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 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 (Bullet) 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.