Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer

Sponsor
University of South Florida (Other)
Overall Status
Completed
CT.gov ID
NCT00369564
Collaborator
National Cancer Institute (NCI) (NIH), Children's Oncology Group (Other)
250
Enrollment
6
Locations
2
Arms
66.1
Duration (Months)
41.7
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Glutamic acid may help lessen or prevent nerve damage caused by vincristine. It is not yet known whether glutamic acid is more effective than a placebo in preventing nerve damage in patients receiving vincristine for Wilms' tumor, rhabdomyosarcoma, acute lymphoblastic leukemia, or non-Hodgkin's lymphoma.

PURPOSE: This randomized phase III trial is studying glutamic acid to see how well it works compared to a placebo in reducing nerve damage caused by vincristine in young patients receiving vincristine for Wilms' tumor, rhabdomyosarcoma, acute lymphoblastic leukemia, or non-Hodgkin's lymphoma.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: glutamic acid
  • Other: placebo
Phase 3

Detailed Description

OBJECTIVES:

Primary

  • Compare the effect of glutamic acid vs placebo, in terms of decreasing neurotoxicity as measured by a scored neurologic examination, in young patients undergoing vincristine-containing treatment for Wilms' tumor, rhabdomyosarcoma, acute lymphoblastic leukemia, or non-Hodgkin's lymphoma.

Secondary

  • Compare the frequency and types of neurotoxicity observed in patients treated with glutamic acid versus placebo.

  • Determine if a greater proportion of patients receiving glutamic acid are able to receive 100% of their scheduled doses of vincristine versus those not treated with glutamic acid.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to disease and duration of planned vincristine-containing treatment (Wilms' tumor or rhabdomyosarcoma with treatment planned for ≥ 9 consecutive weeks [stratum 1] vs acute lymphoblastic leukemia or non-Hodgkin's lymphoma with treatment planned for ≥ 4 consecutive weeks [stratum 2]). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive oral glutamic acid 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) for a total of 4 doses of vincristine or week 10 (stratum 1) for a total of 9 doses of vincristine.

  • Arm II: Patients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) for a total of 4 doses of vincristine or week 10 (stratum 1) for a total of 9 doses of vincristine.

All patients undergo neurologic examination at baseline and at 5 weeks. Patients in stratum 1 also undergo additional neurologic examination at week 10.

PROJECTED ACCRUAL: A total of 250 patients will be accrued for this study.

Study Design

Study Type:
Interventional
Actual Enrollment :
250 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Supportive Care
Official Title:
Glutamic Acid to Decrease Vincristine Toxicity in Children With Cancer
Study Start Date :
May 1, 2007
Actual Primary Completion Date :
Nov 1, 2012
Actual Study Completion Date :
Nov 1, 2012

Arms and Interventions

ArmIntervention/Treatment
Experimental: Arm I Glutamic Acid

Patients receive oral glutamic acid 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).

Drug: glutamic acid
Given orally 3 times daily
Other Names:
  • l-glutamic acid hydrochloride
  • Placebo Comparator: Arm II Placebo

    Patients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).

    Other: placebo
    Given orally 3 times daily

    Outcome Measures

    Primary Outcome Measures

    1. Neurotoxicity as Measured by a Scored Neurologic Examination at Baseline, 5 Weeks, and 10 Weeks (if Applicable) [10 weeks]

      A neurological exam will be completed at baseline and at study week 5 for both strata. An additional exam at week 10 will be done for patients in Stratum 1. Additional exams will be done at any time if the treating oncologist deems it clinically necessary . Neurotoxicity will be scored using a standardized neurological exam form developed for the study that is based on the Modified "Balis" Pediatric Scale of Peripheral Neuropathies. Treatment groups will be compared with respect to the proportion experiencing a grade 2 or higher toxicity from the following list of neurologic toxicities captured on the Neurologic Exam Form including sensory neuropathy, motor neuropathy, laryngeal nerve, constipation/neuro-constipation, jaw pain, or other specified abnormalities noted by the attending physician. Percentage of patients with one or more Grade 2 or higher noted neurotoxicity symptoms on any item in the Balis scale will compared between arms.

    Secondary Outcome Measures

    1. Number of Participants With Neurotoxicity Observed [10 weeks]

      Number of participants with neurotoxicity observed treated with l-glutamic acid hydrochloride as compared to the number of participants with neurotoxicity observed in the placebo control group

    2. Ability to Receive All Scheduled Doses of Vincristine [10 weeks]

      We will determine if a greater proportion of patients receiving l-glutamic acid hydrochloride are able to receive 100% of their scheduled doses of vincristine as compared to those in the placebo control group

    3. Types of Neurotoxicities [10 Weeks]

      Types of neurotoxicities reported. Each patient was only counted once for each type of neurotoxicity, but a patient could be counted in more than 1 type of neurotoxicity. For example, if a patient experienced constipation 3 times, they are included once for constipation. If a patient experienced sensory changes and motor changes, they are included once for sensory changes and once for motor changes.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    3 Years to 20 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    INCLUSION CRITERIA:
    • Patients ≥ 3 and < 21 years of age at the time of study registration.

