Patient case: 78-year-old female with sarcoma; genetic feature: MDM2

Clinical trial: Temozolomide and O6-benzylguanine in Treating Children With Solid Tumors

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: 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

Relevance to patient case: not relevant