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

Sponsor

Children's Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00138216

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Duration (Months)

2.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors Unspecified Childhood Solid Tumor, Protocol Specific	Drug: irinotecan hydrochloride Drug: temozolomide Drug: vincristine sulfate	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

42 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2005

Actual Primary Completion Date :

Jun 1, 2009

Actual Study Completion Date :

Jan 1, 2011

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Oral Irinotecan, temozolomide and vincristine sulfate

see detailed description

Drug: irinotecan hydrochloride

Drug: temozolomide

Drug: vincristine sulfate

Outcome Measures

Primary Outcome Measures

Determine maximum tolerated dose (MTD) of oral irinotecan [length of study]
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

Secondary Outcome Measures

To preliminarily define the antitumor activity [Length of study]
To preliminarily define the antitumor activity of this drug combination within the confines of a Phase 1 study.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

Children's Oncology Group
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