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

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

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.

Study Overview

• Status: Completed
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific; Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: irinotecan hydrochloride; Drug: temozolomide; Drug: vincristine sulfate

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Stanford, California, United States, 94305-5824
      • Stanford Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health and Science University Cancer Institute
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18107
      • Lehigh Valley Hospital - Muhlenberg
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
  • Texas
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 19 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Irinotecan, temozolomide and vincristine sulfate; see detailed description	Drug: irinotecan hydrochloride; Drug: temozolomide; Drug: vincristine sulfate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine maximum tolerated dose (MTD) of oral irinotecan	To estimate the maximum tolerated dose (MTD) of oral irinotecan administered on two different schedules together with fixed-dose temozolomide and vincristine in children with refractory solid tumors or brain tumors	length of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To preliminarily define the antitumor activity	To preliminarily define the antitumor activity of this drug combination within the confines of a Phase 1 study.	Length of study

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Lars M. Wagner, MD, Children's Hospital Medical Center, Cincinnati; Study Chair: John P. Perentesis, MD, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Wagner LM, Perentesis JP, Reid JM, Ames MM, Safgren SL, Nelson MD Jr, Ingle AM, Blaney SM, Adamson PC. Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors: a Children's Oncology Group phase I consortium study. Pediatr Blood Cancer. 2010 Apr;54(4):538-45. doi: 10.1002/pbc.22407.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): June 1, 2009
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: August 29, 2005
• First Submitted That Met QC Criteria: August 29, 2005
• First Posted (Estimated): August 30, 2005

Study Record Updates

• Last Update Posted (Actual): October 2, 2023
• Last Update Submitted That Met QC Criteria: September 28, 2023
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: unspecified childhood solid tumor, protocol specific; childhood high-grade cerebral astrocytoma; childhood infratentorial ependymoma; childhood atypical teratoid/rhabdoid tumor; childhood supratentorial ependymoma; childhood oligodendroglioma; recurrent childhood supratentorial primitive neuroectodermal tumor; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; recurrent childhood ependymoma; recurrent childhood brain tumor; recurrent childhood brain stem glioma; recurrent childhood medulloblastoma; recurrent childhood visual pathway and hypothalamic glioma; childhood craniopharyngioma; childhood central nervous system germ cell tumor; childhood choroid plexus tumor; childhood grade I meningioma; childhood grade II meningioma; childhood grade III meningioma; childhood low-grade cerebral astrocytoma; recurrent childhood subependymal giant cell astrocytoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Temozolomide; Irinotecan; Vincristine
• Other Study ID Numbers: ADVL0414; COG-ADVL0414 (Other Identifier: Children's Oncology Group); CDR0000440069 (Other Identifier: ClinicalTrials.gov)