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

September 1, 2010
September 16, 2014
October 2010
July 2017   (final data collection date for primary outcome measure)
  • 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).
  • Maximum-tolerated dose and recommended phase II dose of vorinostat and risk-adapted chemotherapy with rituximab(phase I) [ Designated as safety issue: Yes ]
  • Complete response (Phase II) [ Designated as safety issue: No ]
  • Toxicity (Phase II) [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01193842 on ClinicalTrials.gov Archive Site
  • 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.
  • 1-year event-free survival [ Designated as safety issue: No ]
  • 1-year overall survival [ Designated as safety issue: No ]
  • Effect of treatment on HIV, HBV, and HHV-8 viral load [ Designated as safety issue: No ]
  • Effect of treatment on T-cell subsets (CD4 and CD8) and plasma immunoglobulin levels [ Designated as safety issue: No ]
  • Gene expression profiling [ Designated as safety issue: No ]
  • EBV gene expression [ Designated as safety issue: No ]
Not Provided
Not Provided
 
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

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.

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 subjects with human immunodeficiency (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, 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 1. 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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • 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
    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 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.
    Interventions:
    • Drug: vorinostat
    • Biological: rituximab
    • Drug: etoposide
    • Drug: doxorubicin hydrochloride
    • Drug: vincristine sulfate
    • Drug: prednisone
    • Drug: cyclophosphamide
    • Other: laboratory biomarker analysis
    • Other: pharmacological study
  • 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.
    Interventions:
    • Biological: rituximab
    • Drug: etoposide
    • Drug: doxorubicin hydrochloride
    • Drug: vincristine sulfate
    • Drug: prednisone
    • Drug: cyclophosphamide
    • Other: laboratory biomarker analysis
    • Other: pharmacological study
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
110
Not Provided
July 2017   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
United States
 
NCT01193842
NCI-2011-02508, NCI-2011-02508, AMC #75, CDR0000683379, AMC-075, AMC-075, U01CA121947
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Juan Ramos AIDS Associated Malignancies Clinical Trials Consortium
National Cancer Institute (NCI)
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP