Temozolomide and O6-benzylguanine in Treating Children With Solid Tumors

NCT ID: NCT00020150

Last Updated: 2015-04-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-06-30

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.

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.

Conditions

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

Study Design

• Primary Study Purpose: TREATMENT

Interventions

O6-benzylguanine

Intervention Type: DRUG

temozolomide

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

Surgery:

• See Disease Characteristics

Other:

• At least 4 weeks since other prior investigational therapy and recovered
• No other concurrent anticancer investigational agents

• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Principal Investigators

Katherine Warren, MD

Role: STUDY_CHAIR

National Cancer Institute (NCI)

Locations

Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support

Bethesda, Maryland, United States

Countries

United States

References

Meany HJ, Warren KE, Fox E, Cole DE, Aikin AA, Balis FM. Pharmacokinetics of temozolomide administered in combination with O6-benzylguanine in children and adolescents with refractory solid tumors. Cancer Chemother Pharmacol. 2009 Dec;65(1):137-42. doi: 10.1007/s00280-009-1015-8. Epub 2009 May 9.

Reference Type: RESULT

PMID: 19430790 (View on PubMed)

Warren KE, Aikin AA, Libucha M, Widemann BC, Fox E, Packer RJ, Balis FM. Phase I study of O6-benzylguanine and temozolomide administered daily for 5 days to pediatric patients with solid tumors. J Clin Oncol. 2005 Oct 20;23(30):7646-53. doi: 10.1200/JCO.2005.02.0024.

Reference Type: RESULT

PMID: 16234526 (View on PubMed)

Other Identifiers

NCI-00-C-0105I

Identifier Type: -

Identifier Source: secondary_id

NCI-237

Identifier Type: -

Identifier Source: secondary_id

CDR0000067880

Identifier Type: -

Identifier Source: org_study_id

NCT00005019

Identifier Type: -

Identifier Source: nct_alias