Patient case: 82-year-old male with glioma; genetic feature: BRAF

Clinical trial: Temozolomide Plus Irinotecan in Treating Patients With Recurrent Malignant Glioma

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/II trial to study the effectiveness of temozolomide plus irinotecan in treating patients who have recurrent malignant glioma.

Detailed description: OBJECTIVES:
  -  Determine the maximum tolerated dose and dose-limiting toxicity of irinotecan when administered with temozolomide in patients with recurrent malignant glioma.
  -  Determine the safety profile of this regimen in this patient population.
  -  Determine the efficacy of this treatment regimen as measured by 6-month progression-free survival and objective tumor response in these patients.
  -  Characterize the pharmacokinetics of this treatment regimen in these patients.
  -  Determine the antitumor activity of this treatment regimen in these patients.
  OUTLINE: This is a multicenter, dose-escalation study of irinotecan. Patients are stratified according to concurrent enzyme-inducing anti-epileptic drugs (EIAEDs) (e.g., phenytoin, phenobarbital, carbamazepine, or primidone) (yes vs no).
  In phase I of the study, patients receive oral temozolomide on days 1-5 and irinotecan IV over 90 minutes on days 1 and 14. Treatment continues every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
  Patients concurrently on EIAEDs undergo dose escalation of irinotecan. Cohorts of 3 to 6 patients receive escalating doses of irinotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 6 patients experience dose-limiting toxicity.
  In phase II of the study, patients receive the same treatment as in phase I at the MTD.
  Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 1 year, every 6 months until progression, and then every 4 months for survival.
  PROJECTED ACCRUAL: A total of 30 patients will be accrued for phase I within 10 months and 48 patients will be accrued for phase II within 6-8 months.

Eligibility: DISEASE CHARACTERISTICS:
  -  Histologically confirmed supratentorial malignant primary glioma of one of the following subtypes:
  -  Glioblastoma multiforme
  -  Anaplastic astrocytoma
  -  Anaplastic oligodendroglioma
  -  Mixed malignant glioma
  -  Original histology of low-grade glioma allowed if subsequent histological confirmation of malignant glioma
  -  Measurable recurrent or residual primary disease by MRI
  -  Lesions with clearly defined margins
  -  Evidence of tumor recurrence or progression by MRI or CT scan
  -  Confirmation of true progressive disease by PET or thallium scan, magnetic resonance spectroscopy, or surgical documentation after prior interstitial brachytherapy or stereotactic radiosurgery
  -  No more than 3 relapses after prior chemotherapy/cytotoxic therapy (including polifeprosan 20 with carmustine implant) for phase I and no more than 2 relapses for phase II
  PATIENT CHARACTERISTICS:
  Age:
  -  18 and over
  Performance status:
  -  Karnofsky 60-100%
  Life expectancy:
  -  Not specified
  Hematopoietic:
  -  WBC at least 3,000/mm^3
  -  Absolute neutrophil count at least 1,500/mm^3
  -  Platelet count at least 100,000/mm^3
  -  Hemoglobin at least 10 g/dL
  Hepatic:
  -  Bilirubin no greater than 1.5 mg/dL
  -  SGOT no greater than 2 times upper limit of normal
  Renal:
  -  Creatinine no greater than 1.5 mg/dL
  Cardiovascular:
  -  No uncontrolled hypertension, unstable angina, or symptomatic congestive heart failure
  -  No myocardial infarction within the past 6 months
  -  No serious uncontrolled cardiac arrhythmia
  Other:
  -  Not pregnant or nursing
  -  Negative pregnancy test
  -  Fertile patients must use effective contraception
  -  No mental incapacitation
  -  HIV negative
  -  No AIDS-related disease
  -  No significant ongoing alcoholism or substance abuse
  -  No severe nonmalignant systemic disease
  -  No active infection
  -  No other severe disease that would preclude study
  PRIOR CONCURRENT THERAPY:
  Biologic therapy:
  -  At least 1 week since prior interferon or thalidomide and recovered
  -  No concurrent anticancer immunotherapy
  -  No concurrent sargramostim (GM-CSF)
  -  No concurrent prophylactic filgrastim (G-CSF) during first course of study therapy
  Chemotherapy:
  -  See Disease Characteristics
  -  Recovered from prior chemotherapy
  -  At least 2 weeks since prior vincristine
  -  At least 3 weeks since prior procarbazine
  -  At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosourea)
  -  Prior radiosensitizers allowed
  -  No prior temozolomide or irinotecan
  -  No other concurrent anticancer chemotherapy
  Endocrine therapy:
  -  At least 1 week since prior tamoxifen and recovered
  -  No concurrent anticancer hormonal therapy
  -  Phase II:
  -  Non-increasing dose of corticosteroids allowed
  Radiotherapy:
  -  See Disease Characteristics
  -  At least 4 weeks since prior radiotherapy and recovered
  -  No concurrent anticancer radiotherapy
  Surgery:
  -  See Disease Characteristics
  -  At least 1-3 weeks since prior surgical resection and recovered
  Other:
  -  At least 1 week since prior noncytotoxic agents (e.g., isotretinoin) and recovered
  -  Concurrent enzyme-inducing anti-epileptic drugs with or without steroids allowed
  -  No concurrent valproic acid as a single agent
  -  No concurrent medication that would preclude study (e.g., nonsteroidal immunosuppressive agents)
  -  No other concurrent investigational drugs
  -  No concurrent participation in other clinical study

Relevance to patient case: not relevant