Clinical trial NCT01092182: Phase II Study of Dose-Adjusted EPOCH-Rituximab in Adults With Untreated Burkitt Lymphoma and c-MYC+ Diffuse Large B-Cell Lymphoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Burkitt Lymphoma
Diffuse Large B-cell Lymphoma, c-MYC Positive
Plasmablastic Lymphoma
Keywords: Microarray
Toxicity
Therapeutic Index
HIV Positive
HIV Negative
HIV Infections
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2010-03-24
Enrollment: 194
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Percentage of Participants With Kaplan-Meier Curve Progression Free Survival (PFS) Constructed With an 95% Confidence Interval
timeFrame: Time of progression or death at 4 years
measure: Percentage of Participants With Kaplan-Meier Curve Event Free Survival (EFS) Constructed With an 95% Confidence Interval
timeFrame: At 4 years
measure: Percentage of Participants Kaplan-Meier Curve Overall Survival (OS) Constructed With an 95% Confidence Interval
timeFrame: At 4 years
Secondary outcomes:
measure: 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
timeFrame: After 2 cycles of therapy and prior to cycle 3
Other outcomes:
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
timeFrame: 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.
Locations:
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Center for Clinical AIDS Research and Education
state: California
city: Atlanta
country: United States
facility: Emory University /Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky /Markey Cancer Center
state: Kentucky
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Centers
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Edina
country: United States
facility: Fairview - Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Unity Hospital
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic - Saint Louis Park
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Kinston
country: United States
facility: Vidant Oncology-Kinston
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Knoxville
country: United States
facility: University of Tennessee - Knoxville
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern /Simmons Cancer Center- Dallas
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: National Cancer Institute (NCI)
name: Mark J Roschewski, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Roschewski M, Dunleavy K, Abramson JS, Powell BL, Link BK, Patel P, Bierman PJ, Jagadeesh D, Mitsuyasu RT, Peace D, Watson PR, Hanna WT, Melani C, Lucas AN, Steinberg SM, Pittaluga S, Jaffe ES, Friedberg JW, Kahl BS, Little RF, Bartlett NL, Fanale MA, Noy A, Wilson WH. Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma. J Clin Oncol. 2020 Aug 1;38(22):2519-2529. doi: 10.1200/JCO.20.00303. Epub 2020 May 26.
citation: Dunleavy K, Fanale MA, Abramson JS, Noy A, Caimi PF, Pittaluga S, Parekh S, Lacasce A, Hayslip JW, Jagadeesh D, Nagpal S, Lechowicz MJ, Gaur R, Lucas A, Melani C, Roschewski M, Steinberg SM, Jaffe ES, Kahl B, Friedberg JW, Little RF, Bartlett NL, Wilson WH. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study. Lancet Haematol. 2018 Dec;5(12):e609-e617. doi: 10.1016/S2352-3026(18)30177-7.