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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)
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  • David Van Mater,
  • Sridharan Gururangan,
  • Oren Becher,
  • Olivia Campagne,
  • Sarah Leary,
  • Joanna Phillips,
  • Jie Huang,
  • Tong Lin,
  • Tina Young-Poussaint,
  • Stewart Goldman,
  • Patricia Baxter,
  • Girish Dhall,
  • Giles Robinson,
  • Mariko DeWire,
  • Eugene Hwang,
  • Clinton Stewart,
  • Arzu Onar,
  • Ira Dunkel,
  • Maryam Fouladi
David Van Mater
Duke University School of Medicine

Corresponding Author:[email protected]

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Sridharan Gururangan
Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida
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Oren Becher
Ann and Robert H Lurie Children's Hospital of Chicago
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Olivia Campagne
St Jude Children's Research Hospital
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Sarah Leary
Seattle Childrens Hospital
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Joanna Phillips
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Jie Huang
St. Jude Children's Research Hospital
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Tong Lin
St. Jude Children's Research Hospital
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Tina Young-Poussaint
Children's Hospital Boston
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Stewart Goldman
Ann & Robert H Lurie Children's Hospital of Chicago
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Patricia Baxter
Baylor College of Medicine
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Girish Dhall
Children's of Alabama
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Giles Robinson
St. Jude
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Mariko DeWire
Cincinnati Children's Hospital Medical Center
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Eugene Hwang
Children's National Medical Center
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Clinton Stewart
St. Jude Children's Research Hospital
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Arzu Onar
St. Jude Children's Research Hospital
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Ira Dunkel
Memorial Sloan Kettering Cancer Center
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Maryam Fouladi
Children's Hospital Cincinnati
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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.
06 Oct 2020Submission Checks Completed
06 Oct 2020Assigned to Editor
06 Oct 2020Submitted to Pediatric Blood & Cancer
07 Oct 2020Reviewer(s) Assigned
28 Oct 2020Review(s) Completed, Editorial Evaluation Pending
28 Oct 2020Editorial Decision: Revise Minor
23 Nov 2020Submission Checks Completed
23 Nov 2020Assigned to Editor
23 Nov 20201st Revision Received
24 Nov 2020Reviewer(s) Assigned
14 Dec 2020Review(s) Completed, Editorial Evaluation Pending
14 Dec 2020Editorial Decision: Accept