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

Study Overview
=================
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.

Official Title
-----------------
Glutamic Acid to Decrease Vincristine Toxicity in Children With Cancer

Conditions
-----------------
Kidney Cancer, Leukemia, Lymphoma, Neurotoxicity, Peripheral Neuropathy, Sarcoma

Intervention / Treatment
-----------------
* Drug: glutamic acid
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I Glutamic Acid<br>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<br>* Given orally 3 times daily<br>* Other names: l-glutamic acid hydrochloride;|
| Placebo Comparator: Arm II Placebo<br>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<br>* Given orally 3 times daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 10 weeks | 
| 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 | 10 weeks | 
| 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. | 10 Weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage II childhood large cell lymphoma, stage III childhood large cell lymphoma, stage IV childhood large cell lymphoma, 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 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