@article{a649a1beba8a4971ba2e6a3bdfaa08a1,
title = "A phase I trial of the CDK 4/6 inhibitor palbociclibin pediatric patients with progressive brain tumors: A Pediatric Brain Tumor Consortium study (PBTC-042)",
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.",
keywords = "PBTC-042, brain tumor, palbociclib, pharmacodynamics, pharmacokinetics",
author = "{Van Mater}, David and Sridharan Gururangan and Oren Becher and Olivia Campagne and Sarah Leary and Phillips, {Joanna J.} and Jie Huang and Tong Lin and Poussaint, {Tina Young} and Stewart Goldman and Patricia Baxter and Girish Dhall and Giles Robinson and Mariko DeWire-Schottmiller and Hwang, {Eugene I.} and Stewart, {Clinton F.} and Arzu Onar-Thomas and Dunkel, {Ira J.} and Maryam Fouladi",
note = "Funding Information: The trial was partially funded by a National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) PBTC U01 Grant: 2UM1CA081457 (UM1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Partial funding was also provided by MSKCC Core Grant (P30 CA008748) and by the American Lebanese Syrian Associated Charities (ALSAC), which provides funding and infrastructure support for the PBTC Operations Core personnel. Pfizer provided palbociclib and financial support for trial conduct, patient research costs, operations costs, and correlative studies. Pfizer reviewed the manuscript but did not have a direct role in trial design, patient recruitment, data collection, analyses, or manuscript preparation. Funding Information: The trial was partially funded by a National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) PBTC U01 Grant: 2UM1CA081457 (UM1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Partial funding was also provided by MSKCC Core Grant (P30 CA008748) and by the American Lebanese Syrian Associated Charities (ALSAC), which provides funding and infrastructure support for the PBTC Operations Core personnel. Pfizer provided palbociclib and financial support for trial conduct, patient research costs, operations costs, and correlative studies. Pfizer reviewed the manuscript but did not have a direct role in trial design, patient recruitment, data collection, analyses, or manuscript preparation. Publisher Copyright: {\textcopyright} 2021 Wiley Periodicals LLC",
year = "2021",
month = apr,
doi = "10.1002/pbc.28879",
language = "English (US)",
volume = "68",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "4",
}