    • Patients newly diagnosed with Wilm's tumor and scheduled to receive at least 9 consecutive weeks of chemotherapy with a vincristine-containing regimen.

    • Patients newly diagnosed with rhabdomyosarcoma and scheduled to receive at least 9 consecutive weeks of chemotherapy with a vincristine-containing regimen.

    • Patients newly diagnosed with ALL and scheduled to receive 4 consecutive weeks of chemotherapy with a vincristine-containing regimen with accompanying steroid therapy.

    • Patients newly diagnosed with Non- Hodgkins Lymphoma (NHL) and scheduled to receive 4 consecutive weeks of chemotherapy with a vincristine-containing regimen with accompanying steroid therapy.

    • Patients with no underlying neuromuscular disease or peripheral neuropathy

    EXCLUSION CRITERIA:
    • Abnormal baseline peripheral neurologic exam (i.e. or peripheral neuropathy)

    • Patients with:

    • seizure disorders

    • primary intracranial malignancy

    • family history of Charcot Marie Tooth Disease

    • a recent history of GuillianBarré26

    • Patients receiving concomitant itraconazole are at risk for increased vincristine toxicity and therefore are ineligible.

    • Patients who are regularly using laxatives or stool softeners for constipation at the time of enrollment are not eligible to participate in the study. Likewise, since prevention of neuro-constipation will be evaluated, patients with an ongoing history of constipation that has required frequent use of laxatives or stool softeners should not be enrolled.

    • Patients should not be scheduled to receive laxatives or stool softeners prophylactically to prevent constipation, as the prevention of neuro-constipation will be evaluated in this study; however, when patients show signs of developing constipation while on chemotherapy, as determined by the treating physician, they may be treated with laxatives or stool softeners at the clinician's discretion. Use of laxatives or stool softeners will be documented on the concomitant medication log.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Lee Cancer Care of Lee Memorial Health SystemFort MyersFloridaUnited States33901
    2Butterworth Hospital at Spectrum HealthGrand RapidsMichiganUnited States49503-2560
    3Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolisMinnesotaUnited States55404
    4Hackensack University Medical Center Cancer CenterHackensackNew JerseyUnited States07601
    5Blumenthal Cancer Center at Carolinas Medical CenterCharlotteNorth CarolinaUnited States28232-2861
    6Nationwide Children's HospitalColumbusOhioUnited States43205-2696

    Sponsors and Collaborators

    • University of South Florida
    • National Cancer Institute (NCI)
    • Children's Oncology Group

    Investigators

    • Study Chair: Scott Bradfield, MD, Nemours Children's Clinic
    • Study Chair: Eric Sandler, MD, Nemours Children's Clinic
    • Study Chair: David R. Freyer, DO, MS, Wake Forest University Health Sciences

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    University of South Florida
    ClinicalTrials.gov Identifier:
    NCT00369564
    Other Study ID Numbers:
    • SCUSF 0402
    • SCUSF 0402
    • ACCL 0731
    • 5U10CA081920-11
    First Posted:
    Aug 29, 2006
    Last Update Posted:
    Aug 11, 2021
    Last Verified:
    Sep 1, 2018

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleArm I Glutamic AcidArm II Placebo
    Arm/Group DescriptionPatients receive oral l-glutamic acid hydrocloride 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1). Patients with a body surface area (BSA) less than 1.0 m^2 will receive a total of 750 mg/day of oral glutamic acid . Patients with a body surface area (BSA) greater or equal to1.0 m^2 will receive a total of 1500 mg/day of oral glutamic acid .Patients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1). Placebo capsules are identical in appearance to the active oral glutamic acid capsules but instead each capsule contains 324 mg of microcrystalline cellulose as a filler, 3 mg of magnesium stearate as a lubricant and 3 mg silicone dioxide as a drying agent for a total fill weight of 330 mg. The manufacturer has certified that the placebo contains no active agent. Patients with a body surface area (BSA) less than 1.0 m^2 will receive a 1 capsule of placebo 3 times daily (total 3 capsules daily). Patients with a body surface area (BSA) greater or equal to1.0 m^2 will receive a 2 placebo capsules 3 times daily (total 6 capsules daily). .
    Period Title: Overall Study
    STARTED127123
    COMPLETED84100
    NOT COMPLETED4323

