Irinotecan and Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases From Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Irinotecan may make tumor cells more sensitive to radiation therapy. Giving irinotecan together with whole-brain radiation therapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of irinotecan when given together with whole-brain radiation therapy and to see how well they work in treating patients with brain metastases from solid tumors. (The study of side effects and best dose has ended as of 4/15/05)

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of irinotecan hydrochloride administered concurrently with whole-brain radiotherapy in patients with brain metastases from solid tumors. (Phase I) (Phase I closed to accrual as of 4/15/05) Determine the toxicity of this regimen in these patients. (Phase I) (Phase I closed to accrual as of 4/15/05) Determine the overall survival of patients treated with this regimen. (Phase II) Secondary Assess the neurocognitive function of these patients by Mini-Mental Status Examination. (Phase II) OUTLINE: This is a phase I, dose-escalation study of irinotecan hydrochloride (phase I closed to accrual as of 4/15/05) followed by a phase II study. Patients enrolled in phase II are stratified according to cognitive dysfunction (yes vs no). Phase I (closed to accrual as of 4/15/05): Patients undergo whole-brain radiotherapy (WBRT) once daily, 5 days a week, for 3 weeks (15 fractions). Patients also receive irinotecan hydrochloride IV over 90 minutes on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating doses of irinotecan hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II (for patients enrolled after 4/15/05): Patients receive irinotecan hydrochloride at the MTD and undergo concurrent WBRT as in phase I. Patients complete the Mini-Mental Status Examination to assess neurocognitive function at baseline, on the last day of radiotherapy, and periodically after completion of study therapy. After completion of study therapy, patients are followed monthly for 3 months, at 6 months, and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 51 patients will be accrued for this study.

Official Title
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Phase I/II Study of Irinotecan and Whole Brain Radiation Therapy in Patients With Brain Metastases From Solid Tumors

Conditions
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Brain and Central Nervous System Tumors, Cognitive/Functional Effects, Long-term Effects Secondary to Cancer Therapy in Adults, Long-term Effects Secondary to Cancer Therapy in Children, Poor Performance Status, Unspecified Adult Solid Tumor, Protocol Specific, Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: irinotecan hydrochloride
* Procedure: cognitive assessment
* Procedure: management of therapy complications
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of brain metastasis from a histologically confirmed solid tumor, meeting the following criteria: Must have histologic proof of original malignancy No germ cell tumor metastasis Biopsy-proven brain metastasis preferred when clinical history and radiographic findings are equivocal At least 1 unidimensionally measurable lesion ≥ 50 mm by head contrast CT scan and/or brain MRI Patients enrolled in the phase II portion of the study must meet the following Radiation Therapy Oncology Group Recursive Partitioning Analysis staging criteria for brain metastases: Class II classification Zubrod performance status 0-1 AND any of the following: Age > 65 years Extracranial metastasis Uncontrolled primary malignancy PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Life expectancy ≥ 3 months Able to participate in the Mini-Mental Status Examination WBC ≥ 3,000/mm³ Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Bilirubin ≤ 1.5 mg/dL AST ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases are present) Hemoglobin ≥ 9.0 g/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No concurrent medical disease that, in the investigator's opinion, would preclude study participation PRIOR CONCURRENT THERAPY: More than 21 days since prior chemotherapy No prior whole-brain radiotherapy No prior DNA topoisomerase I drugs (e.g., irinotecan hydrochloride, topotecan hydrochloride) At least 4 days since prior and no concurrent known CYP3A4 inducers, including any of the following: Phenytoin Carbamazepine Phenobarbital Hypericum perforatum (St. John's wort)

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 120 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: irinotecan hydrochloride|nan|
|Procedure: cognitive assessment|nan|
|Procedure: management of therapy complications|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and toxicity as assessed by NCI CTC v2.0 (Phase I) (Phase I closed to accrual as of 4/15/05) |  |  | 
| Overall survival (Phase II) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurocognitive deterioration as assessed by Mini-Mental Status Examination (Phase II) |  |  | 
| Time to cognitive failure as assessed by Kaplan-Meier (Phase II) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitive/functional effects, poor performance status, long-term effects secondary to cancer therapy in adults, long-term effects secondary to cancer therapy in children, adult tumors metastatic to brain, unspecified adult solid tumor, protocol specific, unspecified childhood solid tumor, protocol specific