Rituximab and Combination Chemotherapy in Treating Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma

November 15, 2021 updated by: Alliance for Clinical Trials in Oncology

Phase III Randomized Study of R-CHOP V. Dose-Adjusted EPOCH-R With Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas

This randomized phase III trial studies rituximab when given together with two different combination chemotherapy regimens to compare how well they work in treating patients with diffuse large B-cell non-Hodgkin's lymphoma. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. 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. Giving rituximab together with combination chemotherapy may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective when given with rituximab in treating diffuse large B-cell non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying rituximab when given together with two different combination chemotherapy regimens to compare how well they work in treating patients with diffuse large B-cell lymphoma.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To compare the event-free survival of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone (R-CHOP) versus dose-adjusted (DA-) etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, and rituximab (EPOCH-R) chemotherapy in untreated cluster of differentiation (CD)20 positive (+) diffuse large B-cell lymphomas.

II. To develop a molecular predictor of outcome of R-CHOP and DA-EPOCH-R chemotherapy using molecular profiling.

SECONDARY OBJECTIVES:

I. To compare the response rates, overall survival and toxicity of R-CHOP versus DA-EPOCH-R.

II. To define the pharmacogenomics of untreated diffuse large B-cell lymphoma (DLBCL) and correlate clinical parameters (toxicity, response, survival outcomes and laboratory results) with molecular profiling.

III. To assess the use of molecular profiling for pathological diagnosis. IV. To identify new therapeutic targets using molecular profiling. V. To perform a comprehensive analysis of somatic alterations to the tumor genome and to understand which genomic alterations are somatically acquired by the tumor and which are encoded in the germ line of the patient.

VI. To identify biomarkers of response to chemotherapy by fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging that are predictive of histopathologic remissions and survival in patients with stage I (mediastinal), II, III, or IV untreated DLBCL.

VII. To evaluate the use of semiquantitative measurements of FDG uptake in defining FDG-PET/CT based biomarkers of response to chemotherapy in patients with DLBCL.

VIII. To determine whether FDG-PET/CT measurements of tumor response after the second cycle of chemotherapy can predict clinical response.

IX. To establish a standardized protocol for FDG-PET/CT image acquisition. X. To determine additional FDG-PET/CT parameters (e.g., the ratio of tumor maximum standard uptake value [SUVmax] to liver SUVmean; SUVs corrected for body surface area and lean body mass; nuclear medicine physician's assessment) and evaluate their utility in refining FDG-PET/CT based biomarkers of response to therapy.

XI. To evaluate inter-institutional reproducibility of FDG-PET/CT measurements for this indication.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Study Type

Interventional

Enrollment (Actual)

