Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD)/phase II recommended dose and describe
toxicities related to PD-0332991 (palbociclib isethionate) in children with retinoblastoma
protein 1 (Rb1) positive recurrent, progressive or refractory primary central nervous system
(CNS) tumors.

II. To determine plasma pharmacokinetics of PD-0332991 in children with Rb1positive
recurrent, progressive or refractory primary CNS tumors.

SECONDARY OBJECTIVES:

I. To record preliminary evidence of efficacy of PD-0332991 in children with recurrent CNS
tumors.

II. To evaluate cyclin-dependent kinase (CDK)4/6, cyclin D1-3, cyclin-dependent kinase
inhibitor 2A (Ink4a-ARF) copy-number variations in available tumor tissue by array
comparative, genomic hybridization (aCGH).

III. To explore the potential relationships between the pharmacokinetics of PD-0332991 and
pharmacodynamic response (e.g. percentage change in absolute neutrophil count [ANC], platelet
counts).

IV. To explore the pharmacogenetic polymorphisms in PD-0332991 metabolizing enzymes and
transporters and relate these polymorphisms to PD-0332991 pharmacokinetics.

OUTLINE: This is a dose-escalation study.

Patients receive palbociclib isethionate orally (PO) once daily (QD) on days 1-21. Treatment
repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients with retinoblastoma protein (Rb1) positive recurrent, progressive or
refractory central nervous system (CNS) tumors

- Histologically confirmed Rb1 positive primary recurrent, progressive, or refractory
central nervous system tumors; patients with low grade gliomas are excluded

- Formalin fixed paraffin embedded tumor tissue (preferably from current recurrence)
must be available to assess Rb1 protein status prior to enrollment; only patients with
recurrent diffuse intrinsic brain stem glioma (DIPG) can be enrolled without the need
for available tumor tissue for Rb1 protein status confirmation

- Patients must have measurable disease (in 2-dimensions) on magnetic resonance imaging
(MRI) scan of brain and/or spine to assess preliminary evidence of response

- Body surface area (BSA):

- Patients enrolled on dose level 1 (50 mg/m^2) must have BSA >= 1.20 m^2

- Patients enrolled on dose level 2 (75 mg/m^2) must have BSA >= 0.93 m^2

- Patients enrolled on dose level 3 (95 mg/m^2) must have BSA >= 0.70 m^2

- Patients must have received no more than 2 prior chemotherapy regimens and/or focal
radiotherapy for their brain tumor and fully recovered from the acute treatment
related toxicities of all prior therapies prior to entering this study; for those
acute baseline adverse events attributable to prior therapy, patients must meet organ
function criteria

- Chemotherapy: patients must have received their last dose of known myelosuppressive
anticancer chemotherapy at least three (3) weeks prior to study enrollment in the
study or at least six (6) weeks for those receiving nitrosourea

- Biologic therapy: patients should have received their last dose of biologic agent >= 7
days prior to enrollment; in the event the patient has received another biologic agent
and has experienced >= grade 2 myelosuppression, then at least three (3) weeks must
have elapsed prior to enrollment; if the investigational or biologic agent has a
prolonged half-life then at least three (3) weeks interval is required

- Radiotherapy: patients must have had their last fraction of:

* Focal irradiation > 2 weeks prior to enrollment

- Corticosteroids: patients who are receiving dexamethasone or other corticosteroids
must be on a stable or decreasing dose for at least 1 week prior to enrollment; it is
recommended that patients be off all steroid therapy or receive the least dose that
will control their neurologic symptoms

- Growth factors: all colony forming growth factor(s) have been discontinued for at
least one week prior to enrollment (filgrastim, sargramostim, and erythropoietin); for
patients on long acting growth factors, the interval should be two weeks

- Patients with neurological deficits that are stable for a minimum of one week prior to
registration

- Patients must be able to swallow capsules

- Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score
(LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 60

- Absolute neutrophil count >= 1,000/mm^3

- Platelets >= 100,000/mm^3 transfusion independent (no platelet transfusion one week
prior to enrollment)

- Hemoglobin >= 8 g/dl

- Total bilirubin =< 1.5 times upper limit of institutional normal (ULN) for age

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional upper limit of normal for age

- Serum albumin >= 3 g/dL

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- 1 to < 2 years: 0.6 (male), 0.6 (female)

- 2 to < 6 years: 0.8 (male), 0.8 (female)

- 6 to < 10 years: 1 (male), 1 (female)

- 10 to < 13 years: 1.2 (male), 1.2 (female)

- 13 to < 16 years: 1.5 (male), 1.4 (female)

- >= 16 years: 1.7 (male), 1.4 (female)

- Female patients of childbearing potential must have a negative serum pregnancy test at
the time of enrollment

- Patients of childbearing or child fathering potential must be willing to use a
medically acceptable form of birth control while being treated on this study

- Patient and/or guardian have the ability to understand and the willingness to sign a
written informed consent document according to institutional guidelines

Exclusion Criteria:

- Patients with any clinical significant unrelated systemic illness (serious infections
or significant cardiac, pulmonary, hepatic or other organ dysfunction) that is likely
to interfere with the study procedures or results

- Patients with low grade gliomas and Rb1 negative tumors

- Patients who have received any of the following:

- > 2 chemotherapy regimens

- Myeloablative chemotherapy with stem cell rescue

- Craniospinal irradiation

- Patients with corrected QT (QTc) interval of > 450 msec or those on medications known
to prolong QTc interval

- Prior treatment on a CDK inhibitor

- Patients who are receiving drugs that are strong inducers or inhibitors of cytochrome
P450, family 3, subfamily A, polypeptide 4 (CYP3A4)

- Patients who are receiving any other investigational therapy

- Patients who require enzyme inducing anti-convulsants to control seizures

- Patients with cataracts on ophthalmologic examination