Phase II Study of Dose-Adjusted EPOCH-Rituximab in Adults With Untreated Burkitt Lymphoma and c-MYC+ Diffuse Large B-Cell Lymphoma

Phase 2

Completed

Conditions: Burkitt Lymphoma
Diffuse Large B-cell Lymphoma, c-MYC Positive
Plasmablastic Lymphoma

Interventions: Drug: EPOCH-R
Drug: EPOCH-RR

Registration Number: NCT01092182

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

* Burkitt lymphoma/leukemia (BL) is highly treatable, but most of the standard therapies require multiple doses of intensive chemotherapy that may require long hospital stays and frequently have severe side effects. In addition, BL is a fairly common type of cancer in patients who also have human immunodeficiency virus (HIV), but treatment outcomes are poor because standard treatments do not work very well in HIV-positive patients and the more intense treatment regimens are highly toxic. New approaches are needed that expand the ways to treat BL with the same efficiency but with reduced side effects.

* Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) is a standard chemotherapy treatment that consists of the drugs etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. It may be able to treat BL with similar effectiveness but with fewer side effects. Researchers are interested in confirming the results of previous studies that investigated the effectiveness of DA-EPOCH-R in treating BL.

Objectives:

- To determine the safety and effectiveness of DA-EPOCH-R in treating Burkitt lymphoma.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with Burkitt lymphoma and have not had any prior chemotherapy treatments.

Design:

* Individuals will have a series of blood and other tests to determine their suitability for participating in the study. Eligible participants will be divided into high-risk and low-risk groups based on their disease prognosis and the possibility that the BL may or already has spread into the central nervous system.

* Participants will receive intravenous infusion of the six chemotherapy drugs in DA-EPOCH-R in 21-day treatment cycles. The exact doses will be adjusted depending on participants white blood cell counts and other tests.

* High-risk participants will receive six cycles of DA-EPOCH-R. To treat BL that may have entered the central nervous system, high-risk participants will also receive infusions of other chemotherapy drugs into their spinal fluid.

* Low-risk participants will receive up to six cycles of DA-EPOCH-R, with an additional dose of rituximab during each cycle.

* Frequent blood and urine tests will be performed during treatment, as well as body imaging scans and other tests of cancer progression as directed by the study doctors. Participants will receive additional medicines to help prevent possible adverse side effects of DA-EPOCH-R.

* Participants who respond successfully to the treatment will be asked to return for follow-up exams every 3 months for the first 18 months, then every year for the next 3 years. Participants who do not respond successfully to the treatment will be given the opportunity to participate in additional research and treatment protocols, if any are available.

Detailed Description: Background:

* Burkitt lymphoma/leukemia (BL) is highly curable. Standard treatment employs dose intense multi-agent chemotherapy and though effective is associated with high morbidity. Therefore, novel approaches are needed that improve the therapeutic index of BL while maintaining or improving efficacy. In human immunodeficiency virus (HIV)+ BL, outcome has been poor, mainly due to the use of cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone (CHOP) based regimens in this disease.

* Two National Cancer Institute (NCI) phase II trials have used etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) chemotherapy with 1 or 2 doses of rituximab (R) per cycle in untreated BL. (Dose-adjusted) etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH)-Rituximab has been used in16 HIV negative BL, and 8 HIV positive patients have received 3 to 4 cycles of EPOCHRR to minimize toxicity and risk of opportunistic infections. All patients remain in continuous remission. Treatment was very well tolerated and represents a novel therapeutic strategy in BL.

* This trial seeks to assess the effectiveness of a risk adaptive approach with DA-EPOCHR in untreated BL (HIV+/-). Because this treatment represents a major conceptual departure from standard treatment, it is important to obtain additional Phase II results in limited/advanced stage BL

* c-MYC positive Diffuse large B cell (DLBCL) is a rare variant of Diffuse Large B-Cell Lymphoma (DLBCL). There is very little data on the biology of this disease and what the optimal therapeutic approach should be has not been defined. Therefore, based on our impression that this behaves aggressively and is likely characterized by a high tumor proliferation rate, we plan to accrue patients with this disease in addition to BL patients.

* Plasmablastic lymphoma, another variant of DLBCL is frequently characterized by the activation of MYC and has had a poor outcome historically with standard treatment. We plan to include these patients in the study also. As they are cluster of differentiation 20 (CD20) negative, they will receive DA-EPOCH without Rituximab.

Objectives:

* Determine progression free survival (PFS), event free survival (EFS) and overall survival (OS) of risk adaptive DA-EPOCH-R in untreated BL and c-MYC + DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma.

* Assess predictive value of early fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans on PFS.

* Obtain pilot comparative molecular profiling in HIV negative and positive BL and c- MYC + DLBCL, including c-MYC+ plasmablastic lymphoma.

Eligibility:

* Burkitt lymphoma, c-MYC + DLBCL and c-MYC + plasmablastic lymphoma age greater than or equal to 18 years.

* No prior treatment except limited-field radiotherapy, short course of glucocorticoids and/or cyclophosphamide for an urgent problem at diagnosis.

* Adequate major organ function unless impairment due to lymphoma.

