CaRD: Carfilzomib, Rituximab and Dexamethasone in Waldenstrom's Macroglobulinemia

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01470196
• Collaborator: Amgen (Industry)
• Enrollment: 31
• Location: 1
• Arm: 1
• Duration (Months): 59
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Carfilzomib is a drug that has shown anti-tumor activity by inhibiting the proteasome within the cell, which is responsible for degrading or breaking down a wide variety of proteins. Carfilzomib has not been approved by the FDA.

Rituximab and dexamethasone are often used to treat Waldenstrom's Macroglobulinemia (WM), alone or in combination with other drugs. Combinations with rituximab, dexamethasone and proteasome inhibitors, like carfilzomib, show high levels of activity in WM patients.

In this research study, the investigators are testing the safety and efficacy of Carfilzomib when used along with Rituximab and Dexamethasone as a possible treatment for Waldenstrom's Macroglobulinemia.

Condition or Disease	Intervention/Treatment	Phase
Waldenstrom's Macroglobulinemia	Drug: Dexamethasone; Drug: Carfilzomib; Drug: Rituximab	Phase 2

Detailed Description

If you take part in this research study, you will receive Carfilzomib and dexamethasone as an infusion on Days 1, 2, 8, and 9 for Cycles 1-6. You will then have a Rituximab infusion on Days 2 and 9. Each cycles lasts 21 days. After completing Cycle 6 and if you are eligible, there will be a 2 month break before the maintenance phase is started. During this break, you will have a study visit with a physical exam, blood tests, and a bone marrow biopsy. If you continue to the maintenance phase, you will receive Carfilzomib and Dexamethasone on Days 1 and 2 and Rituximab on Day 2 of Cycles 1-8. Each cycle will continue to last 21 days, but will take place every 2 months. Infusions will last between 2-6 hours.

During all cycles you will have a physical exam and you will be asked questions about your general health and specific questions about any problems that you might be having and any medications you may be taking. Blood tests will also be done at each Cycle visit, and you will complete a questionnaire. Bone marrow and CT scan will only be repeated at physician discretion when appropriate and in order to ensure your response to treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Carfilzomib, Rituximab, and Dexamethasone (CaRD) in Waldenstrom's Macroglobulinemia
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment Arm Carfilzomib, dexamethasone, rituximab

Drug: Dexamethasone; 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8; Other Names: Decadron ; Drug: Carfilzomib; 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8; Other Names: PR-171 ; Drug: Rituximab; 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8; Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [4 years]

   Overall Response Rate= Minor response (>25%-50% reduction in serum IgM from baseline + Partial Response (>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).

2. Neuropathy Incidence Rate [3 years]

   Number and percentage of participants who experienced neuropathy attributable to CaRD therapy

3. Time to Progression [4 years]

   Progression-free survival is the defined as the time from study entry to disease progression (PD) or death. Patients without PD are censored at the date of last disease evaluation. PD is defined as a greater than 25% increase in serum IgM and 500mg/dL absolute increase from the lowest attained response value as determined by serum electrophoresis, confirmed by at least one other investigation, or progression of clinically significant disease related symptom(s).

4. Major Response Rate [4 years]

   Major Response Rate= Partial Response (>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).

5. Very Good Partial Response and Complete Response Rate [4 years]

   This is the rate of VGPR and CR in patients on CaRD therapy. Very good partial responses are >90% reduction in serum IgM from baseline. Complete response is defined as having resolution of all symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of Waldenstrom's Macroglobulinemia

• Symptomatic disease

• Measurable disease

• Life expectancy of greater than 12 weeks

• Adequate organ and marrow function

• CD20 positive based on any previous performed bone marrow immunohistochemistry or flow cytometric analysis

• Disease free of prior malignancies for >/= 5 years with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast

Exclusion Criteria:

• More than one prior therapy

• Previous therapy with a proteasome inhibitor or rituximab

• Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or not recovered from adverse events due to agents administered more than 4 weeks earlier

• Currently receiving treatment for any malignancy

• Major surgery within 21 days prior to study entry

• Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to study entry

• Uncontrolled hypertension or uncontrolled diabetes

• Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to study entry

• Known history of allergy to Captisol

• Receiving any other study agents

• Known brain metastases

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to carfilzomib, rituximab, and/or dexamethasone

• Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment

• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant or lactating

• HIV-positive on combination antiretroviral therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Amgen

Investigators

• Principal Investigator: Steven P Treon, MD, PhD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Steven P. Treon, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01470196
• Other Study ID Numbers: 11-279
• First Posted: Nov 11, 2011
• Last Update Posted: Nov 20, 2018
• Last Verified: Oct 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Steven P. Treon, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute: WM; untreated; symptomatic
• Additional relevant MeSH terms: Waldenstrom Macroglobulinemia; Dexamethasone; Rituximab

