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

 -  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.
Background:

 -  Burkitt lymphoma/leukemia (BL) is highly curable. Standard treatment employs doseintense
 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 HIV+ BL, outcome has been poor, mainly due to the
 use of CHOP based regimens in this disease.

 -  Two NCI phase II trials have used EPOCH chemotherapy with 1 or 2 doses of rituximab (R)
 per cycle in untreated BL. (Dose-adjusted) 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 DLBCL is a rare variant of 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 CD20 negative, they will

 receive DA-EPOCH without Rituximab.

 Objectives:

 -  Determine PFS, EFS and 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 FDG-PET/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.

 -  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.
-  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 + DLBCL and c-MYC+
 plasmablastic lymphoma.

 If questions arise related to diagnosis, please contact the 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 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 institution s 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.

 -  HIV negative or positive.

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

 -  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 CNS Lymphoma.

 -  Inadequate renal function, defined as serum Cr > 1.5 or creatinine clearance <
 50ml/min/1.73m2 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, 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-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 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 supression 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 AIDS complications should not be enrolled
 on the study.