Clinical trial NCT00138216: Temozolomide, Vincristine, and Irinotecan in Treating Young Patients With Refractory Solid Tumors
Official title: A Phase I Study of Temozolomide, Oral Irinotecan, and Vincristine for Children With Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-08-30
Enrollment: 42
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Determine maximum tolerated dose (MTD) of oral irinotecan
timeFrame: length of study
Secondary outcomes:
measure: To preliminarily define the antitumor activity
timeFrame: Length of study
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
state: Alabama
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University Cancer Institute
state: Oregon
city: Bethlehem
country: United States
facility: Lehigh Valley Hospital - Muhlenberg
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Lars M. Wagner, MD
role: STUDY_CHAIR
affiliation: Children's Hospital Medical Center, Cincinnati
name: John P. Perentesis, MD
role: STUDY_CHAIR
References:
citation: 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.