Rituximab and Combination Chemotherapy in Treating Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma

PRIMARY OBJECTIVES:

I. To compare the event-free survival of rituximab, cyclophosphamide, doxorubicin
hydrochloride, vincristine sulfate, prednisone (R-CHOP) versus dose-adjusted (DA-) etoposide,
prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, and rituximab
(EPOCH-R) chemotherapy in untreated cluster of differentiation (CD)20 positive (+) diffuse
large B-cell lymphomas.

II. To develop a molecular predictor of outcome of R-CHOP and DA-EPOCH-R chemotherapy using
molecular profiling.

SECONDARY OBJECTIVES:

I. To compare the response rates, overall survival and toxicity of R-CHOP versus DA-EPOCH-R.

II. To define the pharmacogenomics of untreated diffuse large B-cell lymphoma (DLBCL) and
correlate clinical parameters (toxicity, response, survival outcomes and laboratory results)
with molecular profiling.

III. To assess the use of molecular profiling for pathological diagnosis. IV. To identify new
therapeutic targets using molecular profiling. V. To perform a comprehensive analysis of
somatic alterations to the tumor genome and to understand which genomic alterations are
somatically acquired by the tumor and which are encoded in the germ line of the patient.

VI. To identify biomarkers of response to chemotherapy by fludeoxyglucose F 18 (FDG)-positron
emission tomography (PET)/computed tomography (CT) imaging that are predictive of
histopathologic remissions and survival in patients with stage I (mediastinal), II, III, or
IV untreated DLBCL.

VII. To evaluate the use of semiquantitative measurements of FDG uptake in defining
FDG-PET/CT based biomarkers of response to chemotherapy in patients with DLBCL.

VIII. To determine whether FDG-PET/CT measurements of tumor response after the second cycle
of chemotherapy can predict clinical response.

IX. To establish a standardized protocol for FDG-PET/CT image acquisition. X. To determine
additional FDG-PET/CT parameters (e.g., the ratio of tumor maximum standard uptake value
[SUVmax] to liver SUVmean; SUVs corrected for body surface area and lean body mass; nuclear
medicine physician's assessment) and evaluate their utility in refining FDG-PET/CT based
biomarkers of response to therapy.

XI. To evaluate inter-institutional reproducibility of FDG-PET/CT measurements for this
indication.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

1. Histologically documented de novo CD20+ DLBCL with stage II, III or IV disease.

- Stage I primary mediastinal (thymic) DLBCL is also eligible.

- Patients with an underlying low-grade lymphoma, such as a transformed lymphoma or
low-grade lymphoma in the bone marrow, are not eligible.

- Diagnosis should be based on an adequate tissue sample, including open biopsy or
core needle biopsy.

- Needle aspiration for primary diagnosis is unacceptable.

- Patients must have one of the following WHO classification subtypes:

- Diffuse large B-cell lymphoma (includes morphological variants:
centroblastic, immunoblastic, T-cell/histiocyte rich, and anaplastic)

- Mediastinal (thymic) large B-cell lymphoma

- Intravascular large B-cell lymphoma

- Note: Failure to submit a pathology block within 60 days of patient registration
will be considered a major protocol violation.

- Fresh (frozen) tumor biopsy must be available or attempted. A frozen tumor
biopsy equivalent to a minimum of four at least 16 gauge needle cores is an
important component of this study.

- Patients without adequate frozen material should have a biopsy performed to
obtain material.

- If a biopsy is performed and does not yield adequate material, the patient
is still eligible for the study. If a biopsy cannot be done safely, the
patient may still be eligible for the study if permission is granted.

- Note: This study does not allow concurrent radiation unless a patient has a
documented CNS treatment failure with no systemic failure.

2. No prior cytotoxic chemotherapy or rituximab. Patients may be entered if they have
received prior limited field radiation therapy or a short course of glucocorticoids (<
10 days) for an urgent local disease complication at diagnosis (e.g., cord
compression, SVC syndrome). Patients who have received chemotherapy for prior
malignancies are not eligible.

3. Age ≥ 18 years

4. ECOG Performance Status 0-2

5. No active ischemic heart disease or congestive heart failure. If there is suspicion of
cardiac disease, a cardiac ejection fraction must show LVEF > 45%, but the study is
not required

6. No known lymphomatous involvement of the CNS. A lumbar puncture prior to study is not
required in the absence of neurological symptoms

7. No known HIV disease. Patients with a history of intravenous drug abuse or any other
behavior associated with an increased risk of HIV infection should be tested for
exposure to the HIV virus. Patients who test positive or who are known to be infected
are not eligible.

8. Non pregnant and non-nursing. Treatment would expose an unborn child to significant
risks. Women and men of reproductive potential should agree to use an effective form
of contraception.

9. Patients with active medical processes (e.g., uncontrolled bacterial or viral
infection, bleeding) not related to their lymphoma should be excluded.

10. Required Initial Laboratory Values (unless non-Hodgkin lymphoma):

- ANC ≥ 1000/μL

- Platelets ≥ 100,000/μL

- Creatinine≤ 1.5 mg/dL or creatinine clearance ≥ 50 cc/min

- Total Bilirubin ≤ 2 mg/dL (unless a history of Gilbert's Disease)