Kidney Cancer, Leukemia, Lymphoma, Neurotoxicity, Peripheral Neuropathy, Sarcoma
Conditions
Keywords
neurotoxicity, peripheral neuropathy, stage I Wilms tumor, stage II Wilms tumor, stage III Wilms tumor, stage IV Wilms tumor, stage V Wilms tumor, previously untreated childhood rhabdomyosarcoma, childhood grade III lymphomatoid granulomatosis, childhood diffuse large cell lymphoma, childhood immunoblastic large cell lymphoma, stage I childhood large cell lymphoma, stage II childhood large cell lymphoma, stage III childhood large cell lymphoma, stage IV childhood large cell lymphoma, stage I childhood lymphoblastic lymphoma, stage II childhood lymphoblastic lymphoma, stage III childhood lymphoblastic lymphoma, stage IV childhood lymphoblastic lymphoma, childhood Burkitt lymphoma, stage I childhood small noncleaved cell lymphoma, stage II childhood small noncleaved cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage IV childhood small noncleaved cell lymphoma, untreated childhood acute lymphoblastic leukemia
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.
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.
Interventions
DRUGglutamic acid
Given orally 3 times daily
OTHERplacebo
Given orally 3 times daily
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
University of South Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
3 Years to 20 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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). | 127 |
| 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). | 123 |
| Total | 250 |
Baseline characteristics
| Characteristic | Arm I Glutamic Acid | Arm II Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 123 Participants | 117 Participants | 240 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 6 Participants | 10 Participants |
| Age, Continuous | 8.5 years STANDARD_DEVIATION 4.8 | 8.6 years STANDARD_DEVIATION 4.9 | 8.6 years STANDARD_DEVIATION 4.9 |
| Region of Enrollment United States | 127 participants | 123 participants | 250 participants |
| Sex/Gender, Customized Gender- Female | 46 participants | 53 participants | 99 participants |
| Sex/Gender, Customized Gender- Male | 81 participants | 69 participants | 150 participants |
| Sex/Gender, Customized Gender Not Reported | 0 participants | 1 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 127 | 5 / 123 |
| serious Total, serious adverse events | 9 / 127 | 6 / 123 |
Outcome results
Primary
Neurotoxicity as Measured by a Scored Neurologic Examination at Baseline, 5 Weeks, and 10 Weeks (if Applicable)
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.
Time frame: 10 weeks
Population: Patients reporting baseline and post-baseline observation
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Arm I Glutamic Acid | Neurotoxicity as Measured by a Scored Neurologic Examination at Baseline, 5 Weeks, and 10 Weeks (if Applicable) | 26 percentage of participants | 95% Confidence Interval 4.4 |
| Arm II Placebo | Neurotoxicity as Measured by a Scored Neurologic Examination at Baseline, 5 Weeks, and 10 Weeks (if Applicable) | 34 percentage of participants | 95% Confidence Interval 4.5 |
Secondary
Ability to Receive All Scheduled Doses of Vincristine
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
Time frame: 10 weeks
Population: Number in stratum 1 and stratum 2 that completed
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I Glutamic Acid | Ability to Receive All Scheduled Doses of Vincristine | 84 Participants |
| Arm II Placebo | Ability to Receive All Scheduled Doses of Vincristine | 100 Participants |
Secondary
Number of Participants With Neurotoxicity Observed
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
Time frame: 10 weeks
Population: Stratum 2 with a \>= grade 2 neurotoxicity
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I Glutamic Acid | Number of Participants With Neurotoxicity Observed | 21 Participants |
| Arm II Placebo | Number of Participants With Neurotoxicity Observed | 25 Participants |
Secondary
Types of Neurotoxicities
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.
Time frame: 10 Weeks
Population: Participants who returned a post baseline Neurotox Questionnaire
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I Glutamic Acid | Types of Neurotoxicities | Sensory Changes | 11 Participants |
| Arm I Glutamic Acid | Types of Neurotoxicities | Jaw Pain | 4 Participants |
| Arm I Glutamic Acid | Types of Neurotoxicities | Motor Changes | 10 Participants |
| Arm I Glutamic Acid | Types of Neurotoxicities | Laryngeal Nerve Dysfunction | 2 Participants |
| Arm I Glutamic Acid | Types of Neurotoxicities | Constipation | 11 Participants |
| Arm II Placebo | Types of Neurotoxicities | Laryngeal Nerve Dysfunction | 1 Participants |
| Arm II Placebo | Types of Neurotoxicities | Constipation | 14 Participants |
| Arm II Placebo | Types of Neurotoxicities | Sensory Changes | 13 Participants |
| Arm II Placebo | Types of Neurotoxicities | Motor Changes | 13 Participants |
| Arm II Placebo | Types of Neurotoxicities | Jaw Pain | 2 Participants |