Temozolomide and O6-benzylguanine in Treating Children With Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of combining temozolomide and O6-benzylguanine in treating children who have solid tumors that have not responded to previous therapy.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of temozolomide administered with a biologically active dose of O6-benzylguanine (O6-BG) in children with refractory solid tumors. Determine the dose-limiting toxicity and the toxicity profile of this combination in these patients. Assess the plasma pharmacokinetics of O6-BG and its active metabolite, 8-oxo-O6-BG, in these patients. Assess the plasma pharmacokinetics of this combination in these patients. Correlate levels of alanine-glyoxylate aminotransferase in peripheral blood mononuclear cells with the degree of hematologic toxicity of this combination in these patients. OUTLINE: This is a dose-escalation study. Patients receive O6-benzylguanine (O6-BG) IV over 1 hour followed 30 minutes later by oral temozolomide daily for 5 days. Treatment continues every 28 days for up to 12 courses in the absence of unacceptable toxicity or disease progression. Sequential dose escalation of O6-BG is followed by sequential dose escalation of temozolomide. Cohorts of 3-6 patients receive escalating doses of O6-BG and temozolomide until the maximum tolerated dose (MTD) of each is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 6 patients experience dose-limiting toxicity. Quality of life is assessed at baseline and prior to courses 1, 3, 6, 8, and 12. PROJECTED ACCRUAL: A total of 21-48 patients will be accrued for this study within 1-2 years.

Official Title
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Phase I Trial and Pharmacokinetic Study of Temozolomide and O6-Benzylguanine in Childhood Solid Tumors

Conditions
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Brain and Central Nervous System Tumors, Childhood Germ Cell Tumor, Extragonadal Germ Cell Tumor, Kidney Cancer, Liver Cancer, Neuroblastoma, Ovarian Cancer, Sarcoma, Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: O6-benzylguanine
* Drug: temozolomide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed solid tumor refractory to standard therapy and for which no potentially curative therapy exists, including, but not limited to: Rhabdomyosarcoma and other soft tissue sarcomas Ewing's family of tumors Osteosarcoma Neuroblastoma Wilms' tumor Hepatic tumors Germ cell tumors Primary brain tumor Histological confirmation may be waived for brainstem or optic gliomas Measurable or evaluable disease Evidence of progressive disease on prior chemotherapy or radiotherapy or persistent disease after prior surgery PATIENT CHARACTERISTICS: Age: 21 and under Performance status: ECOG 0-2 Life expectancy: At least 8 weeks Hematopoietic: Absolute granulocyte count greater than 1,500/mm^3 Hemoglobin greater than 8 g/dL Platelet count greater than 100,000/mm^3 Hepatic: Bilirubin normal SGPT less than 2 times upper limit of normal No significant hepatic dysfunction Renal: Creatinine normal OR Creatinine clearance at least 60 mL/min Cardiovascular: No significant cardiac dysfunction Pulmonary: No significant pulmonary dysfunction Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Able to swallow capsules No significant unrelated systemic illness that would preclude study (e.g., serious infections or organ dysfunction) No prior hypersensitivity to dacarbazine, temozolomide, or polyethylene glycol PRIOR CONCURRENT THERAPY: Biologic therapy: At least 1 week since prior colony-stimulating factors (e.g., filgrastim [G- CSF], sargramostim [GM-CSF], or epoetin alfa) At least 4 months since prior myeloablative therapy requiring bone marrow or stem cell transplantation No concurrent anticancer immunotherapy Chemotherapy: See Disease Characteristics At least 3 weeks since prior chemotherapy (4 weeks for nitrosoureas) and recovered Prior temozolomide allowed provided not administered within past 3 months, no severe toxicities experienced during prior course, and not given in combination with other agents designed to inactivate alanine-glyoxylate aminotransferase No other concurrent investigational or standard anticancer chemotherapy Endocrine therapy: Concurrent corticosteroids for control of brain tumor-associated edema allowed provided on stable or decreasing dose for at least 1 week prior to study Radiotherapy: See Disease Characteristics At least 4 weeks since prior limited-field radiotherapy At least 4 months since prior craniospinal irradiation, total body irradiation, or radiotherapy to more than half of the pelvis Recovered from prior radiotherapy No concurrent anticancer radiotherapy Surgery: See Disease Characteristics Other: At least 4 weeks since other prior investigational therapy and recovered No other concurrent anticancer investigational agents

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: O6-benzylguanine|nan|
|Drug: temozolomide|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood rhabdomyosarcoma, childhood craniopharyngioma, recurrent childhood brain tumor, recurrent neuroblastoma, recurrent childhood liver cancer, recurrent Wilms tumor and other childhood kidney tumors, childhood central nervous system germ cell tumor, recurrent osteosarcoma, unspecified childhood solid tumor, protocol specific, childhood germ cell tumor, recurrent childhood soft tissue sarcoma, childhood oligodendroglioma, childhood choroid plexus tumor, childhood grade I meningioma, childhood grade II meningioma, childhood grade III meningioma, recurrent childhood cerebellar astrocytoma, recurrent childhood cerebral astrocytoma, recurrent childhood medulloblastoma, recurrent childhood visual pathway and hypothalamic glioma, previously treated childhood rhabdomyosarcoma, recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor, recurrent childhood ependymoma, childhood teratoma, childhood malignant testicular germ cell tumor, childhood extragonadal germ cell tumor, childhood malignant ovarian germ cell tumor, recurrent childhood malignant germ cell tumor