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
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This randomized phase I/II trial is studying 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 and alone in treating patients with HIV-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 or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Giving vorinostat together with combination chemotherapy and rituximab may kill more cancer cells
Condition | Intervention | Phase |
---|---|---|
Adult Grade III Lymphomatoid Granulomatosis AIDS-related Diffuse Large Cell Lymphoma Contiguous Stage II Adult Diffuse Large Cell Lymphoma Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma Contiguous Stage II Adult Lymphoblastic Lymphoma Contiguous Stage II Grade 3 Follicular Lymphoma Contiguous Stage II Mantle Cell Lymphoma HIV Infection Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma Noncontiguous Stage II Adult Lymphoblastic Lymphoma Noncontiguous Stage II Grade 3 Follicular Lymphoma Noncontiguous Stage II Mantle Cell Lymphoma Post-transplant Lymphoproliferative Disorder Recurrent Adult Diffuse Mixed Cell Lymphoma Recurrent Adult Grade III Lymphomatoid Granulomatosis Recurrent Adult Immunoblastic Large Cell Lymphoma Recurrent Adult Lymphoblastic Lymphoma Recurrent Grade 3 Follicular Lymphoma Recurrent Mantle Cell Lymphoma Stage I Adult Diffuse Large Cell Lymphoma Stage I Adult Diffuse Mixed Cell Lymphoma Stage I Adult Immunoblastic Large Cell Lymphoma Stage I Adult Lymphoblastic Lymphoma Stage I Grade 3 Follicular Lymphoma Stage I Mantle Cell Lymphoma Stage III Adult Diffuse Large Cell Lymphoma Stage III Adult Diffuse Mixed Cell Lymphoma Stage III Adult Immunoblastic Large Cell Lymphoma Stage III Adult Lymphoblastic Lymphoma Stage III Grade 3 Follicular Lymphoma Stage III Mantle Cell Lymphoma Stage IV Adult Diffuse Large Cell Lymphoma Stage IV Adult Diffuse Mixed Cell Lymphoma Stage IV Adult Immunoblastic Large Cell Lymphoma Stage IV Adult Lymphoblastic Lymphoma Stage IV Grade 3 Follicular Lymphoma Stage IV Mantle Cell Lymphoma |
Drug: doxorubicin hydrochloride Drug: vincristine sulfate Drug: vorinostat Drug: prednisone Biological: rituximab Drug: cyclophosphamide Drug: etoposide Other: laboratory biomarker analysis |
Phase 1 Phase 2 |
Study Type: | Interventional |
Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
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 |
- Recommended phase II dose of vorinostat determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) (Phase I) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
- Complete response rate assessed by RECIST (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]The difference between the complete response rate proportions (i.e., chemo alone vs. chemo + vorinostat) will be tested using the Normal approximation for a two sample test of proportions.
- Frequency and severity of adverse events for each treatment arm assessed by CTCAE v4.0 (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]The frequency of AEs and their severity will be tabulated for each treatment arm (i.e., chemo alone and chemo + vorinostat) overall and by risk group to evaluate tolerance of vorinostat for a treatment of patients with HIV-related B-cell non-Hodgkin's lymphoma.
- Event-free survival (EFS) (Phase II) [ Time Frame: 1 year ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]Binomial proportions and their 95% confidence intervals will be used to determine the 1-year OS rates.
- Changes in HIV, EBV, and HHV-8 viral load and CD4/CD8 count [ Time Frame: Baseline to day 42, and 1, 6, and 12 months after chemotherapy ] [ Designated as safety issue: No ]To assess the effect of vorinostat and/or chemotherapy on T-cell subsets (CD4 and CD8) and plasma immunoglobulin levels, these measures will first be tested to determine if they are normally distributed. If the data do not meet the assumptions of normality, the data will be transformed for analysis purposes. A repeated measures analysis of variance will be used to assess the effect of vorinostat and/or chemotherapy on T-cell subsets across time points. Descriptive statistics such as frequencies and percentages will be used to aid in the evaluation of EBV and HHV-8 gene expression patterns.
