Clinical trial NCT00020150: Temozolomide and O6-benzylguanine in Treating Children With Solid Tumors
Official title: Phase I Trial and Pharmacokinetic Study of Temozolomide and O6-Benzylguanine in Childhood Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Keywords: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Katherine Warren, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.