Rituximab and Combination Chemotherapy in Treating Patients With Previously Untreated High- or High-Intermediate-Risk Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVES:

I. To evaluate 1 year progression-free survival (PFS) following treatment with rituximab
intense dosing and CHOP-21 (RID-CHOP) in previously untreated patients with high risk
(International Prognostic Index [IPI] 3-5) DLBCL.

SECONDARY OBJECTIVES:

I. To evaluate, in previously untreated patients with high risk (IPI 3-5) DLBCL treated with
rituximab intense dosing and CHOP-21: Complete response (CR) rate, (as defined by
International Harmonization Project criteria using 18-fluorodeoxyglucose [FDG] -positron
emission tomography [PET]/computed tomography [CT]).

II. Overall survival.

III. Toxicity profile.

IV. Rituximab pharmacokinetics for this dose and schedule.

V. Effect of immunophenotype of DLBCL on outcome.

VI. Effect of Fc-Gamma Receptor III (FcyRIII) polymorphism genotype on outcome. OUTLINE:
Patients receive rituximab intravenously (IV) on days 0, 1, 4, 8, and 15 of course 1; days
1, 8, and 15 of course 2; and day 1 of all subsequent courses. Patients also receive CHOP
chemotherapy comprising cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine
sulfate IV on day 1, and prednisone orally (PO) on days 1-5. Treatment repeats every 21 days
for 6 courses in the absence of disease progression or unacceptable toxicity. After
completion of study treatment, patients are followed up every 2-3 months for 2 years, every
6 months for 3 years, annually for up to 10 years.

Inclusion Criteria:

- Newly diagnosed cluster of differentiation (CD) 20+ DLBCL with IPI between 3-5

- No prior chemotherapy, radiation therapy or immunotherapy for DLBCL; a short course
(< 2 weeks) of corticosteroids is allowed for symptom control Signed informed consent

- Eastern Cooperative Oncology Group (ECOG) Performance status assessed between 0 and
2; performance status of 3 will be accepted if impairment is caused by DLBCL
complications and improvement is expected once therapy is initiated

- Measurable disease by Non-Hodgkin's Lymphoma Response Criteria on FDG-PET/CT;
baseline measurements and evaluations must be obtained =< 21 days prior to
registration

- Absolute neutrophil count (ANC) >= 1,500/μL unless due to marrow involvement by
lymphoma

- Platelets >= 75,000/μL unless due to marrow involvement by lymphoma Hemoglobin > 7.0
g/dL unless due to marrow involvement by lymphoma

- Creatinine =< 2.0 mg/dL or calculated creatinine clearance >= 40

- Total bilirubin =< 1.5 mg/dL unless due to Gilbert's disease

- Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 2.5 the upper
limit of normal

- Alkaline phosphatase =< 5x upper limit of normal

- Patients with bilirubin between 1.5-3.0 mg/dL due to lymphoma may be entered and
doses adjusted

- Left ventricular ejection fraction (LVEF) >= 50%

Exclusion Criteria:

- Women who are pregnant or breast feeding

- Known seropositivity for human immunodeficiency virus (HIV)

- Known presence of central nervous system (CNS) involvement by lymphoma

- New York Heart Association Classification III or IV heart

- Current or chronic hepatitis B or hepatitis C infection (as detected by positive
testing for Hepatitis B surface Antigen [Hbs Ag] or antibody to Hepatitis C virus
[anti HCV] respectively); patients must be tested for Hepatitis B surface antigen and
anti-HCV =< 21 days prior to registration

- Male patients (with female sexual partners of childbearing potential) and female
patients of childbearing potential who refuse to use effective methods of
contraception

- Unstable or severe uncontrolled medical, psychological, or social condition

- Any evidence of serious active, uncontrolled infection (i.e., requiring an IV
antibiotic or antiviral agent)

- Receipt of live vaccine within 4 weeks prior to study drug administration

- Concurrent active malignancy other than non-melanoma skin cancer or carcinoma in situ
of the cervix; subjects with previous malignancies are eligible provided that they
have been treated with curative intent and remain disease free for 3 years or more

- No prior chemotherapy for lymphoma

- Prior radiation therapy for lymphoma

- Any important medical illness or abnormal laboratory finding that would, in the
investigator's judgment, significantly increase the subject's risk of participating
in this study