Estimated Enrollment: | 130 |
Study Start Date: | October 2010 |
Estimated Primary Completion Date: | July 2017 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
---|---|
Experimental: Arm I
Patients receive oral vorinostat once daily and oral prednisone once daily on days 1-5 and rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Drug: vorinostat
Given orally
Other Names:
Drug: prednisone
Given orally
Other Names:
Biological: rituximab
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Experimental: Arm II
Patients receive prednisone, rituximab, cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate as in arm I.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Drug: prednisone
Given orally
Other Names:
Biological: rituximab
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Experimental: Arm III
Patients receive vorinostat, prednisone, and rituximab as in arm I; etoposide IV over 96 hours, doxorubicin hydrochloride IV over 96 hours, and vincristine sulfate IV over 96 hours on days 1-4; and cyclophosphamide IV over 1 hour on day 5.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Drug: vorinostat
Given orally
Other Names:
Drug: prednisone
Given orally
Other Names:
Biological: rituximab
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: etoposide
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Experimental: Arm IV
Patients receive prednisone and rituximab as in arm I and etoposide, doxorubicin hydrochloride, vincristine sulfate, and cyclophosphamide as in arm III.
|
Drug: doxorubicin hydrochloride
Given IV
Other Names:
Drug: vincristine sulfate
Given IV
Other Names:
Drug: prednisone
Given orally
Other Names:
Biological: rituximab
Given IV
Other Names:
Drug: cyclophosphamide
Given IV
Other Names:
Drug: etoposide
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
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Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Histologically, or cytologically documented diffuse large B-cell lymphoma, and other aggressive CD20+ non-Burkitt non-Hodgkin B-cell lymphoma variants as defined by the 2008 WHO classification; rare aggressive CD20 negative B-cell lymphomas are also eligible
- Subjects who are untreated or who received a maximum of one (1) cycle of chemotherapy prior are eligible; previous treatment must occur at least 4 weeks prior to enrollment
- All stages of disease allowed
- CD4 count ≥ 50 cells/mm³
Must meet 1 of the following risk sets of criteria:
Low-risk
- Age-adjusted (aa)-international prognostic index (IPI) scores: 0-1 factors*
- Ki-67 < 80%
- Germinal center B-cell-like (GCB) DLBCL or non-Burkitt subtype (if known)
High-risk
- aa-IPI: 2-3 factors*
- Ki-67 ≥ 80%
- Activated B-cell-like (ABC, also known as post-GCB) subtype DLBCL if known, or any other aggressive non-Burkitt B-cell lymphomas
Serologically confirmed HIV infection by ELISA or western blot, or by another federally approved licensed HIV test
- Prior documentation of HIV seropositivity allowed
Measurable or non-measurable tumor
- Non-measurable tumor parameters are defined as not having bidimensional measurements (e.g., gastric or marrow involvement), but that can be followed for response by other diagnostic tests such as gallium, PET imaging, and/or bone marrow biopsy
- No CNS involvement including parenchymal brain or spinal cord lymphoma, or known leptomeningeal disease
- Concurrent chronic therapy with potentially myelosuppressive agents allowed provided hematologic criteria are met
- ECOG performance status (PS) 0-2 (Karnofsky PS 50-100%)
- Life expectancy ≥ 2 months
- ANC ≥ 1,000/mm³
- Platelet count ≥ 75,000/mm³ (unless abnormal due to lymphomatous involvement of bone marrow)
- Creatinine < 2.0 mg/dL OR creatinine clearance ≥ 60 mL/min (< 50 mL/min if due to kidney involvement by tumor)
- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless due to hepatic involvement or HIV medication such as indinavir, tenofovir, or atazanavir [drug adjustment may be needed if direct bilirubin > 1.2 times ULN due to hepatic involvement])
- AST and ALT ≤ 2.5 times ULN (unless elevated due to secondary lymphomatous involvement of the liver)
- LVEF normal by MUGA scan or ECHO within the past 6 weeks
- Negative pregnancy test
- Not pregnant or nursing
- Fertile patients must use effective contraception during and for 6 months after completion of study treatment
- Able to swallow oral medications
- 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
