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

Burkitt Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01092182
• Other study ID #: 100052
• Secondary ID: 10-C-0052
• Status: Completed
• Phase: Phase 2
• Start date: March 25, 2010
• Est. completion date: February 16, 2023

Study information

• Verified date: April 2023
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 194
• Est. completion date: February 16, 2023
• Est. primary completion date: September 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• INCLUSION CRITERIA:

Patients must have one of the following histologic diagnoses:

-Patients must have Burkitt Lymphoma. Effective with Amendment J (version date:

06/24/2014), the following histologies were removed as the maximum number allowed for these sub-groups has been reached: B-cell lymphoma: unclassifiable with features intermediate between Diffuse Large B cell lymphoma and Burkitt Lymphoma ; c-MYC + Diffuse large B-cell lymphoma (DLBCL) and c-MYC+ plasmablastic lymphoma.

If questions arise related to diagnosis, please contact the National Cancer Institute (NCI) Principal Investigator, Dr. Mark Roschewski or the NCI study coordinator, A. Nicole Lucas.

• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials

• Pathology confirmed by treating institutions Pathology Department.

• No prior treatment except patients may be entered if they have had prior limited-field radiotherapy, a short course of glucocorticoids, cyclophosphamide for an urgent problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome) and/or a single dose of intrathecal methotrexate (MTX) at the time of the pre-treatment diagnostic lumbar puncture.

• All disease stages.

• Human immunodeficiency virus (HIV) negative or positive.

• HIV positive patients on antiretroviral therapy regimen must be willing to suspend all Highly Active Antiretroviral Therapy (HAART) except in circumstances described in section 6.5.

• Eastern Cooperative Oncology Group (ECOG) 0-4

• Ability of patient or durable power of attorney (DPA) for healthcare to give informed consent.

• Hepatitis B + patients may be enrolled at the discretion of the investigator.

EXCLUSION CRITERIA:

• Patients with Primary central nervous system (CNS) Lymphoma.

• Inadequate renal function, defined as serum creatinine (Cr) > 1.5 or creatinine clearance < 50ml/min/1.73m^2 unless lymphoma related.

• Inadequate hepatic or hematological function: as follows, unless lymphoma-/disease-related: bilirubin greater than 2 mg/dl (total) except greater than 5 mg/dl in patients with Gilbert's syndrome as defined by greater than 80% unconjugated, absolute neutrophil count (ANC) less than 1000 and platelets less than 75,000.

• The effects of EPOCH-R on the developing human fetus are unknown. For this reason and because chemotherapy agents are known to be teratogenic, female subject of child-bearing potential not willing to use an acceptable method of birth control(i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and one year beyond treatment completion will not be eligible to participate in the study.

• Female subject pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-human chorionic gonadotropin (hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for women without child-bearing potential.

• The effects of EPOCH-R on the developing human fetus are unknown. For this reason and because chemotherapy agents are known to be teratogenic, male subject unwilling to use an acceptable method for contraception for the duration of the study and one year beyond treatment completion, will not be eligible to participate in the study.

• History of a prior invasive malignancy in past 5 years.

• Active symptomatic ischemic heart disease, myocardial infarction or congestive heart failure within the past year. If echo is obtained the left ventricular ejection fraction (LVEF) should exceed 40%.

• Serious concomitant medical illnesses that would jeopardize the patient's ability to receive the regimen with reasonable safety.

• HIV positive patients with advanced immune suppression and evidence of HIV resistant to all combinations of antiretroviral therapy considered at high risk of non lymphoma related death within 12-months due to other acquired immunodeficiency syndrome (AIDS) complications should not be enrolled on the study.

Related Conditions & MeSH terms

• Burkitt Lymphoma
• Diffuse Large B-cell Lymphoma, c-MYC Positive
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Large-Cell, Immunoblastic
• Plasmablastic Lymphoma

Intervention

Drug:
• EPOCH-R
Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 6 cycles
• EPOCH-RR
Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 3 cycles

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with serious and 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.	Date treatment consent signed to date off study, approximately 102 months and 25 days for Group A, 125 months and 28 days for Group B and 117 months and 29 days for group C.
Primary	Percentage of Participants With Kaplan-Meier Curve Progression Free Survival (PFS) Constructed With an 95% Confidence Interval	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.	Time of progression or death at 4 years
Primary	Percentage of Participants With Kaplan-Meier Curve Event Free Survival (EFS) Constructed With an 95% Confidence Interval	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.	At 4 years
Primary	Percentage of Participants Kaplan-Meier Curve Overall Survival (OS) Constructed With an 95% Confidence Interval	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.	At 4 years
Secondary	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	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.	After 2 cycles of therapy and prior to cycle 3

External Links

•   NIH Clinical Center Detailed Web Page