Rituximab, Cyclophosphamide, Bortezomib, and Dexamethasone in Treating Patients With Relapsed or Refractory Low-Grade Follicular Lymphoma, Waldenstrom Macroglobulinemia, or Mantle Cell Lymphoma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00711828
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 21
• Locations: 2
• Arm: 1
• Actual Duration (Months): 116.1
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving rituximab and cyclophosphamide together with bortezomib and dexamethasone (R-CyBor-D) works in treating patients with relapsed or refractory low-grade follicular lymphoma, Waldenstrom macroglobulinemia, or mantle cell lymphoma. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab and bortezomib together with combination chemotherapy may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Nodal Marginal Zone Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenstrom Macroglobulinemia	Drug: Bortezomib; Biological: Rituximab; Drug: Cyclophosphamide; Drug: Dexamethasone; Other: Questionnaire Administration; Other: Quality-of-Life Assessment	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess tumor response to R-CyBor-D in patients with relapsed follicular (Gr 1 or 2), mantle cell, marginal zone lymphomas, small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) and lymphoplasmacytic (Waldenstrom's macroglobulinemia) lymphoma.

SECONDARY OBJECTIVES:

1. To evaluate overall survival, progression-free survival, duration of response, and time to treatment failure of patients receiving R-CyBor-D.

2. To describe the adverse event profile (using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v 3.0) of R-CyBor-D.

3. To evaluate quality of life for patient reported neurotoxicity using the Gynecologic Oncology Group's Functional Assessment of Cancer Therapy (FACT/GOG) neurotoxicity questionnaire, version 4.0.

OUTLINE:

Patients receive rituximab intravenously (IV) on day 1and cyclophosphamide orally (PO), bortezomib IV, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Clinical Trial of Rituximab, Cyclophosphamide, Bortezomib (VELCADE), and Dexamethasone (R-CYBOR-D) in Relapsed Low Grade and Mantle Cell Lymphoma
• Actual Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Nov 1, 2013
• Actual Study Completion Date: Apr 6, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (R-CYBOR-D) Patients receive rituximab IV on day 1and cyclophosphamide PO, bortezomib IV, and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Given IV; Biological: Rituximab; Given IV; Other Names: MOAB IDEC-C2B8 ; Drug: Cyclophosphamide; Given PO; Drug: Dexamethasone; Given PO; Other Names: DM ; Other: Questionnaire Administration; Complete a quality of life questionnaire (FACT/GOG neurotoxicity questionnaire, version 4.0); Other: Quality-of-Life Assessment; Complete a quality of life questionnaire (FACT/GOG neurotoxicity questionnaire, version 4.0); Other Names: Quality of Life Assessment

Outcome Measures

Primary Outcome Measures

1. Proportion of Responses (Complete Response or Partial Response) [up to 12 cycles]

   A response is defined to be a Complete Response (CR) or Partial Response (PR) noted as the objective status on any evaluation (i.e., best response). The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. A confidence interval for the true success proportion will be calculated according to the properties of the binomial distribution.

Secondary Outcome Measures

1. Overall Survival [Up to 3 years from registration]

   Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.

2. Progression-free Survival [Up to 3 years from registration]

   Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression or death, whichever occurs first. Progression is defines as having any new lesion or increase by 50% of previously involved sites from nadir. The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier.

3. Duration of Response [Up to 3 years from registration]

   Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest objective status is first noted to be either a CR or PR to the earliest date progression is documented. MR for Waldenstrom lymphoma will not be included as a response. Median duration of response and the confidence interval for the median duration will be computed.

4. Time to Treatment Failure [Up to 3 years from registration]

   Time to treatment failure is defined to be the time from registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they are removed from treatment. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier.

5. Adverse Events [up to 12 cycles (28 days per cycle) of treatment]

   Adverse events were assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 after each cycle of treatment. The maximum grade for each type of adverse event were recorded for each patient, and frequency tables were reviewed to determine patterns. For this endpoint, the number of patients receiving a Grade 3, Grade 4, or Grade 5 as their highest reported grade regardless of attribution are reported. A full list of adverse events are reported in the Adverse Events section of this report.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histological confirmation of relapsed or refractory follicular Grades 1 or 2 lymphoma, mantle cell lymphoma (MCL), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL), extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, or lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia/WM) by biopsy ≤ 6 months prior to registration

• NOTE: MCL diagnosis should be confirmed by cyclin D1 staining or fluorescence in situ hybridization (FISH) (t(11;14))

• Measurable disease by computed tomography (CT), positron emission tomography (PET)/CT or magnetic resonance imaging (MRI) scans with lymph nodes ≥2.0 cm in at least one dimension or tumor cells in the blood ≥ 5 x10^9/L

