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SWOG-S0806: A Phase I/II Trial of Vorinostat (SAHA) (NSC-701852) in Combination with Rituximab-CHOP in Patients with Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL)

Description

PRIMARY OBJECTIVES: I. To find a safe dose of vorinostat to be used in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) (vorinostat-R-CHOP). (Phase I) II. To estimate the 2-year progression-free survival (PFS) rate in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with vorinostat and R-CHOP therapy (vorinostat-R-CHOP). (Phase II) III. To estimate the response rate (complete and partial) and 2-year overall survival rate. (Phase II) IV. To evaluate the toxicity of vorinostat-R-CHOP in patients with newly diagnosed DLBCL. (Phase II) V. To assess whether pre-treatment acetylation status of histones, expression of major histocompatibility complex (MHC) class II genes, and/or percentage of cluster of differentiation (CD)8+ tumor infiltrating lymphocytes correlate with progression-free survival. (Phase II) VI. To explore whether treatment with vorinostat-R-CHOP increases histone acetylation, alters expression of MHC class II proteins, or alters percentage of T-cell subsets (CD8+, CD4+, forkhead box P3 [FOXP3]+) or infiltrating macrophages. (Phase II) VII. To explore whether histone acetylation status of tumor tissues correlates with MHC class II expression of peripheral blood B cells and lymphocyte subsets. (Phase II) VIII. To explore whether the change in systemic levels of immune cytokines with vorinostat-R-CHOP correlates with lymphoma symptoms, response, progression-free or overall survival. (Phase II) OUTLINE: This is a phase I, dose escalation study of vorinostat followed by a phase II study. Patients receive vorinostat orally (PO) once daily on days 1-5 or 1-9 (according to dose level), rituximab intravenously (IV), cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3. Patients also receive prednisone PO once daily on days 3-7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months for 2 years, and then annually for 3 years.

Phase

Phase 1/2 - for trials that are a combination of phases 1 and 2.

Inclusion and Exclusion Criteria

  • Inclusion Criteria:
  • Patients must have biopsy proven, newly diagnosed DLBCL with stage II bulky, stage III or stage IV disease, with an International Prognostic Index (IPI) or revised (R)-IPI score greater than 0; a report providing confirmation of CD20 expression must be submitted
  • Adequate sections from the original diagnostic specimen must be available for submission for review by the Southwest Oncology Group (SWOG) Lymphoma Pathology Laboratory; an adequate biopsy requires sufficient tissue to establish the architecture and World Health Organization (WHO) histologic subtype with certainty; fine needle aspiration or cytology is not adequate
  • Patients must be offered the opportunity to consent to the correlative science studies; patients are encouraged to submit specimens for correlative studies; however, specimen submission is not a requirement for participation in the study
  • Patients must have measurable disease; measurable disease must be determined by computed tomography (CT) scan of chest, abdomen and pelvis performed within 28 days prior to registration; positron emission tomography (PET)/CT may be substituted for CT scan only if CT scan is of diagnostic quality and is contrast enhanced
  • Patients must have a unilateral bone marrow aspirate and biopsy for staging performed within 42 days prior to registration
  • Patients must not have clinical evidence of central nervous system involvement by lymphoma; any laboratory or radiographic tests performed within 42 days prior to registration to assess central nervous system (CNS) involvement must be negative
  • Patients must not have received prior chemotherapy, radiation, or antibody therapy for lymphoma; steroid pre-medication for IV contrast allergy is allowed
  • Patients must have Zubrod performance status of 0-2
  • Patients must have serum lactate dehydrogenase (LDH) measured within 28 days prior to registration
  • Absolute neutrophil count (ANC) > 1,000/mcL within 28 days prior to registration, unless due to bone marrow infiltration by lymphoma
  • Platelets > 100,000/mcL within 28 days prior to registration, unless due to bone marrow infiltration by lymphoma
  • Cardiac ejection fraction ≥ institutional lower limit of normal (ILLN) by multigated acquisition (MUGA) scan or 2-dimensional (2-D) echocardiogram (ECHO) with no significant abnormalities within 42 days prior to registration
  • Patients must not have received valproic acid (a histone deacetylase [HDAC] inhibitor) within 28 days prior to registration
  • Patients must have no known hypersensitivity to the components of treatment
  • Patients must be willing to discontinue taking any medications that are generally accepted to have a risk of causing Torsades de Pointes while on study
  • Patients known to be human immunodeficiency virus (HIV) positive are not eligible; existing therapeutic options are effective and study design does not support assessing the efficacy of treatment on those with HIV
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
  • Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  • All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • At the time of patient registration, the treating institution's name and identification (ID) number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base

