Topoisomerase I Inhibitors Promising as Therapy for CNS Tumors

DURHAM, North Carolina—Topoisomerase-I inhibitors in combination with carmustine (BiCNU, Gliadel) or temozolomide (Temodar) have produced promising early results in patients with malignant gliomas, according to Henry S. Friedman, MD. He is the James B. Powell, Jr., Professor of Neuro-Oncology at Duke University Medical Center in Durham, North Carolina.

Studies of topotecan (Hycamtin), irinotecan (Camptosar), and 9-amino-camptothecin in subcutaneous xenografts of gliomas showed that these agents could retard tumor growth in several cell lines, Dr. Friedman said. Growth delays produced by irinotecan were greater than with other agents. Similar effects were seen in xenografts of medulloblastomas and ependymomas.

Topoisomerase-I inhibitor treatment also produced tumor regressions in subcutaneous xenograft models of gliomas, medulloblastomas, and other central nervous system (CNS) tumors. Subsequent studies in intracranial xenograft models showed that treatment with topoisomerase-I inhibitors could increase median survival, Dr. Friedman said.

Irinotecan Studies

Based in part on these data, irinotecan was tested in a phase II trial in malignant glioma. The trial enrolled 60 patients with recurrent malignant glioma who had measurable disease and no more than one prior chemotherapy regimen. Patients were treated with irinotecan at 125 mg/m² weekly for 4 weeks followed by a 2-week rest. Physical examination and magnetic resonance imaging (MRI) were done after every cycle.

"There were 9 partial responses, 4 minimal responses, and 13 patients with disease stabilization," Dr. Friedman said. Disease progressed in 34 patients.

Toxicity was notably mild, primarily mild diarrhea, minimal neutropenia, and minimal thrombocytopenia.

Irinotecan has also been studied in combination with carmustine in treatment of malignant gliomas. Dr. Friedman said that preclinical studies suggested potential synergy with this combination.

A phase I trial was done to define the maximal tolerated dose (MTD) of irinotecan given in combination with carmustine and to define the activity of the combination in patients with recurrent or progressive malignant glioma. Carmustine was given at 100 mg/m² on week 1. Irinotecan was given on weeks 1, 2, 3, and 4, and doses were escalated after every cohort of 3 patients.

The MTD of irinotecan varied according to whether the patient was taking anticonvulsant drugs or not, according to Dr. Friedman. "The MTD with anticonvulsants was 225 mg/m²/dose. The MTD for patients not taking anticonvulsants was 125 mg/m²/dose," he reported. "This suggests that many patients with CNS tumors who are also taking anticonvulsants are being underdosed on current regimens."

Schedule Dependent

This work was carried forward in an ongoing phase II trial of irinotecan plus carmustine in malignant glioma. The trial was open to patients with newly diagnosed (n=15) or recurrent (n=33) malignant glioma. Patients were treated with carmustine 100 mg/m² on day 1. Irinotecan was given at either 125 mg/m² or 225 mg/m² on days 1, 8, 15, and 22, skipping days 29 and 36.

Dr. Friedman said that irinotecan/carmustine produced partial responses in 3 of 15 patients with newly diagnosed malignant glioma and in 1 patient with recurrent glioma. Stable disease occurred in 4 patients with newly diagnosed gliomas and in 22 of 33 patients with recurrent gliomas. Disease progressed in 8 of the newly diagnosed patients and 10 patients with recurrent gliomas.

The apparent synergy between irinotecan and carmustine appears to be schedule dependent and disappears if irinotecan is delayed.

Tested with Temozolomide

Researchers next combined temozolomide with irinotecan because synergy between these two agents was maintained in preclinical studies independent of schedule. A phase I study is underway in patients with recurrent malignant glioma and no prior failure of temozolomide or irinotecan. The primary study objective is to define the MTD of irinotecan administered in combination with a fixed dose of temozolomide.

"Two strata will be accrued independently of each other to include patients with and without carbamazepine, hydantoin, or phenobarbital," Dr. Friedman said. Irinotecan is administered prior to temozolomide on day 1 of each cycle. Temozolomide is given at 200 mg/m²/d for 5 days every 6 weeks. The irinotecan cycle consists of 4 weekly administrations followed by a 2-week rest, and irinotecan will be dose-escalated in cohorts of 3 patients to levels of 40, 60, 80, 100, and 125 mg/m²/wk.

"Fourteen patients have been treated with irinotecan/temozolomide to date," Dr. Friedman reported. "We have seen 9 patients with stable disease and 5 patients with progressive disease, and dose-limiting toxicities have not yet occurred. We have seen three patients with grade 3 hematologic toxicities."