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Retinoblastoma

A Phase Study of Temozolomide, Oral Irinotecan and Vincristine for Children with Refractory Solid Tumors

Date Last Modified: December 6, 2005
Date First Published: December 6, 2005

Basic Study Information

Type of TrialStatus of TrialAge Range (yrs.)Sponsor of TrialProtocol ID
TreatmentActive1 to 21COGADVL0414

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.

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.

Projected Accrual

A total of 3-36 patients will be accrued for this study within 18 months.

Entry Criteria

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

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

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 ≤ 5 times upper limit of normal (ULN) 
  • 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

Who should I contact for more information?

Peggy Kaiser, RN, BSN
Cincinnati Children's Hospital Medical Center
Division of Hematology / Oncology
3333 Burnet Ave.
Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org