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

Study Overview
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Brief Summary
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This phase II trial studies how well carfilzomib with or without rituximab work in treating patients with Waldenstrom macroglobulinemia or marginal zone lymphoma that is previously untreated, has come back, or does not respond to treatment. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving carfilzomib alone when disease is responding or with rituximab when disease is not responding may work better in treating patients with Waldenstrom macroglobulinemia or marginal zone lymphoma.

Detailed Description
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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.

Official Title
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A Response-Adapted Clinical Trial of Weekly Carfilzomib With or Without Rituximab for Waldenström's Macroglobulinemia and Marginal Zone Lymphoma

Conditions
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Marginal Zone Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Waldenstrom Macroglobulinemia, Refractory Marginal Zone Lymphoma, Refractory Waldenstrom Macroglobulinemia, Waldenstrom Macroglobulinemia

Intervention / Treatment
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* Drug: Carfilzomib
* Other: Laboratory Biomarker Analysis
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (carfilzomib, rituximab)<br>Patients receive carfilzomib 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. | Drug: Carfilzomib<br>* Given IV<br>* Other names: PR-171;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV<br>* Other names: RTXM83;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Descriptive statistics will be used for baseline characteristics, and responses to treatment. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Estimated using Kaplan-Meier analysis. | Up to 1 year | 
| Time to Best Response | Estimated using Kaplan-Meier analysis. | Up to 1 year | 
| Time to Progression | Estimated using Kaplan-Meier analysis. | Up to 1 year |