A phase 1 and pharmacokinetic clinical trial of paclitaxel for the treatment of refractory leukemia in children: A Children's Oncology Group Study

Background. This report summarizes a phase 1 study conducted by the Children's Cancer Group (CCG) to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and anti-leukemia activity of paclitaxel in children with advanced stage leukemias. Procedure. This study examined two dose escalation schedules of intravenous paclitaxel. Doses ranged from 250 to 500 mg/m² every 21 days in schedule A and 105 to 200 mg/m² weekly x 3 every 28 days in schedule B. Serial plasma samples for pharmacokinetic studies were obtained after the first paclitaxel dose. Results. Sixty-three patients (median 10 years) with refractory or relapsed leukemia (ALL) (n = 39), acute myeloid leukemia (AML) (n = 19), biphenotypic (n = 4), and JCML (n = 1) were enrolled. The DLTs in schedule A were grade 4 hypertension and hyperbilirubinemia with an MTD of 430 mg/m² every 21 days. The DLTs in schedule B were coagulopathy, hyperkalemia, hyperbilirubinemia, elevated SGOT (n = 1, 125 mg/m²), peripheral neuropathy (n = 1, 200 mg/m²), and typhlitis (n = 1, 200 mg/m ²) with an MTD of 182 mg/m² weekly x 3 every 28 days. Among 54 evaluable patients, there was one complete response (CR), three partial responses (PR), and five patients with stable disease (SD). The mean terminal elimination half-life was 9.5 ± 3.4 hr and the mean plasma clearance was 23 ± 11 L/hr/m². Conclusions. Paclitaxel was tolerated at 430 mg/m² every 21 days and at 182 mg/m²/dose weekly x 3 every 28 days in pediatric patients. The objective response rate across all dose levels and schedules was <10%.