- Subjects who are Hepatitis B core antibody positive are eligible only if they start or are on prophylactic therapy; subjects with known active Hepatitis B (surface antigen, core antigen, or viral load positive) are ineligible; a hepatitis B viral load should be confirmed negative on all patients who are hepatitis B core antibody positive, but hepatitis B antigen negative
- No known chronic hepatitis C virus infection
- Must be able to comply with protocol requirements and provide adequate informed consent, in the opinion of the principal investigator
- No serious, ongoing, non-malignant disease or infection, including opportunistic infections that, in the opinion of the investigator and/or the sponsor, would compromise other protocol objectives
- No history of cutaneous or mucocutaneous reactions, or other disease due to any cause, severe enough to cause hospitalization or inability to eat or drink for > 2 days
No acute, inter-current infection that may interfere with planned protocol treatment
- Patients with mycobacterium avium infection allowed
None of the following:
- Myocardial infarction within the past 6 months
- NYHA class II-IV heart failure
- Uncontrolled angina
- Severe uncontrolled ventricular arrhythmias
- Clinically significant pericardial disease
- Electrocardiographic evidence of acute ischemic or active conduction system abnormalities
Concurrent highly active antiretroviral (HAART) regimen that is in accordance with the current International AIDS Society guidelines allowed
- Changes to HAART therapy allowed if medically necessary (e.g., toxicity, failure of regimen)
- HAART-naive patients must start therapy after completion of course 1 of chemotherapy
- Concurrent agents currently available on expanded access program allowed
- No experimental antiretroviral agents
No concurrent agents containing zidovudine, including Combivir® and Trizivir®
- Zidovudine or a zidovudine-containing regimen (including Combivir® and Trizivir®) is prohibited until 2 months after completion of study chemotherapy
- At least 24 hours since prior colony-stimulating factor therapy
- More than 4 weeks since prior major surgery other than diagnostic surgery
- Rituximab therapy within the 12 months prior to study entry except as outlined above; patients 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 except as outlined above
- No prior cytotoxic chemotherapy or radiotherapy for this lymphoma, except as outlined above
- No prior valproic acid or another histone deacetylase inhibitor within the past 2 weeks
- Patients who received more than one (1) prior cycle of chemotherapy are not allowed; patients may have received one prior cycle of chemotherapy similar to CHOP or EPOCH with or without rituximab
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United States, Maryland | |
Johns Hopkins University | Recruiting |
Baltimore, Maryland, United States, 21287-8936 | |
Contact: Yvette L. Kasamon 410-955-8804 jhcccro@jhmi.edu | |
Principal Investigator: Yvette L. Kasamon | |
AIDS - Associated Malignancies Clinical Trials Consortium | Recruiting |
Rockville, Maryland, United States, 20850 | |
Contact: Ronald T. Mitsuyasu 310-557-1891 rmitsuya@mednet.ucla.edu | |
Principal Investigator: Juan C. Ramos |
Principal Investigator: | Juan Ramos | AIDS Associated Malignancies Clinical Trials Consortium |
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No publications provided
Responsible Party: | National Cancer Institute (NCI) |
ClinicalTrials.gov Identifier: | NCT01193842 History of Changes |
Other Study ID Numbers: | NCI-2011-02508, AMC-075, U01CA121947 |
Study First Received: | September 1, 2010 |
Last Updated: | February 5, 2013 |
Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
HIV Infections Acquired Immunodeficiency Syndrome Lymphoma Lymphoma, Follicular Lymphoma, Non-Hodgkin Lymphomatoid Granulomatosis Lymphoproliferative Disorders Lymphoma, B-Cell Lymphoma, Large B-Cell, Diffuse Lymphoma, Large-Cell, Immunoblastic Precursor Cell Lymphoblastic Leukemia-Lymphoma Lymphoma, Extranodal NK-T-Cell Lymphoma, Mantle-Cell Lentivirus Infections Retroviridae Infections |
RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Slow Virus Diseases Neoplasms by Histologic Type Neoplasms Lymphatic Diseases Immunoproliferative Disorders Precancerous Conditions Leukemia, Lymphoid Leukemia Lymphoma, T-Cell |
ClinicalTrials.gov processed this record on February 21, 2013