524

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • La Jolla, California, United States, 92093-0658
        • Rebecca and John Moores UCSD Cancer Center
      • Mountain View, California, United States, 94040
        • Camino Medical Group - Treatment Center
      • Palo Alto, California, United States, 94301
        • Palo Alto Medical Foundation
      • Saint Helena, California, United States, 94574
        • Saint Helena Hospital
      • San Diego, California, United States, 92134
        • Naval Medical Center - San Diego
    • Connecticut
      • Norwich, Connecticut, United States, 06360
        • Eastern Connecticut Hematology and Oncology Associates
    • Delaware
      • Newark, Delaware, United States, 19713
        • CCOP - Christiana Care Health Services
    • Illinois
      • Chicago, Illinois, United States, 60611-3013
        • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
      • Chicago, Illinois, United States, 60612-7243
        • University of Illinois Cancer Center
      • Chicago, Illinois, United States, 60657
        • Creticos Cancer Center at Advocate Illinois Masonic Medical Center
      • Maywood, Illinois, United States, 60153
        • Cardinal Bernardin Cancer Center at Loyola University Medical Center
    • Maryland
      • Baltimore, Maryland, United States, 21215
        • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
      • Bethesda, Maryland, United States, 20889-5600
        • National Naval Medical Center
      • Bethesda, Maryland, United States, 20892-1182
        • NIH - Warren Grant Magnuson Clinical Center
    • Michigan
      • Southfield, Michigan, United States, 48075
        • Providence Cancer Institute at Providence Hospital - Southfield Campus
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
      • Saint Louis, Missouri, United States, 63136
        • Christian Hospital Northeast-Northwest
    • New Hampshire
      • Concord, New Hampshire, United States, 03301
        • New Hampshire Oncology - Hematology, PA at Payson Center for Cancer Care
      • Hooksett, New Hampshire, United States, 03106
        • New Hampshire Oncology - Hematology, PA - Hooksett
    • New York
      • Glens Falls, New York, United States, 12801
        • Charles R. Wood Cancer Center at Glens Falls Hospital
      • New York, New York, United States, 10021
        • New York Weill Cornell Cancer Center at Cornell University
      • Rochester, New York, United States, 14642
        • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • North Carolina
      • Charlotte, North Carolina, United States, 28233-3549
        • Presbyterian Cancer Center at Presbyterian Hospital
      • Kinston, North Carolina, United States, 28501
        • Kinston Medical Specialists
      • Statesville, North Carolina, United States, 28677
        • Iredell Memorial Hospital
      • Winston-Salem, North Carolina, United States, 27157-1096
        • Wake Forest University Comprehensive Cancer Center
    • North Dakota
      • Grand Forks, North Dakota, United States, 58201
        • Altru Cancer Center at Altru Hospital
    • Ohio
      • Canton, Ohio, United States, 44708
        • Mercy Cancer Center at Mercy Medical Center
      • Columbus, Ohio, United States, 43210-1240
        • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
    • Pennsylvania
      • Danville, Pennsylvania, United States, 17822-0001
        • Geisinger Cancer Institute at Geisinger Health
      • Easton, Pennsylvania, United States, 18042
        • Easton Regional Cancer Center at Easton Hospital
      • Hazleton, Pennsylvania, United States, 18201
        • Geisinger Hazleton Cancer Center
      • Hershey, Pennsylvania, United States, 17033-0850
        • Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center
      • Pittsburgh, Pennsylvania, United States, 15224-1791
        • Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
      • Wilkes-Barre, Pennsylvania, United States, 18711
        • Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center
    • Vermont
      • Berlin, Vermont, United States, 05602
        • Mountainview Medical
    • Virginia
      • Richmond, Virginia, United States, 23298-0037
        • Virginia Commonwealth University Massey Cancer Center
    • Washington
      • Tacoma, Washington, United States, 98431
        • Madigan Army Medical Center - Tacoma
    • West Virginia
      • Morgantown, West Virginia, United States, 26506
        • Mary Babb Randolph Cancer Center at West Virginia University Hospitals
    • Wisconsin
      • Marshfield, Wisconsin, United States, 54449
        • Saint Joseph's Hospital
      • Marshfield, Wisconsin, United States, 54449
        • Marshfield Clinic - Marshfield Center
      • Minocqua, Wisconsin, United States, 54548
        • Marshfield Clinic - Lakeland Center
      • Rhinelander, Wisconsin, United States, 54501
        • Ministry Medical Group at Saint Mary's Hospital
      • Rice Lake, Wisconsin, United States, 54868
        • Marshfield Clinic - Indianhead Center
      • Stevens Point, Wisconsin, United States, 54481
        • Marshfield Clinic at Saint Michael's Hospital
      • Stevens Point, Wisconsin, United States, 54481
        • Saint Michael's Hospital Cancer Center
      • Weston, Wisconsin, United States, 54476
        • Marshfield Clinic - Weston Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  1. Histologically documented de novo CD20+ DLBCL with stage II, III or IV disease.

    • Stage I primary mediastinal (thymic) DLBCL is also eligible.
    • Patients with an underlying low-grade lymphoma, such as a transformed lymphoma or low-grade lymphoma in the bone marrow, are not eligible.
    • Diagnosis should be based on an adequate tissue sample, including open biopsy or core needle biopsy.
    • Needle aspiration for primary diagnosis is unacceptable.

    • Patients must have one of the following WHO classification subtypes:

      • Diffuse large B-cell lymphoma (includes morphological variants: centroblastic, immunoblastic, T-cell/histiocyte rich, and anaplastic)
      • Mediastinal (thymic) large B-cell lymphoma
      • Intravascular large B-cell lymphoma

    • Note: Failure to submit a pathology block within 60 days of patient registration will be considered a major protocol violation.

      • Fresh (frozen) tumor biopsy must be available or attempted. A frozen tumor biopsy equivalent to a minimum of four at least 16 gauge needle cores is an important component of this study.
      • Patients without adequate frozen material should have a biopsy performed to obtain material.
      • If a biopsy is performed and does not yield adequate material, the patient is still eligible for the study. If a biopsy cannot be done safely, the patient may still be eligible for the study if permission is granted.
    • Note: This study does not allow concurrent radiation unless a patient has a documented CNS treatment failure with no systemic failure.
  2. No prior cytotoxic chemotherapy or rituximab. Patients may be entered if they have received prior limited field radiation therapy or a short course of glucocorticoids (< 10 days) for an urgent local disease complication at diagnosis (e.g., cord compression, SVC syndrome). Patients who have received chemotherapy for prior malignancies are not eligible.
  3. Age ≥ 18 years
  4. ECOG Performance Status 0-2
  5. No active ischemic heart disease or congestive heart failure. If there is suspicion of cardiac disease, a cardiac ejection fraction must show LVEF > 45%, but the study is not required
  6. No known lymphomatous involvement of the CNS. A lumbar puncture prior to study is not required in the absence of neurological symptoms
  7. No known HIV disease. Patients with a history of intravenous drug abuse or any other behavior associated with an increased risk of HIV infection should be tested for exposure to the HIV virus. Patients who test positive or who are known to be infected are not eligible.
  8. Non pregnant and non-nursing. Treatment would expose an unborn child to significant risks. Women and men of reproductive potential should agree to use an effective form of contraception.
  9. Patients with active medical processes (e.g., uncontrolled bacterial or viral infection, bleeding) not related to their lymphoma should be excluded.

  10. Required Initial Laboratory Values (unless non-Hodgkin lymphoma):

    • ANC ≥ 1000/μL
    • Platelets ≥ 100,000/μL
    • Creatinine≤ 1.5 mg/dL or creatinine clearance ≥ 50 cc/min
    • Total Bilirubin ≤ 2 mg/dL (unless a history of Gilbert's Disease)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm A - R-CHOP

Patients receive the following treatment:

  • Rituximab 375 mg/m^2 IV infusion on Day 1 prior to CHOP chemotherapy
  • Cyclophosphamide 750 mg/m^2 IV on Day 1
  • Doxorubicin 50 mg/m^2 IV on Day 1
  • Vincristine 1.4 mg/m^2 IV (2 mg cap) on Day 1
  • Prednisone 40 mg/m^2/day PO on Days 1-5
  • filgrastim or pegfilgrastim as defined in the protocol

Required ancillary medications is administered during all cycles as defined in the protocol.

