Carfilzomib, Rituximab, and Combination Chemotherapy in Treating Patients With Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVES:

I. To determine the safety of carfilzomib in combination with rituximab-cyclophosphamide,
doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) (CR-CHOP) in patients with
newly diagnosed diffuse large B-cell lymphoma (DLBCL) and identify a recommended phase II
dose (RP2D). (Phase I)

SECONDARY OBJECTIVES:

I. To determine if CR-CHOP improves the rates of 1-year progression free survival (PFS) and
overall survival (OS) in non-germinal center (non-GC) DLBCL patients relative to historical
controls treated with R-CHOP(Phase II) II. To determine response rates (complete and partial
remission) in non-GC DLBCL patients treated with CR-CHOP and compare to historical controls
treated with R-CHOP.

III. Because a proportion (~10%) of patients classified as non-GC by immunohistochemical
(IHC) algorithms may not have the activated B-cells (ABC) subtyped of DLBCL, an exploratory
secondary objective will compare the PFS, OS and response rates of the ABC subgroup of
patients with DLBCL as determined by the Gene Expression Profiling with those of the overall
group of non-GC DLBCL.

OUTLINE: This is a phase I, dose-escalation study of carfilzomib followed by a phase II
study.

Patients receive rituximab intravenously (IV) over at least 90 minutes, cyclophosphamide IV
over 30-60 minutes, doxorubicin hydrochloride IV over 3-5 minutes, vincristine sulfate IV
over 1 minute on day 1, and prednisone orally (PO) on days 1-5. Patients also receive
carfilzomib IV over 30 minutes on days 1, 2, 8 and 9. Courses repeat every 21 days for 6
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and at 6, 12, and 24
months.

Inclusion Criteria:

- Patients must have histologically confirmed diffuse large B-cell lymphoma (DLBCL);
patients with previously diagnosed indolent lymphoma (follicular lymphoma and marginal
zone lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are
eligible only if they have not previously been treated for indolent lymphoma. For the
Phase II study, patients must have non-GC DLBCL as determined by Hans Algorithm.

- Patients must have radiographically measurable disease

- Patients must not have been previously treated with chemotherapy or radiation for
diagnosis of lymphoma; brief (< 15 days) treatment with glucocorticoids is acceptable

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

- Hemoglobin ≥ 7.0 g/dl

- Absolute neutrophil count ≥ 1,500/mcL

- Platelet count ≥ 100,000/mcL

- Total bilirubin within normal institutional limits unless due to Gilbert's disease

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) ≤
2.5 X institutional upper limit of normal

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X
institutional upper limit of normal

- Creatinine clearance ≥ 45 mL/min calculated by Cockcroft-Gault

- Adequate cardiac function left ventricular ejection fraction (LVEF) > 50% as assessed
by echocardiogram or MUGA (Multi Gated Acquisition Scan)

- The effects of Carfilzomib on the developing human fetus are unknown. For this reason
and because chemotherapeutic agents used in this study are known to be teratogenic,
women of child-bearing potential and men must agree to use adequate contraception
(double barrier method of birth control or abstinence) 2 weeks prior to initiation of
treatment, for the duration of study participation and for 3 months after completing
treatment. Should a woman become pregnant or suspect that she is pregnant while she or
her partner is participating in this study, she should inform the treating physician
immediately. Men must agree to refrain from sperm donation for at least 90 days after
the last dose of carfilzomib.

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document

- International Prognostic Index must be documented:

- ECOG performance status ≥ 2 (1 point)

- Age ≥ 60 (1 point)

- ≥ 2 extranodal sites (1 point)

- Lactate dehydrogenase (LDH) > upper limit of normal (1 point)

- Ann Arbor stage III or IV (1 point)

Exclusion Criteria:

- Patients who have not recovered from adverse events due to agents administered more
than 4 weeks earlier

- Patients who are receiving any other investigational agents

- Known central nervous system (CNS) involvement by lymphoma

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to carfilzomib or other agents (R-CHOP) used in this study

- Active congestive heart failure (New York heart Association Class III or IV),
symptomatic ischemia, or conduction abnormalities uncontrolled by conventional
intervention or myocardial infarction within four months prior to enrollment

- Patients with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, or psychiatric illness/social situations that would limit
compliance with study requirements

- Pregnant or breastfeeding women are excluded from this study; breastfeeding should be
discontinued if the mother is treated with carfilzomib

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin, or low-risk prostate
cancer after curative therapy

- Patients who have had major surgical procedures or significant traumatic injury within
28 days prior to study treatment

- Patients who are reported to be of direct Asian-Pacific (China, Japan, Taiwan,
Singapore, Republic of Korea, and Thailand) ancestry.