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.