Cycles will be repeated every 21 days for 6 treatment cycles. Restaging will occur after Cycles 4 and 6.
Biological: rituximab
IV
Drug: cyclophosphamide
IV
Drug: doxorubicin
IV or CIVI
Drug: vincristine
IV or CIVI
Drug: prednisone
oral
Drug: filgrastim
IV
Drug: pegfilgrastim
IV
Experimental: Arm B - DA-EPOCH-R

Patients receive the following treatment:

Cycle 1 Doses:

  • Rituximab 375 mg/m^2 IV infusion on Day 1 prior to EPOCH chemotherapy
  • Doxorubicin 10 mg/m^2/day CIVI on Days 1-4
  • Etoposide 50 mg/m^2/day CIVI on Days 1-4
  • Vincristine 0.4 mg/m^2/day (no cap) CIVI on Days 1-4 (total 1.6 mg/m2 over 96 hours)
  • Cyclophosphamide 750 mg/m^2 IV on Day 5 (following completion of 96 hour infusions)
  • Prednisone 60 mg/m^2 PO BID on Days 1-5
  • Administer filgrastim 480 mcg subcutaneous daily from Day 6 until ANC > 5000 after the nadir (nadir usually between Days 10-12) or for 10 days (Days 6-15) if the ANC is not being monitored, during every cycle.

Doses for subsequent cycles will be determined by the absolute neutrophil (ANC) or platelet nadir from the previous cycle.

Required ancillary medications are administered during all cycles as defined in the protocol.

Cycles will be repeated every 21 days for a maximum of 6 cycles. Restaging will occur after Cycles 4 and 6.
Biological: rituximab
IV
Drug: cyclophosphamide
IV
Drug: doxorubicin
IV or CIVI
Drug: vincristine
IV or CIVI
Drug: prednisone
oral
Drug: filgrastim
IV
Drug: etoposide
CIVI

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-Free Survival Rate at 2 and 5 Years
Time Frame: Up to 5 years post-registration

Progression-free survival (PFS) is defined as the time from randomization to progression, relapse, or death from any cause, whichever occurred first. Progression (PD) or Relapse>

  • ≥ 50% increase from nadir in the SPD of any previously identified abnormal node for PRs or nonresponders.>
  • Appearance of any new lesion during or after completion of therapy.>
  • PET+ is not a criterion for progressive disease. Patients only with PET+ findings must have evidence of progression on CT or biopsy proven.>

The PFS rate (percentage of participants who are alive and progression-free) at 2 and 5 years Kaplan Meier estimates and 95% Confidence Intervals are reported below.
Up to 5 years post-registration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response Rate
Time Frame: Up to 5 years post-registration
The overall response rate is defined as the percentage of participants with a response (Complete Response or Partial Response)
Up to 5 years post-registration
Overall Survival Rate at 2 and 5 Years
Time Frame: Up to 5 years post-registration
Overall survival is defined as the time from randomization to death due to any cause. The overall survival (OS) rate (percentage of participants who are still alive) at 2 and 5 years Kaplan Meier estimates and 95% confidence intervals are reported below.
Up to 5 years post-registration

Other Outcome Measures

Outcome Measure
Time Frame
Whether the Gene Expression Signatures That Were Previously Associated With Survival Following CHOP Therapy Are Associated With Survival in Either of the Treatment Arms of the Prospective Trial
Time Frame: Up to 5 years post-registration
Up to 5 years post-registration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Alliance for Clinical Trials in Oncology

Collaborators

National Cancer Institute (NCI)

Investigators

  • Study Chair: Wyndham H. Wilson, MD, PhD, National Cancer Institute (NCI)
  • Study Chair: Andrew D. Zelenetz, MD, PhD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2005

Primary Completion (Actual)

October 1, 2017

Study Completion (Actual)

November 15, 2021

Study Registration Dates

First Submitted

July 8, 2005

First Submitted That Met QC Criteria

July 8, 2005

First Posted (Estimate)

July 11, 2005

Study Record Updates

Last Update Posted (Actual)

November 17, 2021

Last Update Submitted That Met QC Criteria

November 15, 2021

Last Verified

November 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CALGB-50303
  • U10CA180821 (U.S. NIH Grant/Contract)
  • U10CA031946 (U.S. NIH Grant/Contract)
  • CDR0000433265 (Other Identifier: NCI Physician Data Query)
  • NCI-2009-00480 (Registry Identifier: NCI Clinical Trial Reporting Program)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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