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

Phase 1
1 Year
21 Years
Not Enrolling
Brain and Central Nervous System Tumors, Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

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



- 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

- Determine the pharmacokinetics of irinotecan in these patients.


- 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

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

Inclusion Criteria


- 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



- 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


- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3 (transfusion independent)

- Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed)


- ALT ≤ 110 U/L (upper limit of normal [ULN] for ALT is 45 U/L)

- Bilirubin ≤ 1.5 times ULN

- Albumin ≥ 2 g/dL


- 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)


- 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


Biologic therapy

- Recovered from prior immunotherapy

- At least 3 months since prior stem cell transplantation or rescue without total-body

- 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


- 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

- 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


- 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


- Not specified


- 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

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

Lars M. Wagner, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Hospital Medical Center, Cincinnati


United States: Federal Government

Study ID:




Start Date:

October 2005

Completion Date:

Related Keywords:

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



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Mayo Clinic Cancer CenterRochester, Minnesota  55905
Children's Hospital of Orange CountyOrange, California  92668
Children's Hospital and Regional Medical Center - SeattleSeattle, Washington  98105
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390
Indiana University Melvin and Bren Simon Cancer CenterIndianapolis, Indiana  46202-5289
Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455
Herbert Irving Comprehensive Cancer Center at Columbia University Medical CenterNew York, New York  10032
Stanford Cancer CenterStanford, California  94305-5824
Lehigh Valley Hospital - MuhlenbergBethlehem, Pennsylvania  18017
Lurleen Wallace Comprehensive Cancer at University of Alabama - BirminghamBirmingham, Alabama  35294
Oregon Health and Science University Cancer InstitutePortland, Oregon  97239-3098