EPCT-05. A PHASE I TRIAL OF THE CDK 4/6 INHIBITOR PALBOCICLIB IN PEDIATRIC PATIENTS WITH PROGRESSIVE OR REFRACTORY CNS TUMORS: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY

PBTC-042 was a phase I trial of palbociclib to determine the maximum tolerated dose (MTD) and describe toxicities in children. Palbociclib is an oral, selective cyclin dependent kinase 4/6 inhibitor. METHODS: A rolling-6 design was utilized. Eligible patients were children ≥4 and ≤21 years-old with a progressive/refractory CNS tumor with intact retinoblastoma protein, measurable disease, and ability to swallow capsules. Pharmacokinetic studies were performed during the first course. Here, we report on the heavily pretreated stratum, which included patients who received >4 prior treatment regimens (either chemotherapy or biologic agent), and/or craniospinal irradiation, and/or myeloablative chemotherapy plus stem cell rescue. Palbociclib was initiated at 50 mg/m(2)/day for 21 consecutive days of a 28-day course. This was one dosage level below the MTD for the less heavily pretreated stratum (75 mg/m(2)). RESULTS: Fourteen eligible patients were enrolled (median age 12.8 years; male 79%). Eleven patients (79%) had either ependymoma or medulloblastoma. Four eligible and evaluable patients were enrolled at 50 mg/m(2) with no DLTs. This prompted a dosage increase to 75 mg/m(2). Ten eligible subjects were enrolled and 7 were evaluable for DLT assessment. One of 7 evaluable patients experienced a DLT (grade 3 thrombocytopenia). This established 75 mg/m(2) as the MTD for more heavily pretreated patients. Mean ± SD palbociclib apparent oral clearance was 34.6 ± 18.4 L/h/m2. CONCLUSION: The MTD for palbociclib on a 3 week on/1 week off schedule in children with brain tumors is 75 mg/m(2) and does not appear to be influenced by the degree of prior therapy.