Rituximab in Treating Patients With Peripheral Neuropathy Caused by Monoclonal Gammopathy of Undetermined Significance

• Sponsor: Mayo Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00588822
• Collaborator: Genentech, Inc. (Industry), Biogen (Industry), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 21
• Locations: 3
• Arm: 1
• Duration (Months): 73
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study was done to find out if the investigational medication, rituximab, could help relieve the symptoms of peripheral neuropathy (such as numbness [abnormal protein in the blood] and weakness of the lower and upper extremities) in people who have monoclonal gammopathy of undetermined significance and people with a symptomatic or smoldering Waldestrom macroglobulinemia.

Rituximab is an antibody which attacks a particular type of white blood cell (B Cell). By targeting the B-cells which make the abnormal protein which is involved in causing the nerve trouble, it is hoped that damage to nerve fibers will be stopped and improvement will be allowed to proceed.

Condition or Disease	Intervention/Treatment	Phase
Precancerous Condition	Biological: Rituximab	Phase 2

Detailed Description

This was a Phase II single arm trial evaluating the use of Rituximab administered at standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months.

If progression in neuropathy (as indicated by an increase in the Neuropathy Impairment Score (NIS) of greater than or equal to 10 or a modified Rankin Score increase of > 1 grade) the patient was off study. In addition, if the subject elected to pursue other active treatment including but not limited to plasmapheresis, high-dose intravenous immuneglobulin (IVIG), chemotherapeutic agents, or high dose corticosteroids, or if conditions in the exclusion criteria develop subsequent to enrollment, the subject was off study.

If the neuropathy is stable or responding (NIS of < 10 or a modified Rankin Score increase of < 1 grade) the patient would have received Cycle 2 of rituximab followed by a reevaluation at 12 months.

The study had a Simon Optimal two-stage Phase II design (α 5%, β 10%, π0 5%, π1 20%). The minimum clinically important response rate was 20%. The first stage was to include 21 patients and the second stage a total of 41 patients. The treatment would be rejected if there were fewer than 2 responders at the first stage or fewer than 5 responders at the second stage. The treatment would be accepted for further study if there were at least 5 responders out of 41 patients.

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 II Trial of Rituximab for Peripheral Neuropathy Associated With Monoclonal Gammopathy of Undetermined Significance (MGUS)
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Feb 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Rituximab Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).

Biological: Rituximab; Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).; Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Percentage of Subjects With at Least 10 Points Improvement in the Neuropathy Impairment Score (NIS) for Either Side of the Body at 6 Months [baseline, 6 months]

   The Neuropathy Impairment Score [previously called the Neurologic Disability Score (NDS)] is derived from a neurologic examination obtained in a standard way by a specially trained neurologist. Decisions are based on the neurologist's judgment of what is normal considering site, age, sex, weight, height, and physical fitness. The instrument has 35 items, each ranked for left and right sides of the body; weakness is scored 0=normal, 1=25% disability, 2=50% disability, 3=75% disability and 4=100% disability. NIS total score was calculated as the sum of the 35 items, ranging from 0 to 140, with higher score indicating greater disability or impairment. The neurologist measured the NIS score on both sides of the body, but recorded worst score and reported as 1 for each individual subject (i.e., each subject had only 1 reported score.) Improvement was defined as at least 10 points improvement in NIS total score, that is, reduction in the number of points on the scale.

Secondary Outcome Measures

1. Percentage of Subjects Whose Disease Has Stabilized or Responded, for Either Side of the Body, as Measured by NIS at 6 Months [baseline, 6 months]

   The Neuropathy Impairment Score (previously called the Neurologic Disability Score [NDS]) is derived from a neurologic examination obtained in a standard way by a specially trained neurologist. Decisions are based on the neurologist's judgment of what is normal considering site, age, sex, weight, height, and physical fitness. The instrument has 35 items, each ranked for left and right sides of the body; weakness is scored 0=normal, 1=25% disability, 2=50% disability, 3=75% disability and 4=100% disability. NIS total score was calculated as the sum of the 35 items, ranging from 0 to 140, with higher score indicating greater disability or impairment. The NIS score was measured on both sides of the body, the worst score recorded reported as 1 for each individual subject. Stability was defined as change of less than 10 points in the NIS total score. Improvement was defined as at least 10 points improvement in NIS total score, that is, reduction in the number of points on the scale.

