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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



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Mayo Clinic Cancer Center Rochester, Minnesota  55905
Children's Hospital of Orange County Orange, California  92668
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Children's Memorial Hospital - Chicago Chicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts  02115
SUNY Upstate Medical University Hospital Syracuse, New York  13210
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas Dallas, Texas  75390
Indiana University Melvin and Bren Simon Cancer Center Indianapolis, Indiana  46202-5289
Masonic Cancer Center at University of Minnesota Minneapolis, Minnesota  55455
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center New York, New York  10032
Stanford Cancer Center Stanford, California  94305-5824
Lehigh Valley Hospital - Muhlenberg Bethlehem, Pennsylvania  18017
Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham Birmingham, Alabama  35294
Oregon Health and Science University Cancer Institute Portland, Oregon  97239-3098