Sites

  • California

    • Kaiser Permanente, Fresno, California, 93720
    • Kaiser Permanente-Modesto, Modesto, California, 95356
    • Kaiser Permanente-Santa Teresa-San Jose, San Jose, California, 95119
    • Kaiser Permanente, Fremont, Fremont, California, 94538
    • Kaiser Permanente-Stockton, Stockton, California, 95210
    • Kaiser Permanente-Redwood City, Redwood City, California, 94063
    • Kaiser Permanente-Deer Valley Medical Center, Antioch, California, 94531
    • Kaiser Permanente San Leandro, San Leandro, California, 94577
    • Kaiser Permanente-Walnut Creek, Walnut Creek, California, 94596
    • Kaiser Permanente-South San Francisco, South San Francisco, California, 94080
    • Kaiser Permanente-Oakland, Oakland, California, 94611
    • Kaiser Permanente-San Francisco, San Francisco, California, 94115
    • Kaiser Permanente-South Sacramento, Sacramento, California, 95823
    • Kaiser Permanente-Richmond, Richmond, California, 94801
    • Kaiser Permanente - Sacramento, Sacramento, California, 95825
    • Kaiser Permanente-Vallejo, Vallejo, California, 94589
    • Kaiser Permanente-Roseville, Roseville, California, 95661
    • Kaiser Permanente-San Rafael, San Rafael, California, 94903
    • Kaiser Permanente Medical Center-Vacaville, Vacaville, California, 95688
    • Kaiser Permanente-Santa Rosa, Santa Rosa, California, 95403
  • Oregon

    • Saint Charles Medical Center-Bend, Bend, Oregon, 97701
  • Montana

    • Saint James Community Hospital and Cancer Treatment Center, Butte, Montana, 59701
    • Bozeman Deaconess Hospital, Bozeman, Montana, 59715
    • Saint Patrick Hospital - Community Hospital, Missoula, Montana, 59802
    • Montana Cancer Specialists, Missoula, Montana, 59802
    • Saint Peter's Community Hospital, Helena, Montana, 59601
    • Hematology-Oncology Centers of the Northern Rockies PC, Billings, Montana, 59102
    • Frontier Cancer Center and Blood Institute-Billings, Billings, Montana, 59102
    • Montana Cancer Consortium CCOP, Billings, Montana, 59101
    • Saint Vincent Healthcare, Billings, Montana, 59101
    • Billings Clinic Cancer Center, Billings, Montana, 59107
    • Great Falls Clinic, Great Falls, Montana, 59405
    • Glacier Oncology PLLC, Kalispell, Montana, 59901
  • Wyoming

    • Welch Cancer Center, Sheridan, Wyoming, 82801
  • Washington

    • The Polyclinic, Seattle, Washington, 98122
    • Group Health, Seattle, Washington, 98109
  • Missouri

    • Saint Joseph Health Center, Kansas City, Missouri, 64114
    • Ozark Health Ventures LLC-Cancer Research for The Ozarks Springfield, Springfield, Missouri, 65804
    • Saint John's Clinic-Rolla-Cancer and Hematology, Rolla, Missouri, 65401
  • Arkansas

    • Saint Edward Mercy Medical Center, Ft. Smith, Arkansas, 72903
    • Fowler Family Center for Cancer Care, Jonesboro, Arkansas, 72401
    • NEA Baptist Memorial Hospital, Jonesboro, Arkansas, 72401
  • Louisiana

    • Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, 71130
    • Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, 71103
    • Overton Brooks Veteran's Administration Medical Center, Shreveport, Louisiana, 71101
    • DeSoto Regional Health System, Mansfield, Louisiana, 71052
    • Christus Saint Frances Cabrini Hospital, Alexandria, Louisiana, 71301
    • Louisiana State University Sciences Center- Monroe, Monroe, Louisiana, 71202
  • Illinois

    • Cadence Cancer Center at Delnor, Geneva, Illinois, 60134
    • Cadence Cancer Center in Warrenville, Warrenville, Illinois, 60555
  • Alabama

    • Providence Hospital, Mobile, Alabama, 36608
  • Michigan

    • Mercy Health Mercy Campus, Muskegon, Michigan, 49444
    • Mercy Health Saint Mary's, Grand Rapids, Michigan, 49503
    • Grand Rapids Clinical Oncology Program, Grand Rapids, Michigan, 49503
    • Spectrum Health at Butterworth Campus, Grand Rapids, Michigan, 49503
    • Spectrum Health Big Rapids Hospital, Big Rapids, Michigan, 49307
    • Bronson Battle Creek, Battle Creek, Michigan, 49017
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