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

• Sponsor: University of Washington (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03269552
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 4
• Location: 1
• Arm: 1
• Actual Duration (Months): 12.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Marginal Zone Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Waldenstrom Macroglobulinemia; Refractory Marginal Zone Lymphoma; Refractory Waldenstrom Macroglobulinemia; Waldenstrom Macroglobulinemia	Drug: Carfilzomib; Other: Laboratory Biomarker Analysis; Biological: Rituximab	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

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

3. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Response-Adapted Clinical Trial of Weekly Carfilzomib With or Without Rituximab for Waldenström's Macroglobulinemia and Marginal Zone Lymphoma
• Actual Study Start Date: Dec 18, 2017
• Actual Primary Completion Date: Dec 28, 2018
• Actual Study Completion Date: Dec 28, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (carfilzomib, rituximab) 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; Given IV; Other Names: Kyprolis PR-171 ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Rituximab; Given IV; Other Names: ABP 798 BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Rituxan Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar IBI301 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 RTXM83

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [Up to 1 year]

   Descriptive statistics will be used for baseline characteristics, and responses to treatment.

Secondary Outcome Measures

1. Overall Survival [Up to 1 year]

   Estimated using Kaplan-Meier analysis.

2. Time to Best Response [Up to 1 year]

   Estimated using Kaplan-Meier analysis.

3. Time to Progression [Up to 1 year]

   Estimated using Kaplan-Meier analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stephen Smith, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 2, 2018

More Information

Publications

None provided.

• Responsible Party: University of Washington
• ClinicalTrials.gov Identifier: NCT03269552
• Other Study ID Numbers: 9702; NCI-2017-01548; 9702; P30CA015704; RG1716046
• First Posted: Aug 31, 2017
• Last Update Posted: Jan 18, 2020
• Last Verified: Jan 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell, Marginal Zone; Waldenstrom Macroglobulinemia; Recurrence; Rituximab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Pre-assignment Detail	4 participants signed informed consent, met eligibility and continued on to study treatment.

Arm/Group Title	Treatment (Carfilzomib, Rituximab)
Arm/Group Description	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 will continue to receive carfolzomib for 4 more courses. In addition, they will also 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. Carfilzomib: Given IV Laboratory Biomarker Analysis: Correlative studies Rituximab: Given IV
Period Title: Overall Study
STARTED	4
COMPLETED	2
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Carfilzomib, Rituximab)
Arm/Group Description	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. Carfilzomib: Given IV Laboratory Biomarker Analysis: Correlative studies Rituximab: Given IV
Overall Participants	4
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 50%
>=65 years	2 50%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	64.25
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	4 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	4 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	4 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants who were evaluated after cycle 2 day 15 and prior to cycle 3 day 1.

Arm/Group Title	Treatment (Carfilzomib, Rituximab)
Arm/Group Description	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 will continue to receive carfolzomib for 4 more courses. In addition, they will also 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. Carfilzomib: Given IV Laboratory Biomarker Analysis: Correlative studies Rituximab: Given IV
Measure Participants	4
Complete response	0 0%
Very good partial response	0 0%
Partial response	2 50%
Minor response	1 25%
Stable disease	1 25%
Progressive disease	0 0%

2. Secondary Outcome

Title	Overall Survival
Description	Estimated using Kaplan-Meier analysis.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Carfilzomib, Rituximab)
Arm/Group Description	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. Carfilzomib: Given IV Laboratory Biomarker Analysis: Correlative studies Rituximab: Given IV
Measure Participants	4
Count of Participants [Participants]	4 100%

3. Secondary Outcome

Title	Time to Best Response
Description	Estimated using Kaplan-Meier analysis.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Carfilzomib, Rituximab)
Arm/Group Description	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 will continue to receive carfolzomib for 4 more courses. In addition, they will also 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. Carfilzomib: Given IV Laboratory Biomarker Analysis: Correlative studies Rituximab: Given IV
Measure Participants	3
Median (Full Range) [Months]	2

4. Secondary Outcome

Title	Time to Progression
Description	Estimated using Kaplan-Meier analysis.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Carfilzomib, Rituximab)
Arm/Group Description	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 will continue to receive carfolzomib for 4 more courses. In addition, they will also 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. Carfilzomib: Given IV Laboratory Biomarker Analysis: Correlative studies Rituximab: Given IV
Measure Participants	4
Median (Standard Error) [Months]	8 (0.05)

Adverse Events

Time Frame	Adverse events are reported from the time the subject receives their first dose of study drug through 30 days post-last dose of study drug or initiation of a new anti-cancer therapy, whichever occurs first.
Arm/Group Title	Treatment (Carfilzomib, Rituximab)
Arm/Group Description	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 will continue to receive carfolzomib for 4 more courses. In addition, they will also 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. Carfilzomib: Given IV Laboratory Biomarker Analysis: Correlative studies Rituximab: Given IV
All Cause Mortality
	Treatment (Carfilzomib, Rituximab)
	Affected / at Risk (%)	# Events
Total	0/4 (0%)
Serious Adverse Events
	Treatment (Carfilzomib, Rituximab)
	Affected / at Risk (%)	# Events
Total	1/4 (25%)
Blood and lymphatic system disorders
Microangiopathic Hemolytic Anemia	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Carfilzomib, Rituximab)
	Affected / at Risk (%)	# Events
Total	4/4 (100%)
Blood and lymphatic system disorders
Anemia	1/4 (25%)	1
Endocrine disorders
Hypothyroidism	1/4 (25%)	1
Gastrointestinal disorders
Constipation	1/4 (25%)	1
Flatulance	2/4 (50%)	3
Nausea	2/4 (50%)	2
Vomiting	1/4 (25%)	2
General disorders
Chills	2/4 (50%)	3
Cough	1/4 (25%)	1
Fatigue	2/4 (50%)	2
Flu Like Symptoms	1/4 (25%)	1
Fluid Retention	1/4 (25%)	1
Warm Sensation	1/4 (25%)	1
Non-Cardiac Chest Pain	2/4 (50%)	2
Investigations
Neutrophil Count Decreased	1/4 (25%)	1
Platelet Count Decreased	2/4 (50%)	3
White Blood Cell Count Decreased	1/4 (25%)	1
Musculoskeletal and connective tissue disorders
Bursitis	1/4 (25%)	1
Nervous system disorders
Headache	1/4 (25%)	2
Increased Cold Sensitivity	1/4 (25%)	1
Psychiatric disorders
Insomnia	1/4 (25%)	1
Renal and urinary disorders
Decreased Urination	1/4 (25%)	1
Renal Failure	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Dry Skin	1/4 (25%)	1
Vascular disorders
Hypertension	1/4 (25%)	1

Limitations/Caveats

Early termination due to low accrual leading to small number of subjects analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.