Dose-Adjusted EPOCH Chemotherapy and Rituximab (CD20+) in Previously Untreated Aggressive Non-Hodgkin's Lymphoma

June 12, 2025 updated by: Mark Roschewski, M.D., National Cancer Institute (NCI)

Dose-Adjusted EPOCH Chemotherapy and Rituximab (CD20+) in Adults and Children With Previously Untreated Patients With Aggressive Non-Hodgkin's Lymphoma

5-Drug Combination Chemotherapy with Hematologic Toxicity Attenuation. Etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin)(EPOCH): Etoposide, VP-16, NSC-141540; Prednisone, PRED, NSC-10023; Vincristine, VCR, NSC-67574; Cyclophosphamide, CTX, NSC-26271; Doxorubicin, DOX, NSC-123127; with Granulocyte Colony-Stimulating Factor (Amgen), Granulocyte colony-stimulating factor (G-CSF), NSC-614629.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Background:

The treatment of the intermediate and aggressive non-Hodgkin's lymphomas in adults and children commonly induces complete responses in a sizable fraction of the treated population, and about 2/3 of the complete responders appear to have prolonged disease-free survival.

The present study assesses the activity and tolerability in previously untreated patients of a regimen of etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin)(EPOCH) infusional chemotherapy given intensively with granulocyte colony-stimulating factor (G-CSF) support.

Objectives:

Primary:

Assess complete response (CR) and progression-free survival (PFS) of dose-adjusted EPOCH-Rituximab (DA-EPOCH-R) with G-CSF in aggressive B-cell lymphomas.

Eligibility:

Non-Hodgkin's lymphomas in the following categories: mediastinal gray zone lymphoma (MGZL) and primary mediastinal B cell lymphoma (PMBL).

Patients greater than or equal to 12 years old.

Any Stage for PMBL and MGZL.

No prior systemic chemotherapy.

Human immunodeficiency virus (HIV) negative.

Design:

This study will estimate the complete response rate of a group of previously untreated patients and the extent to which EPOCH infusional drug delivery accompanied by a hematopoietic growth factor can increase the dose intensity of treatment.

Patients receive prednisone orally for 5 days, a 96-hour infusion of vincristine, doxorubicin, and etoposide, and a bolus of cyclophosphamide on day 5.

Cycles are repeated every 21 days for a total of 6-8 cycles.

Patients with cluster of differentiation 20 (CD20) expressing tumors (i.e., mature B-cell lymphomas) will also receive rituximab, the humanized monoclonal antibody against the CD20 receptor on day 1 of each cycle.

A total of 348 patients will be enrolled on this protocol.

Study Type

Interventional

Enrollment (Actual)

348

Phase

  • Phase 2

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
    • Florida
      • Fort Lauderdale, Florida, United States, 33308
        • Holy Cross Hospital, Fort Lauderdale
    • Maryland
      • Baltimore, Maryland, United States, 21201-1595
        • University of Maryland, Baltimore
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Brigham and Women's Hospital
    • New York
      • New York, New York, United States, 10025
        • St. Luke's Roosevelt Hospital

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

12 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

  • INCLUSION CRITERIA:

Non-Hodgkin's lymphomas in the following categories: mediastinal gray zone lymphoma and primary mediastinal B cell lymphoma.

Diagnosis confirmed by staff of the Hematopathology Section, Laboratory of Pathology, National Cancer Institute (NCI). Tissue blocks from patients treated in extramural sites must be forwarded to the NCI for analysis of B-cell leukemia/lymphoma 2 (bcl-2) by immunohistochemistry (IHC) and other markers within 1 month of study entry.

Patients greater than or equal to 12 years old.

Stage and Prognosis of Patients: Any stage for mediastinal gray zone lymphoma (MGZL) and primary mediastinal B-cell lymphoma (PMBL).

No prior systemic chemotherapy. Patients may be entered if they have had prior limited-field radiotherapy, a short course of glucocorticoids and/or cyclophosphamide for an urgent problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome).

Human immunodeficiency virus (HIV) negative.

Not pregnant or nursing.

