TY - JOUR
T1 - Pharmacokinetics of nilotinib in pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia or acute lymphoblastic leukemia
AU - Hijiya, Nobuko
AU - Michel Zwaan, C.
AU - Rizzari, Carmelo
AU - Foà, Robin
AU - Abbink, Floor
AU - Lancaster, Donna
AU - Landman-Parker, Judith
AU - Millot, Frédéric
AU - Moppett, John
AU - Nelken, Brigitte
AU - Putti, Maria Caterina
AU - Tian, Xianbin
AU - Sinclair, Karen
AU - Santanastasio, Helene
AU - Buchbinder, Aby
AU - Kearns, Pamela
N1 - Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2020/2/15
Y1 - 2020/2/15
N2 - Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Phþ) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. Patients and Methods: Fifteen patients (aged 1–<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n ¼ 11) or Phþ ALL relapsed on or refractory to standard therapy (n ¼ 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients. Results: The area under the concentration–time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70–1.06]. Body surface area–adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04–1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Phþ ALL achieved complete remission. Conclusions: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Phþ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.
AB - Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Phþ) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. Patients and Methods: Fifteen patients (aged 1–<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n ¼ 11) or Phþ ALL relapsed on or refractory to standard therapy (n ¼ 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients. Results: The area under the concentration–time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70–1.06]. Body surface area–adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04–1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Phþ ALL achieved complete remission. Conclusions: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Phþ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.
UR - http://www.scopus.com/inward/record.url?scp=85079406011&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-0090
DO - 10.1158/1078-0432.CCR-19-0090
M3 - Article
C2 - 31676669
AN - SCOPUS:85079406011
SN - 1078-0432
VL - 26
SP - 812
EP - 820
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -