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.


METHODS
This study examined two dose escalation schedules of intravenous paclitaxel. Doses ranged from 250 to 500 mg/m(2) every 21 days in schedule A and 105 to 200 mg/m(2) 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/m(2) every 21 days. The DLTs in schedule B were coagulopathy, hyperkalemia, hyperbilirubinemia, elevated SGOT (n = 1, 125 mg/m(2)), peripheral neuropathy (n = 1, 200 mg/m(2)), and typhlitis (n = 1, 200 mg/m(2)) with an MTD of 182 mg/m(2) 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/m(2).


CONCLUSIONS
Paclitaxel was tolerated at 430 mg/m(2) every 21 days and at 182 mg/m(2)/dose weekly x 3 every 28 days in pediatric patients. The objective response rate across all dose levels and schedules was <10%.
Horton
Terzah M
TM
Texas Children's Cancer Center/Baylor College of Medicine, Houston, Texas, USA. tmhorton@txccc.org
Ames
Matthew M
MM
Reid
Joel M
JM
Krailo
Mark D
MD
Pendergrass
Thomas
T
Mosher
Revonda
R
Reaman
Gregory H
GH
Seibel
Nita L
NL
D000293:Adolescent; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel