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

Primary Purpose

Precancerous Condition

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Rituximab
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Precancerous Condition focused on measuring monoclonal gammopathy of undetermined significance

Eligibility Criteria

21 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Mayo Clinic Scottsdale
  • Mayo Clinic - Jacksonville
  • Mayo Clinic Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Rituximab

Arm 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).

Outcomes

Primary Outcome Measures

Percentage of Subjects With at Least 10 Points Improvement in the Neuropathy Impairment Score (NIS) for Either Side of the Body at 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

Percentage of Subjects Whose Disease Has Stabilized or Responded, for Either Side of the Body, as Measured by NIS at 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.
Percentage of Subjects With at Least 1 Grade Improvement in the Modified Rankin Score at 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.
Percentage of Patients Having Improvement in the Hand Grip Strength Ergometry Value for Either Hand at 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).
Percentage of Subjects Having One or More Stable Hand Grip Strength Ergometry Values for Either Hand at 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).
Percentage of Subjects With > 50% Reduction of Monoclonal Protein Titer at 6 Months
Monoclonal immunoglobulins measured included Immunoglobulin G (IgG), Immunoglobulin A (IgA), and Immunoglobulin M (IgM).

Full Information

First Posted
December 20, 2007
Last Updated
April 3, 2014
Sponsor
Mayo Clinic
Collaborators
Genentech, Inc., Biogen, National Center for Research Resources (NCRR)
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1. Study Identification

Unique Protocol Identification Number
NCT00588822
Brief Title
Rituximab in Treating Patients With Peripheral Neuropathy Caused by Monoclonal Gammopathy of Undetermined Significance
Official Title
A Phase II Trial of Rituximab for Peripheral Neuropathy Associated With Monoclonal Gammopathy of Undetermined Significance (MGUS)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2014
Overall Recruitment Status
Terminated
Why Stopped
Discontinuation due to the high response rate at the 1st stage and slow accrual.
Study Start Date
January 2005 (undefined)
Primary Completion Date
January 2009 (Actual)
Study Completion Date
February 2011 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Mayo Clinic
Collaborators
Genentech, Inc., Biogen, National Center for Research Resources (NCRR)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Precancerous Condition
Keywords
monoclonal gammopathy of undetermined significance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rituximab
Arm Type
Experimental
Arm 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).
Intervention Type
Biological
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
Rituximab will be given as a 375 mg/m^2 intravenous infusion once weekly for four doses (days 1, 8, 15, and 22).
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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
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
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Benn E. Smith, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic Scottsdale
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259-5499
Country
United States
Facility Name
Mayo Clinic - Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Mayo Clinic Cancer Center
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

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

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