David Van Mater1, Sridharan Gururangan2, Oren Becher3, Olivia Campagne4, Sarah Leary5, Joanna J Phillips6, Jie Huang7, Tong Lin7, Tina Young Poussaint8, Stewart Goldman3, Patricia Baxter9, Girish Dhall10, Giles Robinson11, Mariko DeWire-Schottmiller12, Eugene I Hwang13, Clinton F Stewart4, Arzu Onar-Thomas7, Ira J Dunkel14, Maryam Fouladi12. 1. Division of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina. 2. Preston A. Wells Center for Brain Tumor Therapy, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida. 3. Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois. 4. Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee. 5. Division of Pediatrics, Seattle Children's Hospital, Seattle, Washington. 6. Departments of Neurological Surgery and Pathology, University of California San Francisco, San Francisco, California. 7. Department of Biostatistics, St Jude Children's Hospital, Memphis, Tennessee. 8. Department of Radiology, Boston Children's Hospital, Boston, Massachusetts. 9. Department of Pediatrics, Texas Children's Hospital, Houston, Texas. 10. Division of Hematology and Oncology, Children's of Alabama, Birmingham, Alabama. 11. Division of Neuro-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. 12. Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio. 13. Children's National Medical Center, Washington, District of Columbia. 14. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract
BACKGROUND: Disruption of 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. 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. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. 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 seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.
BACKGROUND: Disruption of 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. 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. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. 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 seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.
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