• NOTE: Lymphoplasmacytic lymphoma (WM) patients without lymphadenopathy must have 1.) >10% lymphocytes, lymphoplasmacytic cells or plasma cells on a bone marrow aspirate/biopsy, and 2.) quantitative IgM ≥ 400mg/dL

• Expected survival > 3 months

• ECOG Performance Status (PS) 0, 1 or 2

• Absolute Neutrophil Count ≥ 1200

• Platelet ≥ 75000

• Hemoglobin ≥ 8.0 g/dL

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

• Alkaline phosphatase ≤ 3 x ULN

• Aspartate aminotransferase (AST) ≤ 3 x ULN

• Creatinine ≤ 1.5 x ULN

• Female subject is either postmenopausal for at least 1 year before the screening visit, is surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of VELCADE (bortezomib), or agree to completely abstain from heterosexual intercourse

• Male subjects, even if surgically sterilized (i.e., status postvasectomy) must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual intercourse

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care

• Willingness to return to Mayo Clinic institution for follow-up

• Negative serum pregnancy test done <7 days prior to registration, for women of childbearing potential only

• Willingness to complete questionnaires by themselves or with assistance

Exclusion Criteria:

• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

• Pregnant women -- confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women;

• Nursing women;

• Men or women of childbearing potential who are unwilling to employ adequate contraception

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse event of the prescribed regimen

• Patients known to be human immunodeficiency virus (HIV) positive

• 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

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

• Diagnosed or treated for another malignancy ≤ 3 years prior to registration, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy or low-risk prostate cancer after curative therapy

• NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer

• Patient has received other investigational drugs ≤ 14 days prior to registration

• Patient has hypersensitivity to bortezomib, boron or mannitol

• Myocardial infarction ≤ 6 months prior to registration or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities

• NOTE: Prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the investigator as not medically relevant

• Previous cancer therapy, hormonal therapy and surgery < 4 weeks prior to registration

• Patient has ≥ Grade 2 peripheral neuropathy

• Radiation therapy within 3 weeks before randomization

• Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Craig Reeder, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00711828
• Other Study ID Numbers: MC0883; NCI-2011-02991; MC0883; P30CA015083
• First Posted: Jul 9, 2008
• Last Update Posted: Apr 16, 2019
• Last Verified: Apr 1, 2019

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Waldenstrom Macroglobulinemia; Recurrence; Dexamethasone; Cyclophosphamide; Rituximab; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Treatment
Arm/Group Description	Rituximab 375 mg/m2 IV on day 1> Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15, 22> Bortezomib 1.3 mg/m2 IV on days 1, 8, 15, 22> Dexamethasone 40 mg PO on days 1, 8, 15, 22
Period Title: Overall Study
STARTED	21
COMPLETED	21
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment
Arm/Group Description	Rituximab 375 mg/m2 IV on day 1> Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15, 22> Bortezomib 1.3 mg/m2 IV on days 1, 8, 15, 22> Dexamethasone 40 mg PO on days 1, 8, 15, 22
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	8 38.1%
Male	13 61.9%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Responses (Complete Response or Partial Response)
Description	A response is defined to be a Complete Response (CR) or Partial Response (PR) noted as the objective status on any evaluation (i.e., best response). The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. A confidence interval for the true success proportion will be calculated according to the properties of the binomial distribution.
Time Frame	up to 12 cycles

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Rituximab 375 mg/m2 IV on day 1 > Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15, 22 > Bortezomib 1.3 mg/m2 IV on days 1, 8, 15, 22 > Dexamethasone 40 mg PO on days 1, 8, 15, 22
Measure Participants	21
Complete Response (CR)	19.0 90.5%
Partial Response (PR)	42.9 204.3%

2. Secondary Outcome

Title	Overall Survival
Description	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
Time Frame	Up to 3 years from registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Rituximab 375 mg/m2 IV on day 1 > Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15, 22 > Bortezomib 1.3 mg/m2 IV on days 1, 8, 15, 22 > Dexamethasone 40 mg PO on days 1, 8, 15, 22
Measure Participants	21
Median (95% Confidence Interval) [months]	54.8

3. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival time is defined as the time from registration to the earliest date of documentation of disease progression or death, whichever occurs first. Progression is defines as having any new lesion or increase by 50% of previously involved sites from nadir. The distribution of progression-free survival time will be estimated using the method of Kaplan-Meier.
Time Frame	Up to 3 years from registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Rituximab 375 mg/m2 IV on day 1 > Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15, 22 > Bortezomib 1.3 mg/m2 IV on days 1, 8, 15, 22 > Dexamethasone 40 mg PO on days 1, 8, 15, 22
Measure Participants	21
Median (95% Confidence Interval) [months]	11.6

4. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest objective status is first noted to be either a CR or PR to the earliest date progression is documented. MR for Waldenstrom lymphoma will not be included as a response. Median duration of response and the confidence interval for the median duration will be computed.
Time Frame	Up to 3 years from registration

Outcome Measure Data

Analysis Population Description

Thirteen patients achieved a CR or a PR and are included in this analysis.

