Temozolomide and O6-benzylguanine in Treating Children With Solid Tumors

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00020150

Collaborator

(none)

Location

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of combining temozolomide and O6-benzylguanine in treating children who have solid tumors that have not responded to previous therapy.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors Childhood Germ Cell Tumor Extragonadal Germ Cell Tumor Kidney Cancer Liver Cancer Neuroblastoma Ovarian Cancer Sarcoma Unspecified Childhood Solid Tumor, Protocol Specific	Drug: O6-benzylguanine Drug: temozolomide	Phase 1

Detailed Description

OBJECTIVES:

Determine the maximum tolerated dose of temozolomide administered with a biologically active dose of O6-benzylguanine (O6-BG) in children with refractory solid tumors.
Determine the dose-limiting toxicity and the toxicity profile of this combination in these patients.
Assess the plasma pharmacokinetics of O6-BG and its active metabolite, 8-oxo-O6-BG, in these patients.
Assess the plasma pharmacokinetics of this combination in these patients.
Correlate levels of alanine-glyoxylate aminotransferase in peripheral blood mononuclear cells with the degree of hematologic toxicity of this combination in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive O6-benzylguanine (O6-BG) IV over 1 hour followed 30 minutes later by oral temozolomide daily for 5 days. Treatment continues every 28 days for up to 12 courses in the absence of unacceptable toxicity or disease progression.

Sequential dose escalation of O6-BG is followed by sequential dose escalation of temozolomide. Cohorts of 3-6 patients receive escalating doses of O6-BG and temozolomide until the maximum tolerated dose (MTD) of each is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 6 patients experience dose-limiting toxicity.

Quality of life is assessed at baseline and prior to courses 1, 3, 6, 8, and 12.

PROJECTED ACCRUAL: A total of 21-48 patients will be accrued for this study within 1-2 years.

Study Design

Study Type:

Interventional

Primary Purpose:

Treatment

Official Title:

Phase I Trial and Pharmacokinetic Study of Temozolomide and O6-Benzylguanine in Childhood Solid Tumors

Study Start Date :

Jun 1, 2000

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed solid tumor refractory to standard therapy and for which no potentially curative therapy exists, including, but not limited to:
Rhabdomyosarcoma and other soft tissue sarcomas
Ewing's family of tumors
Osteosarcoma
Neuroblastoma
Wilms' tumor
Hepatic tumors
Germ cell tumors
Primary brain tumor
Histological confirmation may be waived for brainstem or optic gliomas
Measurable or evaluable disease
Evidence of progressive disease on prior chemotherapy or radiotherapy or persistent disease after prior surgery

PATIENT CHARACTERISTICS:

Age:

21 and under

Performance status:

ECOG 0-2

Life expectancy:

At least 8 weeks

Hematopoietic:

Absolute granulocyte count greater than 1,500/mm^3
Hemoglobin greater than 8 g/dL
Platelet count greater than 100,000/mm^3

Hepatic:

Bilirubin normal
SGPT less than 2 times upper limit of normal
No significant hepatic dysfunction

Renal:

Creatinine normal OR
Creatinine clearance at least 60 mL/min

Cardiovascular:

No significant cardiac dysfunction

Pulmonary:

No significant pulmonary dysfunction

Other:

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Able to swallow capsules
No significant unrelated systemic illness that would preclude study (e.g., serious infections or organ dysfunction)
No prior hypersensitivity to dacarbazine, temozolomide, or polyethylene glycol

PRIOR CONCURRENT THERAPY:

Biologic therapy:

At least 1 week since prior colony-stimulating factors (e.g., filgrastim [G- CSF], sargramostim [GM-CSF], or epoetin alfa)
At least 4 months since prior myeloablative therapy requiring bone marrow or stem cell transplantation
No concurrent anticancer immunotherapy

Chemotherapy:

See Disease Characteristics
At least 3 weeks since prior chemotherapy (4 weeks for nitrosoureas) and recovered
Prior temozolomide allowed provided not administered within past 3 months, no severe toxicities experienced during prior course, and not given in combination with other agents designed to inactivate alanine-glyoxylate aminotransferase
No other concurrent investigational or standard anticancer chemotherapy

Endocrine therapy:

Concurrent corticosteroids for control of brain tumor-associated edema allowed provided on stable or decreasing dose for at least 1 week prior to study

Radiotherapy:

See Disease Characteristics
At least 4 weeks since prior limited-field radiotherapy
At least 4 months since prior craniospinal irradiation, total body irradiation, or radiotherapy to more than half of the pelvis
Recovered from prior radiotherapy
No concurrent anticancer radiotherapy