Eligibility
Subjects were ≥4 years and ≤21 years of age with progressive or refractory brain tumors (except low grade gliomas) with measurable disease and Lansky or Karnofsky score ≥ 60. All subjects were required to be able to swallow pills, and there were minimum body surface area restrictions at each dosing level based on available capsule strengths. Since Rb is required for palbociclib-mediated suppression of the CDK4/6 signaling pathway, a screening test for the presence or absence of Rb was performed in all types of brain tumors except for diffuse intrinsic pontine glioma (DIPG),12medulloblastoma,13,14 and atypical teratoid rhabdoid tumor (ATRT),15 all of which have been shown to haveRB1 mutation/loss or at a very low frequency or not at all. Since myelosuppression is the main dose limiting toxicity (DLT) in adults treated with palbociclib6,7 and more heavily pretreated patients are likely to experience more severe hematologic toxicity, subjects were divided into two strata: Stratum I included patients that were not heavily pretreated, while Stratum II included heavily pretreated patients, defined as having received >4 prior regimens (either chemotherapy or biologic agents with myelosuppressive effects), and/or craniospinal irradiation (CSI), and/or myeloablative chemotherapy plus bone marrow or peripheral blood stem cell rescue. Subjects not meeting these criteria were eligible for Stratum I. Subjects must have had at least 3 weeks from last myelosuppressive therapy, at least 6 weeks from nitrosourea, ≥7 days from a biologic agent (at least 3 weeks if prolonged half-life), >2 weeks from focal irradiation, and ≥3 months from a bone marrow/stem cell infusion or CSI. Subjects were required to be on a stable dose of corticosteroids and have a stable neurological examination for at least 1 week prior to study enrollment. Subjects had to have adequate bone marrow (absolute neutrophil count ≥1000/μL, platelet count ≥100,000/μL, hemoglobin ≥8.0 g/dL), renal (sex and age-adjusted normal serum creatinine or glomerular filtration rate ≥70 mL/min/1.73 m2), and liver function (total bilirubin ≤1.5× and alanine aminotransferase ≤3× the institutional upper limit of normal for age and albumin ≥3 g/dL). Subjects were excluded if pregnant or lactating, cataracts noted on ophthalmologic examination, QTc >450 msec, or prior treatment with a CDK inhibitor. Subjects of childbearing/fathering potential had to consent to birth control. Informed consent and assent were obtained according to institutional guidelines. Institutional review boards of participating institutions maintained protocol approval throughout the study.