VNP40101M in Treating Young Patients With Recurrent, Progressive, or Refractory Primary Brain Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as VNP40101M, work in different ways to stop tumor cells from dividing so they stop growing or die. PURPOSE: This phase I trial is studying the side effects and best dose of VNP40101M in treating young patients with recurrent, progressive, or refractory primary brain tumors.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose and dose-limiting toxicity of VNP40101M in pediatric patients with recurrent, progressive, or refractory primary brain tumors. Secondary Determine the pharmacokinetics of this drug and its active metabolite VNP4090CE in these patients. Determine the efficacy of this drug in these patients. OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to receiving ≥ 1 of the following prior therapies: craniospinal irradiation (yes vs no), autologous bone marrow transplant (yes vs no), and > 2 myelosuppressive chemotherapy or myelosuppressive biologic therapy regimens (yes vs no). Patients receive VNP40101M IV over 30 minutes on days 1-5. Treatment repeats every 42 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 2-6 patients per stratum receive escalating doses of VNP40101M until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 25% of patients experience dose-limiting toxicity. A total of 12 patients are treated at the MTD. Patients are followed for 3 months. PROJECTED ACCRUAL: A total of 4-60 patients (2-30 per stratum) will be accrued for this study within 18 months.

Official Title
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Phase I Study Of Cloretazine (VNP40101M) In Children With Recurrent, Progressive Or Refractory Primary Brain Tumors

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Drug: laromustine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed* primary brain tumor, including benign brain tumors (e.g., low-grade glioma) Recurrent or progressive disease OR refractory to standard therapy NOTE: *Patients with intrinsic brain stem or diffuse optic pathway tumors do not require histological confirmation, but must have clinical and/or radiographic evidence of disease progression No bone marrow disease PATIENT CHARACTERISTICS: Age 21 and under Performance status Karnofsky 50-100% (for patients > 16 years of age) OR Lansky 50-100% (for patients ≤ 16 years of age) Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,000/mm^3* Platelet count ≥ 100,000/mm^3* Hemoglobin ≥ 8 g/dL* NOTE: *Unsupported Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) ALT and AST ≤ 2.5 times ULN No overt hepatic disease Renal BUN < 25 mg/dL Creatinine ≤ 1.5 times ULN for age OR Glomerular filtration rate > 70 mL/min No overt renal disease Cardiovascular Shortening fraction ≥ 30% by echocardiogram OR Ejection fraction ≥ 50% by gated radionucleotide study No clinically significant cardiac arrhythmia by EKG No overt cardiac disease Pulmonary DLCO ≥ 60% of predicted Chest X-ray normal (defined as absence of pulmonary infiltrates, pneumonitis, pleural effusion, pulmonary hemorrhage, or fibrosis) AND a resting pulse oximetry reading of > 94% in room air (for patients who cannot perform the DLCO) No overt pulmonary disease Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Neurologic deficits allowed provided there has been no deficit progression for ≥ 1 week before study entry No uncontrolled infection No known hypersensitivity to polyethylene glycol PRIOR CONCURRENT THERAPY: Biologic therapy At least 6 months since prior allogeneic bone marrow or stem cell transplantation At least 3 months since prior autologous bone marrow or stem cell transplantation More than 1 week since prior colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or epoetin alfa) At least 3 weeks since prior myelosuppressive anticancer biologic therapy No concurrent routine colony-stimulating factors Chemotherapy At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered Endocrine therapy Concurrent corticosteroids allowed provided dose is stable or decreasing for ≥ 1 week before study entry Radiotherapy At least 3 months since prior craniospinal irradiation ≥ 18 Gy At least 2 weeks since prior focal irradiation to the primary tumor and/or symptomatic metastatic sites Surgery Not specified Other At least 7 days since prior nonmyelosuppressive anticancer therapy At least 7 days since prior investigational agents Concurrent enzyme-inducing anticonvulsant drugs allowed No other concurrent anticancer or experimental agents or therapies

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

| Intervention/Treatment |
| --- |
|Drug: laromustine|This is a dose escalation study. Participants receive 20, 30, 45, 60, 78, 103, 137, 182, or 242 mg/m2/day intravenously over 30 minutes for 5 consecutive days every 6 weeks up to 48 weeks.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate the maximum tolerated dose |  | First 6 weeks of therapy | 
| Number of participants with dose limiting toxicities |  | First 6 weeks of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics | Plasma samples for pharmacokinetic studies will be collected with the first dose of the study drug pre-infusion, and 5, 15, and 30 minutes, 1 hour, 2 hours, and 4 hours after the end of infusion. VNP40101M plasma concentration-time data will be modeled and the individual pharmacokinetic pararmeters volume of the central compartment, elimination rate constant, and half-life will be estimated. | Day 1 of therapy | 
| Tumor response to VNP40101M | MRI of the brain will be obtained prior to couses 3, 5, and 7 and at the end of therapy | Prior to course 3, 5, and 7 and end of therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood brain stem glioma, recurrent childhood visual pathway and hypothalamic glioma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood ependymoma, recurrent childhood medulloblastoma, recurrent childhood supratentorial primitive neuroectodermal tumor, childhood central nervous system germ cell tumor, childhood choroid plexus tumor, childhood craniopharyngioma, childhood infratentorial ependymoma, childhood grade I meningioma, childhood grade II meningioma, childhood grade III meningioma, childhood high-grade cerebral astrocytoma, childhood low-grade cerebral astrocytoma