Study Results

Participant Flow

Arm/Group Title	Carfilzomib, Dexamethasone, and Rituximab
Arm/Group Description	Carfilzomib, dexamethasone, rituximab Dexamethasone: 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8 Carfilzomib: 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8 Rituximab: 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8
Period Title: Overall Study
STARTED	31
COMPLETED	31
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment Arm
Arm/Group Description	Carfilzomib, dexamethasone, rituximab Dexamethasone: 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8 Carfilzomib: 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8 Rituximab: 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8
Overall Participants	31
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	21 67.7%
>=65 years	10 32.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	12 38.7%
Male	19 61.3%
Region of Enrollment (Count of Participants)
United States	31 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Overall Response Rate= Minor response (>25%-50% reduction in serum IgM from baseline + Partial Response (>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Carfilzomib, dexamethasone, rituximab Dexamethasone: 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8 Carfilzomib: 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8 Rituximab: 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8
Measure Participants	31
Count of Participants [Participants]	25 80.6%

2. Primary Outcome

Title	Neuropathy Incidence Rate
Description	Number and percentage of participants who experienced neuropathy attributable to CaRD therapy
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Carfilzomib, dexamethasone, rituximab Dexamethasone: 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8 Carfilzomib: 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8 Rituximab: 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8
Measure Participants	31
Count of Participants [Participants]	6 19.4%

3. Primary Outcome

Title	Time to Progression
Description	Progression-free survival is the defined as the time from study entry to disease progression (PD) or death. Patients without PD are censored at the date of last disease evaluation. PD is defined as a greater than 25% increase in serum IgM and 500mg/dL absolute increase from the lowest attained response value as determined by serum electrophoresis, confirmed by at least one other investigation, or progression of clinically significant disease related symptom(s).
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Carfilzomib, dexamethasone, rituximab Dexamethasone: 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8 Carfilzomib: 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8 Rituximab: 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8
Measure Participants	31
Median (Inter-Quartile Range) [months]	58

4. Primary Outcome

Title	Major Response Rate
Description	Major Response Rate= Partial Response (>50-90% reduction in serum IgM from baseline) + Very Good Partial Response (>90% reduction in serum IgM from baseline) + Complete Response (resolution of all symptoms, normalization of serum IgM with disappearance of IgM paraprotein, resolution of any adenopathy or splenomegaly).
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Carfilzomib, dexamethasone, rituximab Dexamethasone: 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8 Carfilzomib: 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8 Rituximab: 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8
Measure Participants	31
Count of Participants [Participants]	22 71%

5. Primary Outcome

Title	Very Good Partial Response and Complete Response Rate
Description	This is the rate of VGPR and CR in patients on CaRD therapy. Very good partial responses are >90% reduction in serum IgM from baseline. Complete response is defined as having resolution of all symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Arm
Arm/Group Description	Carfilzomib, dexamethasone, rituximab Dexamethasone: 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8 Carfilzomib: 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8 Rituximab: 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8
Measure Participants	31
Count of Participants [Participants]	12 38.7%

Adverse Events

Time Frame	Adverse events were assessed at every cycle visit (every 3 weeks during induction, and every 2 months during maintenance) and up to 30 days post end of treatment, up to 3 years.
Arm/Group Title	Treatment Arm
Arm/Group Description	Carfilzomib, dexamethasone, rituximab Dexamethasone: 20 mg IV on Days 1, 2, 8, 9, of 21 day cycle for cycles 1-6 20 mg IV on Days 1, 2 of 21 day cycles q 2 months for cycles 1-8 Carfilzomib: 20 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycle 1 36 mg/m2 IV on Days 1, 2, 8, 9 of 21 day cycles for Cycles 2-6 36 mg/m2 IV on Days 1, 2 of 21 day cycles q 2 months for Cycles 1-8 Rituximab: 375 mg/m2 IV on Days 2, 9 of 21 day cycles for Cycles 1-6 375 mg/m2 IV on Day 2 of 21 day cycles q 2 months for Cycles 1-8
All Cause Mortality
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	0/31 (0%)
Serious Adverse Events
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	5/31 (16.1%)
Cardiac disorders
Atypical chest pain	1/31 (3.2%)	1
Cardiomyopathy	1/31 (3.2%)	1
Infections and infestations
Pneumonia	1/31 (3.2%)	1
Injury, poisoning and procedural complications
Postoperative thoracic procedure complication	1/31 (3.2%)	1
Investigations
Grade 4 Neutrophil count decreased	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	Treatment Arm
	Affected / at Risk (%)	# Events
Total	31/31 (100%)
Gastrointestinal disorders
Oral mucositis	2/31 (6.5%)
GI cramping	1/31 (3.2%)
General disorders
Infusion related reaction	8/31 (25.8%)
Fatigue	2/31 (6.5%)
Infections and infestations
Skin infection	9/31 (29%)
Investigations
Lipase increased	17/31 (54.8%)
Serum amylase increased	8/31 (25.8%)
Blood bilirubin increased	8/31 (25.8%)
Neutrophil count decreased	11/31 (35.5%)
Creatinine increased	3/31 (9.7%)
Platelet count decreased	1/31 (3.2%)
Metabolism and nutrition disorders
Hyperglycemia	31/31 (100%)
Hyperkalemia	1/31 (3.2%)
Hypokalemia	1/31 (3.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/31 (9.7%)
Nervous system disorders
Peripheral Sensory Neuropathy	6/31 (19.4%)

Limitations/Caveats

[Not Specified]

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.