    Baseline Characteristics

    Arm/Group TitleArm I Glutamic AcidArm II PlaceboTotal
    Arm/Group DescriptionPatients receive oral glutamic acid 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).Patients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).Total of all reporting groups
    Overall Participants127123250
    Age (Count of Participants)
    <=18 years
    123
    96.9%
    117
    95.1%
    240
    96%
    Between 18 and 65 years
    4
    3.1%
    6
    4.9%
    10
    4%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    8.5
    (4.8)
    8.6
    (4.9)
    8.6
    (4.9)
    Sex/Gender, Customized (participants) [Number]
    Gender- Female
    46
    36.2%
    53
    43.1%
    99
    39.6%
    Gender- Male
    81
    63.8%
    69
    56.1%
    150
    60%
    Gender Not Reported
    0
    0%
    1
    0.8%
    1
    0.4%
    Region of Enrollment (participants) [Number]
    United States
    127
    100%
    123
    100%
    250
    100%

    Outcome Measures

    1. Primary Outcome
    TitleNeurotoxicity as Measured by a Scored Neurologic Examination at Baseline, 5 Weeks, and 10 Weeks (if Applicable)
    DescriptionA neurological exam will be completed at baseline and at study week 5 for both strata. An additional exam at week 10 will be done for patients in Stratum 1. Additional exams will be done at any time if the treating oncologist deems it clinically necessary . Neurotoxicity will be scored using a standardized neurological exam form developed for the study that is based on the Modified "Balis" Pediatric Scale of Peripheral Neuropathies. Treatment groups will be compared with respect to the proportion experiencing a grade 2 or higher toxicity from the following list of neurologic toxicities captured on the Neurologic Exam Form including sensory neuropathy, motor neuropathy, laryngeal nerve, constipation/neuro-constipation, jaw pain, or other specified abnormalities noted by the attending physician. Percentage of patients with one or more Grade 2 or higher noted neurotoxicity symptoms on any item in the Balis scale will compared between arms.
    Time Frame10 weeks

    Outcome Measure Data

    Analysis Population Description
    Patients reporting baseline and post-baseline observation
    Arm/Group TitleArm I Glutamic AcidArm II Placebo
    Arm/Group DescriptionPatients receive oral glutamic acid 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).Patients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).
    Measure Participants97107
    Number (95% Confidence Interval) [percentage of participants]
    26
    (4.4) 20.5%
    34
    (4.5) 27.6%
    2. Secondary Outcome
    TitleNumber of Participants With Neurotoxicity Observed
    DescriptionNumber of participants with neurotoxicity observed treated with l-glutamic acid hydrochloride as compared to the number of participants with neurotoxicity observed in the placebo control group
    Time Frame10 weeks

    Outcome Measure Data

    Analysis Population Description
    Stratum 2 with a >= grade 2 neurotoxicity
    Arm/Group TitleArm I Glutamic AcidArm II Placebo
    Arm/Group DescriptionPatients receive oral glutamic acid 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1). glutamic acid: Given orally 3 times dailyPatients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1). placebo: Given orally 3 times daily
    Measure Participants7988
    Count of Participants [Participants]
    21
    16.5%
    25
    20.3%
    3. Secondary Outcome
    TitleAbility to Receive All Scheduled Doses of Vincristine
    DescriptionWe will determine if a greater proportion of patients receiving l-glutamic acid hydrochloride are able to receive 100% of their scheduled doses of vincristine as compared to those in the placebo control group
    Time Frame10 weeks

    Outcome Measure Data

    Analysis Population Description
    Number in stratum 1 and stratum 2 that completed
    Arm/Group TitleArm I Glutamic AcidArm II Placebo
    Arm/Group DescriptionPatients receive oral l-glutamic acid hydrocloride 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1). Patients with a body surface area (BSA) less than 1.0 m^2 will receive a total of 750 mg/day of oral glutamic acid . Patients with a body surface area (BSA) greater or equal to1.0 m^2 will receive a total of 1500 mg/day of oral glutamic acid .Patients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1). Placebo capsules are identical in appearance to the active oral glutamic acid capsules but instead each capsule contains 324 mg of microcrystalline cellulose as a filler, 3 mg of magnesium stearate as a lubricant and 3 mg silicone dioxide as a drying agent for a total fill weight of 330 mg. The manufacturer has certified that the placebo contains no active agent. Patients with a body surface area (BSA) less than 1.0 m^2 will receive a 1 capsule of placebo 3 times daily (total 3 capsules daily). Patients with a body surface area (BSA) greater or equal to1.0 m^2 will receive a 2 placebo capsules 3 times daily (total 6 capsules daily). .
    Measure Participants127123
    Count of Participants [Participants]
    84
    66.1%
    100
    81.3%
    4. Secondary Outcome
    TitleTypes of Neurotoxicities
    DescriptionTypes of neurotoxicities reported. Each patient was only counted once for each type of neurotoxicity, but a patient could be counted in more than 1 type of neurotoxicity. For example, if a patient experienced constipation 3 times, they are included once for constipation. If a patient experienced sensory changes and motor changes, they are included once for sensory changes and once for motor changes.
    Time Frame10 Weeks