2. Percentage of Subjects With at Least 1 Grade Improvement in the Modified Rankin Score at 6 Months [baseline, 6 months]

   The Modified Rankin Scale was used to determine functional disability as follows: 0 = asymptomatic; 1 = symptoms not interfering with manual activities/walking normally; 2 = minor difficulties in manual activities/walking independently without support; 3 = unable to perform some manual activities/walking independently with support; 4 = unable to eat, dress or wash independently/needing assistance to walk; 5 = no useful tasks performed with upper limbs/confined to wheelchair. Therefore, scores could range from 0 to 5, with higher values indicating greater disability.

3. Percentage of Patients Having Improvement in the Hand Grip Strength Ergometry Value for Either Hand at 6 Months [baseline, 6 months]

   Grip strength was measured by a dynamometer in both hands at baseline and every three months until the final study visit. Response criteria was defined as achieving improvement in hand grip strength dynamometry values (>10% better relative to baseline at the 6 month visit on either side).

4. Percentage of Subjects Having One or More Stable Hand Grip Strength Ergometry Values for Either Hand at 6 Months [baseline, 6 months]

   Grip strength was measured by a dynamometer in both hands at baseline and every three months until the final study visit. Response criteria was defined as achieving stable hand grip strength dynamometry values (no more than 10% better or worse relative to baseline at the 6 month visit on either side).

5. Percentage of Subjects With > 50% Reduction of Monoclonal Protein Titer at 6 Months [baseline, 6 months]

   Monoclonal immunoglobulins measured included Immunoglobulin G (IgG), Immunoglobulin A (IgA), and Immunoglobulin M (IgM).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of monoclonal gammopathy of undetermined significance (MGUS), as evidenced by 1 of the following criteria:

• Documented monoclonal protein in the serum (< 3 g/dL) or urine

• Monoclonal serum free light chain, with at least 50% of patients having an immunoglobulin M (IgM) paraprotein (the balance being immunoglobulin G (IgG) or immunoglobulin A (IgA) subtypes)

• Neuropathy Impairment Score (NIS) ≥ 25

• Stable or progressive neuropathy (i.e., not currently improving), as judged by NIS values that have not fallen ≥ 10 (between enrollment and the last documented value), at least 1 month but not greater than 3 months prior to enrollment

• No evidence of amyloidosis or overt lymphoma, overt myeloma, or Waldenström macroglobulinemia with end organ damage

• No evidence of multiple myeloma, Amyloid Light-chain (AL)-amyloidosis

• No evidence of Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, diabetes mellitus, alcohol induced neuropathy, untreated hypothyroidism, vitamin B12 deficiency, Sjögren syndrome, and other causes of neuropathy

PATIENT CHARACTERISTICS:

Inclusion Criteria:

• Not pregnant

• Negative serum pregnancy test

• Fertile patients must use an acceptable method of birth control during treatment and for 6 months after completion of treatment

• One of the following birth control measures must be used: birth control pills, intrauterine device, contraceptive injections (Depo-Provera), barrier methods such diaphragm, condom or contraceptive sponge with spermicide

• Adequate bone marrow function as indicated by sufficient precursors of all three cell lines and cellularity of at least 20% on bone marrow biopsy within 6 months

• Platelets > 100,000/mm^3

• Absolute neutrophil count (ANC) > 1,000/mm^3

• Hemoglobin > 7 g/dL

• Serum creatinine < 3.0 mg/dL

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2 times upper limit of normal

• No history of psychiatric disorder requiring hospitalization, psychiatric consultation, or psychotropic medications within the last year

