Carfilzomib With or Without Rituximab in the Treatment of Waldenstrom Macroglobulinemia or Marginal Zone Lymphoma

PRIMARY OBJECTIVES:

I. Determine the overall response rate of single-agent weekly carfilzomib (CFZ), measured
after 2 cycles of therapy, in Waldenstrom's macroglobulinemia (WM) and marginal zone lymphoma
(MZL).

SECONDARY OBJECTIVES:

I. Assess safety and tolerability of single agent, weekly CFZ in patients with WM and MZL,
and determine the tolerability of weekly CFZ+rituximab for applicable patients.

II. Estimate the time to best response, response duration, and survival with weekly CFZ for
WM and MZL.

III. Evaluate the overall response rate associated with weekly CFZ in a subset of patients
with rituximab refractory WM or MZL.

OUTLINE:

Patients receive carfilzomib intravenously (IV) over 30 minutes on days 1, 8, and 15.
Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
unacceptable toxicity. Patients who fail to achieve at least 25% M-protein reduction for
Waldenstrom's macroglobulinemia or partial response for marginal zone lymphoma after 2
courses of carfilzomib, receive rituximab IV weekly on days 1, 8, 15, and 22 of course 3 and
then monthly on day 1 of courses 4-6 in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 1
year.

Inclusion Criteria:

- Waldenstrom's macroglobulinemia (WM) or marginal zone lymphoma (MZL) based on
institutional pathology review; patients may have either previously untreated or
relapsed/refractory disease

- Measurable disease: for WM presence of monoclonal IgM immunoglobulin concentration on
serum electrophoresis, with lymphoplasmacytic marrow infiltrate; for MZL: measurable
nodal disease measuring at least 1.5 cm in longest dimension, or splenomegaly

- Indication for initiation of therapy

- Absolute neutrophil count (ANC) > 1,000/uL unless disease-related (due to marrow
infiltration or splenomegaly)

- Platelet count > 75,000/uL unless disease-related (due to marrow infiltration or
splenomegaly)

- Serum creatinine < 2.5 mg/dL or creatinine clearance > 30 cc/min

- Bilirubin < 2 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN

- All patients must be informed of the investigational nature of this study and have
given written consent in accordance with institutional and federal guidelines

- Expected survival of > 90 days

- Females of childbearing potential (FCBP) must agree to pregnancy testing and to
practice contraception

- Male subjects must agree to practice contraception

Exclusion Criteria:

- Known human immunodeficiency virus (HIV), hepatitis C, or hepatitis B positivity
(subjects with hepatitis B surface antigen [SAg] or core antibody positivity, who are
receiving and responding to antiviral therapy directed at hepatitis B or are negative
for hepatitis B virus [HBV] deoxyribonucleic acid [DNA], are allowed)

- Candidate for potentially curative antibiotic therapy for gastric mucosa-associated
lymphoid tissue (MALT); (gastric MALT lymphoma patients with stage I/II helicobacter
[H.] pylori positive lymphoma must fail therapy with H.-pylori directed therapy before
being considered for this study)

- Eastern Cooperative Oncology Group (ECOG) performance status 3 or higher

- Known active central nervous system (CNS) involvement

- Pregnant or lactating females

- Inadequate cardiac function, as measured by left ventricular ejection fraction (LVEF)
that is less than or equal to 40%, or the presence of New York Heart Association
(NYHA) classification of greater than stage II congestive heart failure

- Significant neuropathy (grades 3-4, or grade 2 with pain) within 14 days prior to
screening

- Uncontrolled inter-current illness including, but not limited to, unstable angina,
recent myocardial infarction within 6 months of screening and uncontrolled cardiac
arrhythmias, psychiatric illness, or psychosocial difficulty that would limit
compliance with study requirements

- Non-hematologic malignancy within the past 3 years with the exception of a) adequately
treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b)
carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason grade 6 or
less with stable prostate-specific antigen levels; or d) cancer considered cured by
surgical resection or unlikely to impact survival during the duration of the study