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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00138216
• Other study ID #: ADVL0414
• Secondary ID: COG-ADVL0414CDR0
• Status: Completed
• Phase: Phase 1
• Start date: October 2005
• Est. completion date: January 2011

Study information

• Verified date: February 2014
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: January 2011
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• irinotecan hydrochloride

• temozolomide

• vincristine sulfate

Locations

Country	Name	City	State
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham	Birmingham	Alabama
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health and Science University Cancer Institute	Portland	Oregon
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Stanford Cancer Center	Stanford	California
United States	SUNY Upstate Medical University Hospital	Syracuse	New York

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

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 Childre — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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