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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01193842
First received: September 1, 2010
Last updated: September 16, 2014
Last verified: July 2014
  Purpose

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 and 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, 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
Recurrent Adult Diffuse Large Cell Lymphoma
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: vorinostat
Biological: rituximab
Drug: etoposide
Drug: doxorubicin hydrochloride
Drug: vincristine sulfate
Drug: prednisone
Drug: cyclophosphamide
Other: laboratory biomarker analysis
Other: pharmacological study
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    Toxicity data will be presented by severity for each dose group. The incidence of toxicity related dose reductions and treatment discontinuations will be summarized for each dose group. If there are a sufficient number of patients in each dose group, chi square analyses will be used to compare dose groups with respect to the incidence of specific toxicities.

  • Complete response rate assessed by Response Evaluation Criteria in Solid Tumors (Phase II) [ Time Frame: Up to 5 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.

  • Incidence of adverse events (AEs) 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).


Secondary Outcome Measures:
  • Changes in CD4 cell counts (Phase I) [ Time Frame: Baseline up to 12 months ] [ Designated as safety issue: No ]
    Evaluated using analyses of variance. For each dose group and for all groups combined, the Wilcoxon signed rank test will be used to evaluate the changes in HIV viral load and CD4 count. If there is sufficient number of patients in each dose group, the Kruskal-Wallis test will be used to compare dose groups with respect to changes in HIV viral load and CD4 count.

  • Change in CD8 cell counts (Phase I) [ Time Frame: Baseline up to 12 months ] [ Designated as safety issue: No ]
    Evaluated using analyses of variance.

  • Percentage of plasma associated HIV-1 RNA (Phase I) [ Time Frame: Baseline up to 12 months ] [ Designated as safety issue: No ]
    Evaluated using analyses of variance. For each dose group and for all groups combined, the Wilcoxon signed rank test will be used to evaluate the changes in HIV viral load and CD4 count. If there is sufficient number of patients in each dose group, the Kruskal-Wallis test will be used to compare dose groups with respect to changes in HIV viral load and CD4 count.

  • Pharmacokinetic profile and the parameters of clearance and the AUC (area under the curve) (Phase I) [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
    Summary statistics will be used to describe pharmacokinetic results by dose level. Comparisons across dose levels will be made to assess proportionality or variability of the different parameters.

  • Tumor response rate (Phase I) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The tumor response rate will be estimated for each dose group and for all groups combined. The 95% confidence intervals will be constructed for tumor response rates.

  • 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 viral load [ Time Frame: Baseline up to 12 months ] [ Designated as safety issue: No ]
    A repeated measures analysis of variance will be used to assess the effect across time points.

  • Changes in EBV viral load [ Time Frame: Baseline up to 12 months ] [ Designated as safety issue: No ]
    Descriptive statistics such as frequencies and percentages will be used to aid in the evaluation of EBV and HHV-8 gene expression patterns.

  • Changes in HHV-8 viral load [ Time Frame: Baseline up to 12 months ] [ Designated as safety issue: No ]
    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: 110
Study Start Date: October 2010
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (VR-DA-EPOCH)
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 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: prednisone
Given PO
Other Names:
  • DeCortin
  • Deltra
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Experimental: ARM B (DA-R-EPOCH)
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.
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: prednisone
Given PO
Other Names:
  • DeCortin
  • Deltra
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients 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
  • Subjects 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 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 that 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 subjects 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 subjects 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; patients 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 patients 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; subjects who are hepatitis C antibody positive, with or without a positive hepatitis C ribonucleic acid (RNA) level, will be permitted to enroll in the study provided liver function tests meet criteria, and have no evidence of cirrhosis; patients 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 (< 50 mL/min if 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 subjects 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 subjects 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
  • Subjects 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 subjects: subjects 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 subject's completion of chemotherapy as part of this protocol
  • Subjects 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
  • Subjects must be able to swallow oral medications

Exclusion Criteria:

  • Subjects may have received one prior cycle of chemotherapy similar to cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) or EPOCH with or without rituximab; subjects who received more than one (1) prior cycle of chemotherapy are not allowed
  • 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
  • CNS involvement by lymphoma including parenchymal brain or spinal cord lymphoma or known presence of leptomeningeal disease prior to registration
  • Subjects with viral hepatitis who do not meet the criteria will not be eligible; all patients who present with acute hepatitis B including those with normal transaminases who are HBsAg+ and IgM + for hepatitis core antigen will not be eligible; subjects 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 patients who are hepatitis B core antibody positive, but hepatitis B antigen negative; patients refusing to take any anti-hepatitis B therapy during study will also be excluded; patients diagnosed with hepatitis C are eligible if they meet criteria
  • Pregnant women or nursing mothers
  • ECOG Performance Score >= 3 (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; subjects with active opportunistic infections are ineligible
  • Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study entry
  • Rituximab therapy within the 12 months prior to study entry; 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
  • 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 patients who have had severe skin disease or reactions in the past
  • Use of zidovudine as part of the HAART regimen (a drug substitution for zidovudine at the time of study entry is allowed)
  • Any acute, inter-current infection that may interfere with planned protocol treatment; patients 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
  • Subjects should not have taken valproic acid or another histone deacetylase inhibitor for at least 2 weeks prior to study enrollment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01193842

Locations
United States, Florida
University of Miami Miller School of Medicine-Sylvester Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Juan C. Ramos    305-243-6611    jramos2@med.miami.edu   
Principal Investigator: Juan C. Ramos         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Richard F. Ambinder    410-955-8839    ambinri@jhmi.edu   
Principal Investigator: Richard F. Ambinder         
United States, New York
Montefiore Medical Center-Einstein Campus Recruiting
Bronx, New York, United States, 10461
Contact: Joseph A. Sparano    718-904-2555    jsparano@montefiore.org   
Principal Investigator: Joseph A. Sparano         
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ariela Noy    212-639-7423    noya@mskcc.org   
Principal Investigator: Ariela Noy         
United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Dirk P. Dittmer    919-966-7960    ddittmer@med.unc.edu   
Principal Investigator: Dirk P. Dittmer         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Melanie Percy    713-798-4075    melanie.percy@bcm.edu   
Principal Investigator: Martha P. Mims         
Sponsors and Collaborators
Investigators
Principal Investigator: Juan Ramos AIDS Associated Malignancies Clinical Trials Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01193842     History of Changes
Other Study ID Numbers: NCI-2011-02508, NCI-2011-02508, AMC #75, CDR0000683379, AMC-075, AMC-075, U01CA121947
Study First Received: September 1, 2010
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
HIV Infections
Acquired Immunodeficiency Syndrome
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Immunoblastic
Lymphoma
Lymphoma, Extranodal NK-T-Cell
Lymphoma, B-Cell
Lymphomatoid Granulomatosis
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Slow Virus Diseases
Lymphoma, T-Cell
Precancerous Conditions
Rituximab
Vorinostat
Etoposide phosphate

ClinicalTrials.gov processed this record on September 30, 2014