Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Temozolomide and O6-benzylguanine in Treating Children With Solid Tumors

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	21 and under	NCI	NCI-00-C-0105I NCI-237, 237, NCT00020150

Objectives

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

Entry 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

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

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/mm³
• Hemoglobin greater than 8 g/dL
• Platelet count greater than 100,000/mm³

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

Expected Enrollment

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

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.

Warren KE, Aikin AA, Libucha M, et al.: Phase I study of O6-benzylguanine and temozolomide administered daily for 5 days to pediatric patients with solid tumors. J Clin Oncol 23 (30): 7646-53, 2005.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Katherine Warren, MD, Protocol chair		Ph: 301-435-4683

Registry Information
Official Title		Phase I Trial and Pharmacokinetic Study of Temozolomide and O6-Benzylguanine in Childhood Solid Tumors
Trial Start Date		2000-06-14
Registered in ClinicalTrials.gov		NCT00020150
Date Submitted to PDQ		2000-04-20
Information Last Verified		2004-08-16