• Patients with controlled depression are eligible, as defined by the following:

• Stable for at least 6 months

• No increase in psychotropic medications

Exclusion criteria:

• History of HIV infection or seropositivity

• History or serological profile suggesting prior hepatitis B virus (HBV) infection (i.e., HbsAg or anti-HBs with anti-HBc)

• Prior HBV vaccination with isolated anti-HBs antibodies is not an exclusion criterion

• HBV infection or non-vaccination-related HBV seropositivity

• Active infection

• New York Heart Association class III or IV heart disease

• History or baseline ECG tracing demonstrating severe recurrent or severe recent (within 3 months) cardiac dysrhythmia (e.g., ventricular tachycardia, torsades de pointes ("Twisting of the Points," a rapid polymorphic Ventricular Tachycardia), or other serious ventricular dysrhythmias) requiring implanted defibrillator treatment

• Confirmed diagnosis of systemic lupus erythematosus (SLE)

• An isolated low titer positive antinuclear antibody test without clinical evidence of SLE is not an exclusion criterion

• Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix

• Malignancy associated with a paraneoplastic neuropathy

• A history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies

• A history of known severe primary or secondary immunodeficiency (e.g., common variable immunodeficiency)

• Significant other uncontrolled medical illnesses that may interfere with drug delivery or interpretation of results

PRIOR CONCURRENT THERAPY:

• No live vaccine therapy within 30 days of enrollment

• No plasmapheresis within 3 months

• No high-dose intravenous immunoglobulin, chemotherapeutic agents, or high-dose corticosteroids (> 10 mg daily or every other day) within 3 months

• No systemic corticosteroids within 3 months (unless needed for adrenal insufficiency or at a stable dose ≤ 10 mg daily)

• No high-dose (> 250 mg/day) vitamin B6 within the past month

• No prior treatment with thalidomide or neurotoxic drugs (e.g., vinca alkaloids, taxol, or platinum)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259-5499
2	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
3	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• Genentech, Inc.
• Biogen
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Benn E. Smith, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00588822
• Other Study ID Numbers: 1191-04; UL1RR024150
• First Posted: Jan 9, 2008
• Last Update Posted: May 6, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by , ,: monoclonal gammopathy of undetermined significance
• Additional relevant MeSH terms: Precancerous Conditions; Peripheral Nervous System Diseases; Paraproteinemias; Monoclonal Gammopathy of Undetermined Significance; Rituximab

Study Results

Participant Flow

Recruitment Details	Subjects were enroll from January 2005 to June 2008 at the Mayo Clinic in Arizona, Florida, and Minnesota.

Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Period Title: Overall Study
STARTED	21
COMPLETED	13
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Overall Participants	21
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.4 (7.7)
Sex: Female, Male (Count of Participants)
Female	6 28.6%
Male	15 71.4%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Subjects With at Least 10 Points Improvement in the Neuropathy Impairment Score (NIS) for Either Side of the Body at 6 Months
Description	The Neuropathy Impairment Score [previously called the Neurologic Disability Score (NDS)] is derived from a neurologic examination obtained in a standard way by a specially trained neurologist. Decisions are based on the neurologist's judgment of what is normal considering site, age, sex, weight, height, and physical fitness. The instrument has 35 items, each ranked for left and right sides of the body; weakness is scored 0=normal, 1=25% disability, 2=50% disability, 3=75% disability and 4=100% disability. NIS total score was calculated as the sum of the 35 items, ranging from 0 to 140, with higher score indicating greater disability or impairment. The neurologist measured the NIS score on both sides of the body, but recorded worst score and reported as 1 for each individual subject (i.e., each subject had only 1 reported score.) Improvement was defined as at least 10 points improvement in NIS total score, that is, reduction in the number of points on the scale.
Time Frame	baseline, 6 months

Outcome Measure Data

Analysis Population Description

A dichotomous measure was used so that subjects who discontinued participation prematurely could be included as non-responders.

Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Measure Participants	21
Number (95% Confidence Interval) [percentage of subjects]	62

2. Secondary Outcome

Title	Percentage of Subjects Whose Disease Has Stabilized or Responded, for Either Side of the Body, as Measured by NIS at 6 Months
Description	The Neuropathy Impairment Score (previously called the Neurologic Disability Score [NDS]) is derived from a neurologic examination obtained in a standard way by a specially trained neurologist. Decisions are based on the neurologist's judgment of what is normal considering site, age, sex, weight, height, and physical fitness. The instrument has 35 items, each ranked for left and right sides of the body; weakness is scored 0=normal, 1=25% disability, 2=50% disability, 3=75% disability and 4=100% disability. NIS total score was calculated as the sum of the 35 items, ranging from 0 to 140, with higher score indicating greater disability or impairment. The NIS score was measured on both sides of the body, the worst score recorded reported as 1 for each individual subject. Stability was defined as change of less than 10 points in the NIS total score. Improvement was defined as at least 10 points improvement in NIS total score, that is, reduction in the number of points on the scale.
Time Frame	baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Measure Participants	21
Number (95% Confidence Interval) [percentage of subjects]	86

3. Secondary Outcome

Title	Percentage of Subjects With at Least 1 Grade Improvement in the Modified Rankin Score at 6 Months
Description	The Modified Rankin Scale was used to determine functional disability as follows: 0 = asymptomatic; 1 = symptoms not interfering with manual activities/walking normally; 2 = minor difficulties in manual activities/walking independently without support; 3 = unable to perform some manual activities/walking independently with support; 4 = unable to eat, dress or wash independently/needing assistance to walk; 5 = no useful tasks performed with upper limbs/confined to wheelchair. Therefore, scores could range from 0 to 5, with higher values indicating greater disability.
Time Frame	baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Measure Participants	21
Number (95% Confidence Interval) [percentage of subjects]	19

4. Secondary Outcome

Title	Percentage of Patients Having Improvement in the Hand Grip Strength Ergometry Value for Either Hand at 6 Months
Description	Grip strength was measured by a dynamometer in both hands at baseline and every three months until the final study visit. Response criteria was defined as achieving improvement in hand grip strength dynamometry values (>10% better relative to baseline at the 6 month visit on either side).
Time Frame	baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Measure Participants	21
Number (95% Confidence Interval) [percentage of subjects]	52

5. Secondary Outcome

Title	Percentage of Subjects Having One or More Stable Hand Grip Strength Ergometry Values for Either Hand at 6 Months
Description	Grip strength was measured by a dynamometer in both hands at baseline and every three months until the final study visit. Response criteria was defined as achieving stable hand grip strength dynamometry values (no more than 10% better or worse relative to baseline at the 6 month visit on either side).
Time Frame	baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Measure Participants	21
Number (95% Confidence Interval) [percentage of subjects]	76

6. Secondary Outcome

Title	Percentage of Subjects With > 50% Reduction of Monoclonal Protein Titer at 6 Months
Description	Monoclonal immunoglobulins measured included Immunoglobulin G (IgG), Immunoglobulin A (IgA), and Immunoglobulin M (IgM).
Time Frame	baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Measure Participants	21
IgG Responder	0
IgA Responder	0
IgM Responder	5

Adverse Events

Time Frame	Subjects were monitored for adverse events weekly per cycle ( Day 1, 8, 15, and 22); each subject could receive up to 2 cycles (4 infusions each.) Adverse event monitoring continued for at least 12 months following the subject's last Rituximab infusion.
Arm/Group Title	Rituximab
Arm/Group Description	Subjects will receive rituximab administered at the standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months. If the neuropathy is stable or responding at 6 months, the subject will receive Cycle 2 of rituximab, followed by a re-evaluation at 12 months. Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
All Cause Mortality
	Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)
Cardiac disorders
Myocardial infarction	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	0/21 (0%)

Limitations/Caveats

The study was discontinued at the first stage to the high response rate and slow accrual.

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.