Arm/Group Title	Treatment
Arm/Group Description	Rituximab 375 mg/m2 IV on day 1 > Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15, 22 > Bortezomib 1.3 mg/m2 IV on days 1, 8, 15, 22 > Dexamethasone 40 mg PO on days 1, 8, 15, 22
Measure Participants	13
Median (95% Confidence Interval) [months]	25.9

5. Secondary Outcome

Title	Time to Treatment Failure
Description	Time to treatment failure is defined to be the time from registration to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a non-protocol failure, the patient will be censored on the date they are removed from treatment. The distribution of time to treatment failure will be estimated using the method of Kaplan-Meier.
Time Frame	Up to 3 years from registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Rituximab 375 mg/m2 IV on day 1 > Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15, 22 > Bortezomib 1.3 mg/m2 IV on days 1, 8, 15, 22 > Dexamethasone 40 mg PO on days 1, 8, 15, 22
Measure Participants	21
Median (95% Confidence Interval) [months]	6.6

6. Secondary Outcome

Title	Adverse Events
Description	Adverse events were assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 after each cycle of treatment. The maximum grade for each type of adverse event were recorded for each patient, and frequency tables were reviewed to determine patterns. For this endpoint, the number of patients receiving a Grade 3, Grade 4, or Grade 5 as their highest reported grade regardless of attribution are reported. A full list of adverse events are reported in the Adverse Events section of this report.
Time Frame	up to 12 cycles (28 days per cycle) of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Rituximab 375 mg/m2 IV on day 1 > Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15, 22 > Bortezomib 1.3 mg/m2 IV on days 1, 8, 15, 22 > Dexamethasone 40 mg PO on days 1, 8, 15, 22
Measure Participants	21
Grade 3	19 90.5%
Grade 4	8 38.1%
Grade 5	0 0%

Adverse Events

Arm/Group Title	Treatment
Arm/Group Description	Dexamethasone 40 mg PO on days 1, 8, 15, 22
All Cause Mortality
	Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	7/21 (33.3%)
Blood and lymphatic system disorders
Hemoglobin decreased	1/21 (4.8%)	1
Cardiac disorders
Left ventricular failure	1/21 (4.8%)	1
Restrictive cardiomyopathy	1/21 (4.8%)	1
Gastrointestinal disorders
Abdominal pain	1/21 (4.8%)	1
Infections and infestations
Appendicitis	1/21 (4.8%)	1
Encephalomyelitis infection	1/21 (4.8%)	1
Investigations
Leukocyte count decreased	3/21 (14.3%)	4
Platelet count decreased	2/21 (9.5%)	3
Nervous system disorders
Peripheral sensory neuropathy	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	21/21 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	18/21 (85.7%)	105
Cardiac disorders
Cardiac pain	1/21 (4.8%)	1
Gastrointestinal disorders
Abdominal pain	2/21 (9.5%)	2
Constipation	3/21 (14.3%)	3
Diarrhea	8/21 (38.1%)	15
Gastritis	1/21 (4.8%)	5
Nausea	3/21 (14.3%)	3
Vomiting	1/21 (4.8%)	1
General disorders
Fatigue	20/21 (95.2%)	111
Fever	1/21 (4.8%)	1
Immune system disorders
Hypersensitivity	1/21 (4.8%)	1
Infections and infestations
Infectious colitis	1/21 (4.8%)	1
Pneumonia	1/21 (4.8%)	1
Skin infection	2/21 (9.5%)	3
Upper respiratory infection	1/21 (4.8%)	2
Investigations
Leukocyte count decreased	17/21 (81%)	63
Lymphocyte count decreased	1/21 (4.8%)	4
Neutrophil count decreased	12/21 (57.1%)	33
Platelet count decreased	14/21 (66.7%)	66
Metabolism and nutrition disorders
Anorexia	1/21 (4.8%)	1
Blood glucose increased	1/21 (4.8%)	1
Serum potassium increased	1/21 (4.8%)	1
Tumor lysis syndrome	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Arthritis	1/21 (4.8%)	1
Back pain	1/21 (4.8%)	1
Myalgia	1/21 (4.8%)	1
Nervous system disorders
Peripheral motor neuropathy	1/21 (4.8%)	1
Peripheral sensory neuropathy	17/21 (81%)	97
Taste alteration	1/21 (4.8%)	1
Psychiatric disorders
Agitation	2/21 (9.5%)	8
Anxiety	3/21 (14.3%)	4
Depression	1/21 (4.8%)	1
Insomnia	1/21 (4.8%)	9
Renal and urinary disorders
Cystitis	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/21 (14.3%)	3
Pleural effusion	1/21 (4.8%)	1
Vascular disorders
Hypotension	1/21 (4.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.