    Outcome Measure Data

    Analysis Population Description
    Participants who returned a post baseline Neurotox Questionnaire
    Arm/Group TitleArm I Glutamic AcidArm II Placebo
    Arm/Group DescriptionPatients receive oral glutamic acid 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).Patients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).
    Measure Participants127123
    Constipation
    11
    8.7%
    14
    11.4%
    Sensory Changes
    11
    8.7%
    13
    10.6%
    Motor Changes
    10
    7.9%
    13
    10.6%
    Jaw Pain
    4
    3.1%
    2
    1.6%
    Laryngeal Nerve Dysfunction
    2
    1.6%
    1
    0.8%

    Adverse Events

    Time Frame10 weeks
    Adverse Event Reporting Description Subjects and parents completed daily study medication logs and noted any adverse events or symptoms. Site personnel reviewed study medication logs with subjects to assess for adverse events and completed an in-person neurological exam and chemistry profile at weeks 5 and 10 to assess for adverse events. Adverse events reviewed by independent DSMB.
    Arm/Group TitleArm I Glutamic AcidArm II Placebo
    Arm/Group DescriptionPatients receive oral glutamic acid 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).Patients receive oral placebo 3 times daily beginning prior to the first dose of vincristine and continuing through week 5 (stratum 2) or week 10 (stratum 1).
    All Cause Mortality
    Arm I Glutamic AcidArm II Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total/ (NaN) / (NaN)
    Serious Adverse Events
    Arm I Glutamic AcidArm II Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total9/127 (7.1%) 6/123 (4.9%)
    Cardiac disorders
    Hypertension0/127 (0%) 01/123 (0.8%) 1
    Endocrine disorders
    Adrenal Insufficiency1/127 (0.8%) 10/123 (0%) 0
    General disorders
    Pain0/127 (0%) 01/123 (0.8%) 1
    Tumor lysis syndrome1/127 (0.8%) 11/123 (0.8%) 1
    Hepatobiliary disorders
    Pancreatitis0/127 (0%) 01/123 (0.8%) 1
    Infections and infestations
    Colitis, infectious (e.g., Clostridium difficile)1/127 (0.8%) 10/123 (0%) 0
    Febrile neutropenia1/127 (0.8%) 11/123 (0.8%) 2
    Infection-Other1/127 (0.8%) 10/123 (0%) 0
    Infection with unknown ANC1/127 (0.8%) 20/123 (0%) 0
    Metabolism and nutrition disorders
    Bilirubin (hyperbilirubinemia)1/127 (0.8%) 11/123 (0.8%) 1
    Nervous system disorders
    Cognitive disturbance1/127 (0.8%) 10/123 (0%) 0
    Confusion1/127 (0.8%) 11/123 (0.8%) 1
    Encephalopathy1/127 (0.8%) 11/123 (0.8%) 1
    Leukoencephalopathy (radiographic findings)1/127 (0.8%) 10/123 (0%) 0
    Seizure3/127 (2.4%) 33/123 (2.4%) 3
    Somnolence1/127 (0.8%) 10/123 (0%) 0
    Syncope (fainting)1/127 (0.8%) 10/123 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary/Upper Respiratory - Other1/127 (0.8%) 10/123 (0%) 0
    Vascular disorders
    Vascular - Other0/127 (0%) 01/123 (0.8%) 1
    Other (Not Including Serious) Adverse Events
    Arm I Glutamic AcidArm II Placebo
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total16/127 (12.6%) 5/123 (4.1%)
    Gastrointestinal disorders
    Vomiting9/127 (7.1%) 103/123 (2.4%) 3
    General disorders
    Pain7/127 (5.5%) 73/123 (2.4%) 6

    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.

    Results Point of Contact

    Name/TitleScott Bradfield, MD
    OrganizationNemours Children's Clinic
    Phone904-697-3793
    Emailsbradfie@nemours.org
    Responsible Party:
    University of South Florida
    ClinicalTrials.gov Identifier:
    NCT00369564
    Other Study ID Numbers:
    • SCUSF 0402
    • SCUSF 0402
    • ACCL 0731
    • 5U10CA081920-11
    First Posted:
    Aug 29, 2006
    Last Update Posted:
    Aug 11, 2021
    Last Verified:
    Sep 1, 2018