Adequate major organ function [in adults: serum creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than 60 ml/min; and in children serum creatinine (CR) less than or equal to age-adjusted normal (age 12 to 15 maximum serum creatinine 1.2 mg/dl and age greater than 15 maximum serum creatinine 1.5 mg/dl); bilirubin less than 1.5 mg/dl; absolute neutrophil count (ANC) greater than 1,000 and platelets greater than 100,000) unless impairment is due to organ involvement by lymphoma or immune-mediated mechanism caused by lymphoma.

No active symptomatic ischemic heart disease, myocardial infarction or congestive heart failure within the past year. If multi-gated acquisition (MUGA) is obtained, the left ventricular ejection fraction (LVEF) should exceed 40%.

No other serious concomitant medical illnesses or uncontrolled active infection that would jeopardize the patient's ability to receive the regimen with reasonable safety.

No history of unrelated (non-lymphomatous) neoplasms within past 5 years other than non-melanoma skin cancer or in-situ cancer.

Ability to give informed consent.

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: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: With EPOCH-R (Etoposide, Doxorubicin, Prednisone, Cyclophosphamide and Rituximab)
Subgroup 1 (SG1) - All participants who received combination Rituximab (EPOCH-R). Rituximab 375 mg/m^2 intravenous (IV) on day 1, every 21 days, prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days, and cyclophosphamide 750mg/m^2 on day 5 every 21 days. Doxorubicin 10mg/m^2/day, vincristine 0.4mg/m^2/day, and etoposide 50mg/m^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days. Dose levels were adjusted on doxorubicin, etoposide, and cyclophosphamide each cycle based on neutrophil nadir.
Drug: Etoposide

Etoposide 50mg/m^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • VP-16
Biological: Rituximab

Rituximab given on Day 1 of combination chemotherapy (EPOCH-R) every 3 weeks for 6 cycles.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Rituxan
Drug: Prednisone

Prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Deltasone
  • Prednisone Intensol
  • Rayos
Drug: Cyclophosphamide

Cyclophosphamide 750mg/m^2 on day 5 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Cytoxan
Drug: Vincristine

Vincristine 0.4mg/m^2/day.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Marqibo
  • Vincasar PFS
Drug: Doxorubicin

Doxorubicin 10mg/m^2/day.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Doxil
  • Lipodox 50
  • Lipodox
Diagnostic test: MRI
Baseline and/or on completion of therapy.
Other Names:
  • Magnetic resonance imaging
Diagnostic test: CT
Baseline and/or on completion of therapy.
Other Names:
  • Computed tomography
Procedure: Biopsy
Baseline and/or on completion of therapy.
Diagnostic test: PET scan
As clinically indicated.
Other Names:
  • positron emission tomography scan
Procedure: Laparotomy
As clinically indicated.
Other: Ondansetron
Nausea and/or vomiting.
Other Names:
  • Zofran
  • Zofran ODT
  • Zuplenz
Other: Prochlorperazine
Nausea and/or vomiting.
Other Names:
  • Compro
Other: Omeprazole
Gastroesophageal reflux disease (GERD).
Other Names:
  • Zegerid
  • Prilosec OTC
  • OmePPi
Other: Docusate Sodium + Sennosides
Constipation.
Other Names:
  • Senna-Plus
  • Colace 2-in-1
  • Dok Plus
Other: Lactulose
Constipation
Other Names:
  • Enulose
  • Generlac
  • Kristalose
Experimental: EPOCH Alone (Etoposide, Doxorubicin, Prednisone, and Cyclophosphamide)
Subgroup 2 (SG2) - EPOCH alone: All participants who received Prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days, and cyclophosphamide 750mg/m^2 on day 5 every 21 days. Doxorubicin 10mg/m^2/day, vincristine 0.4mg/m^2/day, and etoposide 50mg/m^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days. Dose levels were adjusted on doxorubicin, etoposide, and cyclophosphamide each cycle based on neutrophil nadir.
Drug: Etoposide

Etoposide 50mg/m^2/day were delivered as continuous intravenous (CIV) infusions over 96 hours starting on day 1 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • VP-16
Drug: Prednisone

Prednisone 100mg by mouth (PO) twice a day (bid) on days 1 through 5 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Deltasone
  • Prednisone Intensol
  • Rayos
Drug: Cyclophosphamide

Cyclophosphamide 750mg/m^2 on day 5 every 21 days.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Cytoxan
Drug: Vincristine

Vincristine 0.4mg/m^2/day.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Marqibo
  • Vincasar PFS
Drug: Doxorubicin

Doxorubicin 10mg/m^2/day.

