Vinblastine and Carboplatin in Treating Young Patients With Newly Diagnosed or Recurrent Low-Grade Glioma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as vinblastine and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of vinblastine when given together with carboplatin in treating young patients with newly diagnosed or recurrent low-grade glioma.

Detailed Description
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OBJECTIVES: Primary Estimate the maximum tolerated dose and recommended phase II dose of vinblastine when given in combination with carboplatin in pediatric patients with newly diagnosed or recurrent low-grade gliomas. Define and describe the acute and dose-limiting toxicities of this regimen. Describe the toxicities associated with repeated courses of the combination chemotherapy regimen and the number of treatment modifications required over the course of treatment. Secondary Describe the radiographic responses in patients treated with this regimen. Describe changes in diffusion/perfusion imaging during study therapy. OUTLINE: This is a multicenter, dose-escalation study of vinblastine. Patients are stratified according to amount of prior therapy (heavily pretreated vs less heavily pretreated). Patients receive carboplatin IV over 30 minutes on day 1 and vinblastine IV on days 1, 8, 15. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of vinblastine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. After completion of study treatment, patients are followed for 30 days. PROJECTED ACCRUAL: A total of 18 patients will be accrued for this study.

Official Title
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A Phase I Study of Vinblastine in Combination With Carboplatin for Children With Newly Diagnosed and Recurrent Low-Grade Gliomas

Conditions
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Brain and Central Nervous System Tumors, Neurofibromatosis Type 1

Intervention / Treatment
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* Drug: carboplatin
* Drug: vinblastine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed* low-grade glioma, including 1 of the following subtypes: Astrocytoma variants Fibrillary, protoplasmic, or mixed Pilocytic astrocytoma, including pilomyxoid variants Pleomorphic xanthoastrocytoma Infantile desmoplastic astrocytoma Ganglioglioma Oligodendroglial tumors Mixed glioma, including oligoastrocytoma NOTE: *Biopsy not required for patients who have visual pathway tumors involving the optic nerves and/or optic radiations (i.e., not isolated to the hypothalamus/chiasm) Biopsy proven focal low-grade gliomas of the brainstem with measurable disease allowed No diffuse, intrinsic brainstem tumors Residual tumor visible on MRI Patients without NF-1 must meet the following criteria: Progressive disease after surgery/biopsy based on clear radiographic or clinical evidence of progression OR gross residual tumor (> 1.5 cm²) after surgery/biopsy that is felt to be a high risk to the patient for neurologic and/or visual impairment if the tumor progresses Visual pathway tumors that are not isolated to the hypothalamus/chiasm and are not biopsied must be a high risk to the patient for neurologic and/or visual impairment Patients with NF-1 must have evidence of radiographic progression on MRI and/or clinical worsening (e.g., worsening of ophthalmologic exam for visual pathway tumors) Meets 1 of the following criteria: Newly diagnosed disease Recurrent disease No ventriculoperitoneal shunt-related ascites PATIENT CHARACTERISTICS: Karnofsky performance status (PS) 50-100% (for patients > 10 years of age) OR Lansky PS 50-100% (for patients ≤ 10 years of age) Absolute neutrophil count ≥ 1,000/mm³ Platelet count ≥ 100,000/mm³ (transfusion independent) Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed) Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR creatinine based on age, as follows: No greater than 0.8 mg/dL (for patients ≤ 5 years of age) No greater than 1.0 mg/dL (for patients 6-10 years of age) No greater than 1.2 mg/dL (for patients 11-15 years of age) No greater than 1.5 mg/dL (for patients > 15 years of age) Bilirubin ≤ 1.5 times upper limit of normal ALT ≤ 110 U/L Albumin ≥ 2 g/dL No history of allergy to carboplatin No hyponatremia requiring treatment No uncontrolled infection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior therapy except for corticosteroids and surgery (for patients with newly diagnosed disease) Prior chemotherapy and/or radiotherapy in addition to surgery and corticosteroids allowed (for patients with recurrent disease) Prior carboplatin and/or vinblastine allowed if there was no evidence of progressive disease while on therapy and there were no dose reductions due to toxicity (for patients with recurrent disease) At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered (for patients with recurrent disease) At least 7 days since prior hematopoietic growth factors (for patients with recurrent disease) At least 7 days since prior biological agents (for patients with recurrent disease) At least 9 months since prior external beam radiotherapy or gamma knife therapy that included all target lesions (i.e., there is no restriction if a new lesion arises outside the radiation field or a nonirradiated lesion progresses) and recovered (for patients with recurrent disease) No other concurrent investigational drugs No other concurrent anticancer agents No other concurrent chemotherapy, radiotherapy, immunotherapy, or biological therapy No concurrent corticosteroids for antiemesis Concurrent steroids allowed for tumor edema/increased intracranial pressure provided dose of dexamethasone is stable or decreasing for the past 7 days Concurrent physiologic or stress doses of steroids allowed for endocrine deficiencies

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vinblastine sulfate and carboplatin<br>The MTD of vinblastine in combination with a monthly dose of carboplatin will be determined during the first cycle of therapy. Each 4-week cycle will consist of carboplatin once every 4 weeks on day 1. Vinblastine will be given once a week for 3 weeks followed by a one week break. Doses of carboplatin and vinblastine sulfate will be assigned at study enrollment. Patients may receive eleven additional four week cycles, barring tumor progression or unacceptable toxicity. The total duration of therapy will be approximately 48 weeks. | Drug: carboplatin<br> <br> Drug: vinblastine sulfate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and recommended phase II dose of vinblastine in combination with carboplatin |  | length of study | 
| Acute and dose-limiting toxicities |  | length of study | 
| Other toxicities |  | length of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic response |  | length of study | 
| Changes in diffusion/perfusion imaging |  | length of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood low-grade cerebral astrocytoma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, childhood oligodendroglioma, neurofibromatosis type 1, recurrent childhood visual pathway and hypothalamic glioma, untreated childhood visual pathway and hypothalamic glioma