Temozolomide, Vincristine, and Irinotecan in Treating Young Patients With Refractory Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as temozolomide, vincristine, and irinotecan, 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 irinotecan when given together with temozolomide and vincristine in treating young patients with refractory solid tumors.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose and recommended phase II dose of irinotecan when administered with temozolomide and vincristine in young patients with refractory solid tumors, including brain tumors. Determine the toxic effects of this regimen in these patients. Compare the toxic effects of this regimen in patients with low- vs high-risk UGT1A1 genotypes. Determine the pharmacokinetics of irinotecan in these patients. Secondary Determine, preliminarily, the antitumor activity of this regimen in these patients. Correlate UGT1A1, UGT1A7, UGT1A9, and BCRP genotypes with the pharmacokinetics and pharmacodynamics of irinotecan and its metabolites in these patients. OUTLINE: This is a multicenter, dose-escalation study of irinotecan. Patients are stratified according to UGT1A1 genotype (high-risk [7/7 or 6/7 genotype AND bilirubin ≥ 0.6 mg/dL] vs low-risk [absence of high-risk criteria]) if a high-risk patient experiences a dose-limiting toxicity (DLT). Patients receive oral temozolomide on days 1-5 and oral irinotecan on days 1-5 and 8-12. Patients also receive vincristine IV over 1 minute on days 1 and 8. Treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience DLT. After completion of study treatment, patients are followed for 1 month and then annually thereafter. PROJECTED ACCRUAL: A total of 3-36 patients will be accrued for this study within 18 months.

Official Title
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A Phase I Study of Temozolomide, Oral Irinotecan, and Vincristine for Children With Refractory Solid Tumors

Conditions
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Brain and Central Nervous System Tumors, Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: irinotecan hydrochloride
* Drug: temozolomide
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed* malignant solid tumor, including brain tumor, at original diagnosis or relapse Refractory disease NOTE: *Histologic confirmation not required for intrinsic brain stem tumors Measurable or evaluable disease No known curative therapy OR therapy proven to prolong survival with an acceptable quality of life exists No known bone marrow metastases PATIENT CHARACTERISTICS: Age 1 to 21 Performance status Lansky 50-100% (for patients ≤ 10 years of age) Karnofsky 50-100% (for patients > 10 years of age) Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,000/mm^3 Platelet count ≥ 100,000/mm^3 (transfusion independent) Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed) Hepatic ALT ≤ 110 U/L (upper limit of normal [ULN] for ALT is 45 U/L) Bilirubin ≤ 1.5 times ULN Albumin ≥ 2 g/dL Renal 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 to 10 years of age) No greater than 1.2 mg/dL (for patients 11 to 15 years of age) No greater than 1.5 mg/dL (for patients > 15 years of age) Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Neurologic deficits in patients with CNS tumors must be stable for ≥ 1 week prior to study entry No uncontrolled infection No documented allergy to cephalosporins or dacarbazine PRIOR CONCURRENT THERAPY: Biologic therapy Recovered from prior immunotherapy At least 3 months since prior stem cell transplantation or rescue without total-body irradiation No evidence of active graft-versus-host disease At least 7 days since prior antineoplastic biologic agents At least 7 days since prior hematopoietic growth factors No concurrent biologic therapy or immunotherapy No concurrent prophylactic filgrastim (G-CSF) during the first course of study treatment Chemotherapy Recovered from prior chemotherapy Prior temozolomide, vincristine, irinotecan, or topotecan allowed No prior coadministration of temozolomide and irinotecan No disease progression during treatment with either irinotecan or temozolomide More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) No other concurrent chemotherapy Endocrine therapy Patients with CNS tumors must be on a stable or decreasing dose of dexamethasone for ≥ 7 days prior to study entry Radiotherapy Recovered from prior radiotherapy At least 6 months since prior total-body irradiation, craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis At least 6 weeks since other prior substantial bone marrow radiotherapy At least 2 weeks since prior local palliative radiotherapy (small port) No concurrent radiotherapy Surgery Not specified Other No other concurrent investigational drugs No other concurrent anticancer therapy No concurrent enzyme-inducing anticonvulsants, including any of the following: Phenobarbital Phenytoin Carbamazepine Oxcarbazepine No concurrent administration of any of the following: Rifampin Voriconazole Itraconazole Ketoconazole Aprepitant Hypericum perforatum (St. John's wort) No concurrent treatment for clostridium difficile infection

Ages Eligible for Study
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Minimum Age: 1 Year
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: Oral Irinotecan, temozolomide and vincristine sulfate<br>see detailed description | Drug: irinotecan hydrochloride<br> <br> Drug: temozolomide<br> <br> Drug: vincristine sulfate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine maximum tolerated dose (MTD) of oral irinotecan | To estimate the maximum tolerated dose (MTD) of oral irinotecan administered on two different schedules together with fixed-dose temozolomide and vincristine in children with refractory solid tumors or brain tumors | length of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To preliminarily define the antitumor activity | To preliminarily define the antitumor activity of this drug combination within the confines of a Phase 1 study. | Length of study | 

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