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

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.

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