minus baseline) in (HHV)-8 viral load.

Differences from baseline (specified follow-up assessment minus baseline) in HIV viral load. Undetectable viral load results were treated as 0 values.

The percentage of participants surviving without events (relapse or death) one year after starting treatment.

The percentage of participants surviving one year after starting treatment.

Serial plasma samples for pharmacokinetic analysis were collected at 24-48, 48-72, and 72-96 hours after the start of the first chemotherapy infusion. Doxorubicin, etoposide, and vincristine concentrations were determined using a validated liquid chromatography-tandem mass spectrometry method. The clearance was determined by dividing the drug-infusion rate by the steady-state concentrations, which was the average of the three time points.

The percentage of participants whose best tumor response is complete response (CR) or partial response (PR). Based on clinical, radiologic (CT), and pathologic criteria, CR requires 1) complete disappearance of all detectable disease and disease-related symptoms if present before therapy, 2) bone marrow aspirate and biopsy to confirm a CR if initially positive or if clinically indicated by new abnormalities in the peripheral blood counts or blood smear, 3) negative PET results, depending on typically, variably, or unknown pre-treatment FDG status, and 4) spleen and/or liver, if considered to be enlarged before therapy on physical examination or CT scan, not being palpable on physical examination and considered normal size by imaging studies, and nodules related to lymphoma disappeared. PR includes 1) ≥50% decrease in sum of product of diameters (SPD), 2) no increase in size of nodes, liver, or spleen, 3) splenic/hepatic nodules regressed by ≥ 50% SPD, 4) no new sites of disease

National Cancer Institute (NCI)

Arm A (VR-DA-EPOCH) with Vorinostat at 300 mg once a day on days 1-5 of a cycle (Phase I Dose Level 1)

Phase I: VR-DA-EPOCH, Dose Level 1

Arm A (VR-DA-EPOCH) with Vorinostat at 400 mg once a day on days 1-5 of a cycle (Phase I Dose Level 2)

Phase I: VR-DA-EPOCH, Dose Level 2

Arm C (VR-CHOP) with Vorinostat at 300 mg once a day on days 1-5 of a cycle (Phase I Dose Level 1 for low risk participants). This arm was discontinued due to low accrual.

Phase I: VR-CHOP, Dose Level 1

Arm A (VR-DA-EPOCH) at the recommended phase II dose of Vorinostat (300 mg once a day for days 1-5 of a cycle)

Phase II: VR-DA-EPOCH

Arm B (DA-R-EPOCH), which is the same treatment as Arm A but without Vorinostat

Phase II: DA-R-EPOCH

Phase II, V+DA-EPOCH

Arm B (DA-R-EPOCH), which is the same treatment as Arm A, but without Vorinostat

Phase II, DA-R-EPOCH

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Eligible participants completing at least one cycle of treatment; 3 ineligible participants and 1 participant not completing one cycle of Phase I treatment were not included.

Experimental Arm C (VR-CHOP) was discontinued early in phase I due to low accrual; only 2 participants received VR-CHOP.

AMC Statistical Center

Reviewed responses from participants who completed at least one cycle of treatment. In phase II, there are two arms: Vorinostat RPTD+rituximab-DA-EPOCH arm (VR-DA-EPOCH) and Rituximab-DA-EPOCH arm (DA-R-EPOCH).

In phase I, patients in DA-R-EPOCH were not included in the analysis.

Percentage of Participants With Complete Response (CR) as Assessed by Response Evaluation Criteria in Solid Tumors (Phase II)

Death

Life-threatening

Severe

Moderate

Mild

Percentage of Participant Experiencing Adverse Events (AEs) for Each Treatment Arm as Assessed by Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0) (Phase II)

Phase I: VR-DA-EPOCH

Eligible Phase I Arm A (VR-DA-EPOCH) participants who completed at least 1 cycle of treatment. This arm includes participants treated at 300 mg once a day (n=6) or 400 mg once a day (n=6) of Vorinostat for days 1-5.

Recommended Phase II Dose of Vorinostat Determined According to Dose-limiting Toxicities Graded Using Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0) (Phase I)

End of cycle 2

Treatment discontinuation

6-month follow-up

12-month follow-up

Phase I, Arm A (VR-DA-EPOCH) with Vorinostat at 300 mg once a day on days 1-5 of a cycle (Phase I Dose Level 1)

Phase I, Arm A (VR-DA-EPOCH) with Vorinostat at 400 mg once a day on days 1-5 of a cycle (Phase I Dose Level 2)

Eligible participants who returned for follow-up with evaluable data.

Change in CD8 Cell Counts (Phase I)

Phase I, Arm C (VR-CHOP) with Vorinostat at 300 mg once a day on days 1-5 of a cycle (Phase I Dose Level 1 for low risk participants). This arm was discontinued due to low accrual.

Eligible participants who completed at least 1 cycle of treatment with evaluable data.

Changes in Absolute CD4 Cell Counts (Phase I)

End of Cycle 2

At treatment discontinuation

Arm A (VR-DA-EPOCH) at the recommended phase II dose of Vorinostat (300 mg once a day for days 1-5 of a cycle).

Phase II, VR-DA-EPOCH

Arm A (VR-DA-EPOCH) with Vorinostat at 300mg once a day on days 1-5 of a cycle (Phase I dose Level 1)

Arm A (VR-DA-EPOCH) with Vorinostat at 400mg once a day on days 1-5 of a cycle (Phase I dose Level 1)

Median Change from the baseline and IQR were calculated. The measurement unit is IU/mL.

Changes in Epstein-Barr Virus (EBV) Viral Load

Outcome measure is the difference between the baseline and specific time points (End of Cycle 2, Treatment discontinuation, 6-month, and 12-month follow-ups.

Only a few differences can be calculated.

Changes in Human Herpes Virus (HHV)-8 Viral Load

Phase II participants who returned for follow-up with evaluable data.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT01193842	AIDS-Related Pl... AIDS-Related Pr... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... HIV Infection Plasmablastic L... Primary Effusio... Recurrent Diffu... Recurrent Grade...	Cyclophosphamid... Doxorubicin Hyd... Etoposide Laboratory Biom... Pharmacological... Prednisone Rituximab Vincristine Sul... Vorinostat	18 Years -	National Cancer Institute (NCI)
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	NCT01193842	AIDS-Related Pl... AIDS-Related Pr... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... Ann Arbor Stage... HIV Infection Plasmablastic L... Primary Effusio... Recurrent Diffu... Recurrent Grade...	Cyclophosphamid... Doxorubicin Hyd... Etoposide Laboratory Biom... Pharmacological... Prednisone Rituximab Vincristine Sul... Vorinostat	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for ann arbor stage i grade 3 follicular lymphoma