Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results

Abstract

Purpose The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment. Methods Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m2/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m2. A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal. Results There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3–4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 cleareance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule. Conclusions Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.

Phase II NCCTG trial of RT + irinotecan and adjuvant BCNU plus irinotecan for newly diagnosed GBM

“…Plasma samples were assayed by high performance liquid chromatography as previously described [8]. Irinotecan, APC and unconjugated SN-38 concentrations were determined by direct analysis of plasma.…”

Glioblastoma metastases: a literature review and a description of six clinical observations

“…Отмечаются послеоперационные изменения в зоне первичной операции. описаны единичные наблюдения [23,26,33,37,40], в одной работе показаны 2 случая метастазов ГБ [43] и еще в одной -8 случаев [44].…”

UGT1A1 genotype-guided phase I study of irinotecan, oxaliplatin, and capecitabine

“…Plasma samples were assayed for irinotecan, SN-38 and APC using validated, sensitive and specific isocratic high-performance liquid chromatography (HPLC) methods [22]. In brief, the plasma specimen was mixed with the internal standard camptothecin in acidified acetonitrile to precipitate plasma proteins, and incubated for 15 minutes at 40°C to convert the analytes to their respective lactones.…”