Temozolomide and O6-benzylguanine in Treating Children With Solid Tumors

• ClinicalTrials.gov Identifier: NCT00020150
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Last Update Posted: April 29, 2015
• Sponsor: National Cancer Institute (NCI)
• Information provided by: National Cancer Institute (NCI)

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 (Clinical Trial)
• Primary Purpose: Treatment
• Official Title: Phase I Trial and Pharmacokinetic Study of Temozolomide and O6-Benzylguanine in Childhood Solid Tumors
• Study Start Date: June 2000

Arms and Interventions

Outcome Measures

Eligibility Criteria

• Ages Eligible for Study: up to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Maryland

Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support

Bethesda, Maryland, United States, 20892-1182

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Study Chair: Katherine Warren, MD; National Cancer Institute (NCI)

More Information

Publications of Results:

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.

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.

• ClinicalTrials.gov Identifier: NCT00020150 History of Changes
• Obsolete Identifiers: NCT00005019
• Other Study ID Numbers: CDR0000067880; NCI-00-C-0105I; NCI-237
• First Posted: January 27, 2003
• Last Update Posted: April 29, 2015
• Last Verified: August 2004

Keywords provided by National Cancer Institute (NCI):

recurrent childhood rhabdomyosarcoma; childhood craniopharyngioma; recurrent childhood brain tumor; recurrent neuroblastoma; recurrent childhood liver cancer; recurrent Wilms tumor and other childhood kidney tumors; childhood central nervous system germ cell tumor; recurrent osteosarcoma; unspecified childhood solid tumor, protocol specific; childhood germ cell tumor; recurrent childhood soft tissue sarcoma; childhood oligodendroglioma; childhood choroid plexus tumor; childhood grade I meningioma; childhood grade II meningioma; childhood grade III meningioma; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; recurrent childhood medulloblastoma; recurrent childhood visual pathway and hypothalamic glioma; previously treated childhood rhabdomyosarcoma; recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor; recurrent childhood ependymoma; childhood teratoma; childhood malignant testicular germ cell tumor; childhood extragonadal germ cell tumor; childhood malignant ovarian germ cell tumor; recurrent childhood malignant germ cell tumor

Additional relevant MeSH terms:

Sarcoma; Neuroblastoma; Liver Neoplasms; Neoplasms, Germ Cell and Embryonal; Nervous System Neoplasms; Central Nervous System Neoplasms; Neoplasms; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms by Site; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Nervous System Diseases; Temozolomide; O(6)-benzylguanine; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors