A phase I trial of the CDK 4/6 inhibitor palbociclib in pediatric
patients with progressive brain tumors: a Pediatric Brain Tumor
Consortium study (PBTC-042)
Abstract
Background Disruption of critical cell cycle regulators is a potential
therapeutic target for brain tumors in children and adolescents. The aim
of this study was to determine the maximum tolerated dose (MTD) and
describe toxicities related to palbociclib, a selective cyclin dependent
kinase 4/6 (CDK4/6) inhibitor in pediatric patients with
progressive/refractory brain tumors with intact retinoblastoma protein.
Methods Palbociclib was administered orally starting at 50 mg/m2 daily
for the first 21 days of a 28 day course. Dose escalation was according
to the Rolling-6 statistical design in less heavily (Stratum I) and
heavily pretreated (Stratum II) patients, and MTD was determined
separately for each group. Pharmacokinetic studies were performed during
the first course, and pharmacodynamic studies were conducted to evaluate
relationships between drug levels and toxicities. Pharmacogenetic
analyses were based on pre-treatment samples. Results A total of 21
patients were enrolled on Stratum I and 14 patients on Stratum II. The
MTD for both strata was 75 mg/m2. Palbociclib absorption (mean Tmax
between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and
19.5 h) were assessed. The most common toxicity was myelosuppression.
Higher palbociclib exposure was associated with grade 3/4 neutropenia
and leukopenia. No patients had an objective response to palbociclib
therapy. Conclusions Palbociclib was safely administered to children and
adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by
7 days of rest in both strata. Future studies will be required to
establish its optimal utilization in pediatric patients with brain
tumors.