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

Children's Oncology Group

Status and phase: Completed; Phase 1

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

Treatments: Drug: vincristine sulfate; Drug: temozolomide; Drug: irinotecan hydrochloride

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00138216

CDR0000440069 (Other Identifier)

ADVL0414

COG-ADVL0414 (Other Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 42 patients

Sex: All

Ages: 1 to 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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42 participants in 1 patient group

Oral Irinotecan, temozolomide and vincristine sulfate

Experimental group

Description:

see detailed description

Treatment:

Drug: irinotecan hydrochloride

Drug: temozolomide

Drug: vincristine sulfate