A phase I study with MAG-camptothecin intravenously administered weekly for 3 weeks in a 4-week cycle in adult patients with solid tumours

摘要

In MAG-camptothecin (MAG-CPT), the topoisomerase inhibitor camptothecin is linked to a water-soluble polymer. Preclinical experiments showed enhanced antitumour efficacy and limited toxicity compared to camptothecin alone. Prior phase I trials guided the regimen used in this study. The objectives were to determine the maximum tolerated dose, dose-limiting toxicities, safety profile, and pharmacokinetics of weekly MAG-CPT. Patients with solid tumours received MAG-CPT intravenously administered weekly for 3 weeks in 4-week cycles. At the starting dose level (80?mg?m?2?week?1), no dose-limiting toxicities occurred during the first cycle (n=3). Subsequently, three patients were enrolled at the second dose level (120?mg?m?2 week?1). Two of three patients at the 80?mg?m?2?week?1 cohort developed haemorrhagic cystitis (grade 1/3 dysuria and grade 2/3 haematuria) during the second and third cycles. Next, the 80?mg?m?2?week?1 cohort was enlarged to a total of six patients. One other patient at this dose level experienced grade 1 haematuria. At 120?mg?m?2?week?1, grade 1 bladder toxicity occurred in two of three patients. Dose escalation was stopped at 120?mg?m?2?week?1. Cumulative bladder toxicity was dose-limiting toxicity at 80?mg?m?2?week?1. Pharmacokinetics revealed highly variable urinary camptothecin excretion, associated with bladder toxicity. Due to cumulative bladder toxicity, weekly MAG-CPT is not a suitable regimen for treatment of patients with solid tumours.