Study Design:

* Phase II Study of risk adapted DA-EPOCH-R in BL, c-MYC + DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma

* Low risk: DA-EPOCH-RR x 3 cycles.

* High risk , c-MYC + DLBCL and c-MYC+ plasmablastic lymphoma : DA-EPOCH (+/-) R x 6 cycles or 8 cycles in select patients.

* Cerebrospinal fluid (CSF) cytology and flow cytometry for analysis of BL.

* High Risk CSF negative - Prophylactic intrathecal treatment

* CSF positive - Active intrathecal treatment

* FDG-PET/CT pre- and post-cycle 2 in all patients.

* A total of 194 patients will be enrolled in the protocol.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 194

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group C - DLBCL high risk arm	EPOCH-R	Diffuse large B-cell lymphoma (DLBCL) high risk arm Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 6 cycles
Group B - Burkitt lymphoma High Risk Arm	EPOCH-R	Burkitt lymphoma High Risk Arm Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 6 cycles
Group A - Burkitt lymphoma Low Risk Arm	EPOCH-RR	Burkitt lymphoma Low Risk Arm Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 6 cycles

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Kaplan-Meier Curve Progression Free Survival (PFS) Constructed With an 95% Confidence Interval	Time of progression or death at 4 years	PFS is the time interval from start of treatment to documented evidence of disease progression. Disease progression was measured by the International Workshop Criteria (IWC). Progression is a positive positron emission tomography (PET) finding corresponding to the computed tomography (CT) abnormality (new lesion, increasing size of previous lesion), or a negative PET and a CT abnormality (new lesion, increasing size of previous lesion) of \< 1.5 cm (\< 1.0 cm in the lungs). Kaplan-Meier curves were constructed with an 95% confidence interval.
Percentage of Participants With Kaplan-Meier Curve Event Free Survival (EFS) Constructed With an 95% Confidence Interval	At 4 years	EFS was determined from the date of enrolment in the study until the date of progression, last documentation of disease at or after the last treatment cycle, death, or last follow-up (whichever occurred first). Disease progression was measured by the International Workshop Criteria (IWC). Progression is a positive positron emission tomography (PET) finding corresponding to the computed tomography (CT) abnormality (new lesion, increasing size of previous lesion), or a negative PET and a CT abnormality (new lesion, increasing size of previous lesion) of \< 1.5 cm (\< 1.0 cm in the lungs). Kaplan-Meier curves were constructed with an 95% confidence interval.
Percentage of Participants Kaplan-Meier Curve Overall Survival (OS) Constructed With an 95% Confidence Interval	At 4 years	OS was calculated from the enrolment date until date of death or last follow-up using the Kaplan Meier. Kaplan-Meier curves were constructed with an 95% confidence interval.

Secondary Outcome Measures

Name	Time	Method
Kaplan-Meier Progression Free Survival (PFS) Constructed With an 95% Confidence Interval in Participants Who Underwent Fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET) and/or Computed Tomography (CT) Scans After Cycle 2	After 2 cycles of therapy and prior to cycle 3	The predictive value of early FDG-PET/CT scans on PFS was assessed after cycle 2. PFS is the time interval from start of treatment to documented evidence of disease progression, assessed by the International Workshop Criteria (IWC). Progression is a positive positron emission tomography (PET) finding corresponding to the computed tomography (CT) abnormality (new lesion, increasing size of previous lesion), or a negative PET and a CT abnormality (new lesion, increasing size of previous lesion) of \< 1.5 cm (\< 1.0 cm in the lungs). Kaplan-Meier curves were constructed with an 95% confidence interval.

Trial Locations

Locations (30): University of Illinois
🇺🇸
Chicago, Illinois, United States
Massachusetts General Hospital Cancer Centers
🇺🇸
Boston, Massachusetts, United States
Case Western Reserve University
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Cleveland, Ohio, United States
MetroHealth Medical Center
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Cleveland, Ohio, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
West Michigan Cancer Center
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Kalamazoo, Michigan, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Fairview - Southdale Hospital
🇺🇸
Edina, Minnesota, United States
Park Nicollet Clinic - Saint Louis Park
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Saint Louis Park, Minnesota, United States
Unity Hospital
🇺🇸
Fridley, Minnesota, United States
University of Tennessee - Knoxville
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Knoxville, Tennessee, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
UC San Diego Moores Cancer Center
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La Jolla, California, United States
UCLA Center for Clinical AIDS Research and Education
🇺🇸
Los Angeles, California, United States
Emory University /Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
University of Iowa/Holden Comprehensive Cancer Center
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Iowa City, Iowa, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Vidant Oncology-Kinston
🇺🇸
Kinston, North Carolina, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
UT Southwestern /Simmons Cancer Center- Dallas
🇺🇸
Dallas, Texas, United States
MD Anderson Cancer Center
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Houston, Texas, United States
University of Nebraska Medical Center
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Omaha, Nebraska, United States
Froedtert and the Medical College of Wisconsin
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Milwaukee, Wisconsin, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
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Bethesda, Maryland, United States
Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States
University of Kentucky /Markey Cancer Center
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Lexington, Kentucky, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
University of Rochester
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Rochester, New York, United States
Wake Forest University Health Sciences
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Winston-Salem, North Carolina, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States