Clinical Trials /

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

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Non-Hodgkin Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Vorinostat</span> and Combination <span class="go-doc-concept go-doc-intervention">Chemotherapy</span> With <span class="go-doc-concept go-doc-intervention">Rituximab</span> in Treating Patients With HIV-Related Diffuse Large B-Cell <span class="go-doc-concept go-doc-disease">Non-Hodgkin Lymphoma</span> or Other Aggressive B-Cell Lymphomas

Title

  • Brief Title: 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
  • 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 Lymphoma
  • Clinical Trial IDs

    NCT ID: NCT01193842

    ORG ID: NCI-2011-02508

    NCI ID: NCI-2011-02508

    Trial Conditions

    Adult Grade III Lymphomatoid Granulomatosis

    AIDS-Related Diffuse Large Cell Lymphoma

    HIV Infection

    Recurrent Adult Diffuse Large Cell Lymphoma

    Recurrent Adult Diffuse Mixed Cell Lymphoma

    Recurrent Adult Grade III Lymphomatoid Granulomatosis

    Recurrent Adult Immunoblastic 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 Lymphoma

    Stage I Adult Lymphoblastic Lymphoma

    Stage I Grade 3 Follicular Lymphoma

    Stage I Mantle Cell Lymphoma

    Stage II Adult Contiguous Immunoblastic Lymphoma

    Stage II Adult Non-Contiguous Immunoblastic Lymphoma

    Stage II Contiguous Adult Diffuse Large Cell Lymphoma

    Stage II Contiguous Adult Diffuse Mixed Cell Lymphoma

    Stage II Contiguous Adult Lymphoblastic Lymphoma

    Stage II Contiguous Mantle Cell Lymphoma

    Stage II Grade 3 Contiguous Follicular Lymphoma

    Stage II Grade 3 Non-Contiguous Follicular Lymphoma

    Stage II Non-Contiguous Adult Diffuse Large Cell Lymphoma

    Stage II Non-Contiguous Adult Diffuse Mixed Cell Lymphoma

    Stage II Non-Contiguous Adult Lymphoblastic Lymphoma

    Stage II Non-Contiguous Mantle Cell Lymphoma

    Stage III Adult Diffuse Large Cell Lymphoma

    Stage III Adult Diffuse Mixed Cell Lymphoma

    Stage III Adult Immunoblastic 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 Lymphoma

    Stage IV Adult Lymphoblastic Lymphoma

    Stage IV Grade 3 Follicular Lymphoma

    Stage IV Mantle Cell Lymphoma

    Trial Interventions

    Drug Synonyms Arms
    Cyclophosphamide (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, CYCLOPHOSPHAMIDE, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719 Arm A (VR-DA-EPOCH), ARM B (DA-R-EPOCH)
    Doxorubicin Hydrochloride 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, DOXORUBICIN HYDROCHLORIDE, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, Rubex Arm A (VR-DA-EPOCH), ARM B (DA-R-EPOCH)
    Etoposide Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, ETOPOSIDE, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213 Arm A (VR-DA-EPOCH), ARM B (DA-R-EPOCH)
    Prednisone .delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, PREDNISONE, Prednisonum, Prednitone, Promifen, Servisone, SK-Prednisone Arm A (VR-DA-EPOCH), ARM B (DA-R-EPOCH)
    Vincristine Sulfate Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, VINCRISTINE SULFATE, Vincristine, sulfate Arm A (VR-DA-EPOCH), ARM B (DA-R-EPOCH)
    Vorinostat L-001079038, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, VORINOSTAT, Zolinza Arm A (VR-DA-EPOCH)

    Trial 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.

    Detailed Description

    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.

    Trial Arms

    Name Type Description Interventions
    Arm A (VR-DA-EPOCH) Experimental 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. Cyclophosphamide, Doxorubicin Hydrochloride, Etoposide, Prednisone, Vincristine Sulfate, Vorinostat
    ARM B (DA-R-EPOCH) Experimental 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. Cyclophosphamide, Doxorubicin Hydrochloride, Etoposide, Prednisone, Vincristine Sulfate

    Eligibility 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 nave 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Complete response rate assessed by Response Evaluation Criteria in Solid Tumors (Phase II)

    Incidence of adverse events (AEs) for each treatment arm assessed by CTCAE v4.0 (Phase II)

    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)

    Secondary Outcome Measures

    Change in CD8 cell counts (Phase I)

    Changes in CD4 cell counts (Phase I)

    Changes in EBV viral load

    Changes in HHV-8 viral load

    Changes in HIV viral load

    Event-free survival (EFS) (Phase II)

    Overall survival (OS) (Phase II)

    Percentage of plasma associated HIV-1 RNA (Phase I)

    Pharmacokinetic profile and the parameters of clearance and the AUC (area under the curve) (Phase I)

    Tumor response rate (Phase I)

    Trial Keywords