Gimatecan in Treating Patients With Recurrent or Progressive Primary Malignant Glioma

Oral ST1481 in Adults With Malignant Glioma: A Phase I-II Clinical Trial

RATIONALE: Drugs used in chemotherapy, such as gimatecan, work in different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: This phase I/II trial is studying the side effects and best dose of gimatecan in treating patients with recurrent or progressive primary malignant glioma.

OBJECTIVES:

Primary

• Determine the maximum tolerated dose (MTD) of gimatecan in patients with recurrent or progressive primary malignant glioma treated with or without concurrent enzyme-inducing anticonvulsant drugs.
• Determine whether this drug has sufficient activity to warrant further development in these patients. (phase II)

Secondary

• Determine the qualitative and quantitative toxic effects of this drug in these patients.
• Determine the pharmacokinetic behaviors of this drug in these patients.
• Correlate the principal toxic effects with the pertinent pharmacokinetic parameters of this drug in these patients.
• Determine the antitumor activity of this drug in these patients.

OUTLINE: This is an open-label, dose-escalation, multicenter study. Patients are stratified according to the concurrent use of enzyme-inducing anticonvulsant drugs (yes vs no).

• Phase I: Patients receive oral gimatecan once daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of gimatecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive gimatecan as in phase I at the MTD. Patients are followed for at least 1 month and then every 2 months thereafter.

PROJECTED ACCRUAL: Approximately 30-83 patients (30-42 for phase I [15-21 per stratum] and 21-41 for phase II) will be accrued for this study within 24 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, or anaplastic oligodendroglioma)

  • Recurrent or progressive primary CNS neoplasm by contrast-enhanced MRI

• Tumor progression after prior surgery, radiotherapy, or chemotherapy

• Measurable or evaluable disease

• Failed prior standard curative or palliative therapy (phase I only)

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Karnofsky 60-100%

Life expectancy

• At least 3 months

Hematopoietic

• Absolute neutrophil count ≥ 2,000/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• SGPT and SGOT ≤ 1.5 times upper limit of normal (ULN) (3 times ULN if liver metastases are present)
• Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN if liver metastases are present)
• Bilirubin normal

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No myocardial infarction with the past year
• No heart failure (including cardiac insufficiency controlled by digitalis and diuretics)
• No irreversible arrhythmias requiring permanent medication
• No uncontrolled hypertension

Gastrointestinal

• No gastrointestinal dysfunction that would alter absorption or motility, such as any of the following:

  • Active peptic ulcer
  • Inflammatory bowel disease
  • Known intolerance to lactose
  • Malabsorption syndromes
  • Intestinal sub-occlusion

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception
• No active infection
• No mentally incapacitated patients
• No other concurrent severe disease that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent immunotherapy

Chemotherapy

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas)
• No more than 1 prior chemotherapy regimen
• No other concurrent chemotherapy

Endocrine therapy

• Concurrent corticosteroids allowed if dose stable for the past 2 weeks
• No concurrent hormonal therapy

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy
• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• At least 3 weeks since prior surgical resection
• No prior gastrointestinal surgery that would affect drug absorption

Other

• More than 4 weeks since prior participation in any other investigational drug study

• More than 72 hours since prior systemic antibiotics

• No concurrent H2 antagonists, antacids, or proton pump inhibitors

  • If any of these therapies are necessary, ≥ 3 hours must elapse after gimatecan administration

• No other concurrent anticancer therapy

• No other concurrent investigational drugs

• No other concurrent immunosuppressive agents