Combination chemotherapy given with Rituximab, Etoposide, VP-16; Prednisone, Cyclophosphamide, Vincristine, and Doxorubicin (EPOCH-R) intravenous (IV) every 3 weeks for 6 cycles.

Other Names:
  • Doxil
  • Lipodox 50
  • Lipodox
Diagnostic test: MRI
Baseline and/or on completion of therapy.
Other Names:
  • Magnetic resonance imaging
Diagnostic test: CT
Baseline and/or on completion of therapy.
Other Names:
  • Computed tomography
Procedure: Biopsy
Baseline and/or on completion of therapy.
Diagnostic test: PET scan
As clinically indicated.
Other Names:
  • positron emission tomography scan
Procedure: Laparotomy
As clinically indicated.
Other: Ondansetron
Nausea and/or vomiting.
Other Names:
  • Zofran
  • Zofran ODT
  • Zuplenz
Other: Prochlorperazine
Nausea and/or vomiting.
Other Names:
  • Compro
Other: Omeprazole
Gastroesophageal reflux disease (GERD).
Other Names:
  • Zegerid
  • Prilosec OTC
  • OmePPi
Other: Docusate Sodium + Sennosides
Constipation.
Other Names:
  • Senna-Plus
  • Colace 2-in-1
  • Dok Plus
Other: Lactulose
Constipation
Other Names:
  • Enulose
  • Generlac
  • Kristalose

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Response (Complete Response + Partial Response)
Time Frame: Time frame was from beginning of therapy until the end of therapy, an average of 6 months
Overall response defined as a Complete Response + Partial Response was measured by the Response Criteria. Complete Response is disappearance of all signs and symptoms of lymphoma for a period of at least one month. Partial Response is 50% or greater decrease in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for a period of at least one month.
Time frame was from beginning of therapy until the end of therapy, an average of 6 months
Progression Free Survival (PFS)
Time Frame: Progression free survival was calculated from study entry until progression or death from any cause. Median follow up of evaluable participants was 5 years (range 2-7 years)
The Dixon-Simon method will be used to determine whether large B-cell lymphomas expressing BCL-2 (+) participants may experience an improved progression free survival with Etoposide, VP-16, and Doxorubicin with Prednisone, Cyclophosphamide, and Rituximab (EPOCH-R) compared to EPOCH alone, and to obtain a concurrent, precisely determined measure of progression free survival. PFS is the time from start of treatment to documented evidence of disease progression. Progression is an increase of 25% or more in the sum of the products of the longest perpendicular diameters of all measured lesions, or the appearance of any new lesions measured by the Response Criteria.
Progression free survival was calculated from study entry until progression or death from any cause. Median follow up of evaluable participants was 5 years (range 2-7 years)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of Participants With Serious and/or Non-serious Adverse Events Leading to Discontinuation of Therapy
Time Frame: Initiation of study drug until 30 days after treatment, an average of 6 months
Here is the proportion of participants with adverse events leading to discontinuation of therapy. A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the participant and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Initiation of study drug until 30 days after treatment, an average of 6 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Time Frame: Time frame is from study entry until 30 days after completing study therapy, approximately 5 years.
Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame is from study entry until 30 days after completing study therapy, approximately 5 years.

Collaborators and Investigators

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

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Mark J Roschewski, M.D., National Cancer Institute (NCI)

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

Helpful Links

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 8, 1993

Primary Completion (Actual)

May 24, 2024

Study Completion (Actual)

May 24, 2024

Study Registration Dates

First Submitted

November 3, 1999

First Submitted That Met QC Criteria

November 3, 1999

First Posted (Estimated)

November 4, 1999

Study Record Updates

Last Update Posted (Actual)

June 22, 2025

Last Update Submitted That Met QC Criteria

June 12, 2025

Last Verified

June 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 930133
  • 93-C-0133

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

IPD Sharing Time Frame

Clinical data available during the study and indefinitely.

IPD Sharing Access Criteria

Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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