Vorinostat, Rituximab, and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II, Stage III, or Stage IV Diffuse Large B-Cell Lymphoma

Phase 1

Active, not recruiting

Conditions: Ann Arbor Stage III Non-Hodgkin Lymphoma
Ann Arbor Stage II Non-Hodgkin Lymphoma
Ann Arbor Stage IV Non-Hodgkin Lymphoma

Interventions: Drug: Cyclophosphamide
Drug: Doxorubicin Hydrochloride
Other: Laboratory Biomarker Analysis
Drug: Prednisone
Biological: Rituximab
Drug: Vincristine Sulfate
Drug: Vorinostat

Registration Number: NCT00972478

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase I/II trial is studying the side effects and best dose of vorinostat when given together with rituximab and combination chemotherapy and to see how well it works in treating patients with newly diagnosed stage II, stage III, or stage IV diffuse large B-cell lymphoma. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Monoclonal antibodies, such as rituximab, can block cancer cell growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cell-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with rituximab and combination chemotherapy may kill more cancer cells.

Detailed 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 83

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (combination chemotherapy)	Vincristine Sulfate	Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab 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.
Treatment (combination chemotherapy)	Cyclophosphamide	Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab 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.
Treatment (combination chemotherapy)	Doxorubicin Hydrochloride	Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab 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.
Treatment (combination chemotherapy)	Laboratory Biomarker Analysis	Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab 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.
Treatment (combination chemotherapy)	Prednisone	Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab 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.
Treatment (combination chemotherapy)	Rituximab	Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab 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.
Treatment (combination chemotherapy)	Vorinostat	Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab 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.

Primary Outcome Measures

Name	Time	Method
Safe Dose of Vorinostat to be Used in Combination With R-CHOP Assessed by CTCAE Version 4.0 (Phase I)	21 days	Safe dose of Vorinostat (in combination with R-CHOP) at which 3/10 or fewer patients have doselimiting toxicities (DLT). Toxicities graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0). DLT apply only during cycle 1 and should be drug-related (possible, probable, or definite).
Progression-free Survival (Phase II)	Up to 2 years	From date of registration to date of first documentation of progressive disease, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (Phase II)	Up to 2 years	From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
Toxicity of Vorinostat-R-CHOP in Patients With Newly Diagnosed DLBCL	Up to week 26	Incidence of toxicity as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
Response Rate (Complete Response [CR]+Partial Response [PR]) (Phase II)	Up to week 26	Objective disease status is evaluated according to the 2007 revised Cheson et al. criteria. Complete Response(CR) is a complete disappearance of all disease with the exception of nodes. No new lesions. previously enlarged organs must have regressed and not be palpable. Bone marrow (BM) must be negative if positive at baseline. Normalization of markers. Partial Response (PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes.

Trial Locations

Locations (190): Providence Hospital
🇺🇸
Mobile, Alabama, United States
University of Arizona Cancer Center-Orange Grove Campus
🇺🇸
Tucson, Arizona, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸
Tucson, Arizona, United States
Mercy Hospital Fort Smith
🇺🇸
Fort Smith, Arkansas, United States
NEA Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro
🇺🇸
Jonesboro, Arkansas, United States
NEA Baptist Memorial Hospital
🇺🇸
Jonesboro, Arkansas, United States
Kaiser Permanente-Deer Valley Medical Center
🇺🇸
Antioch, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Kaiser Permanente-Fremont
🇺🇸
Fremont, California, United States
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Providence Hospital
🇺🇸Mobile, Alabama, United States