Clinical trial NCT02255461: Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors
Official title: Phase I Study of CDK 4-6 Inhibitor PD-0332991 (Palbociclib; IBRANCE) in Children With Recurrent, Progressive or Refractory Central Nervous System Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Childhood Choroid Plexus Tumor
Childhood Ependymoblastoma
Childhood Grade III Meningioma
Childhood High-grade Cerebellar Astrocytoma
Childhood High-grade Cerebral Astrocytoma
Childhood Medulloepithelioma
Recurrent Childhood Anaplastic Astrocytoma
Recurrent Childhood Anaplastic Oligoastrocytoma
Recurrent Childhood Anaplastic Oligodendroglioma
Recurrent Childhood Brain Stem Glioma
Recurrent Childhood Cerebellar Astrocytoma
Recurrent Childhood Cerebral Astrocytoma
Recurrent Childhood Giant Cell Glioblastoma
Recurrent Childhood Glioblastoma
Recurrent Childhood Gliomatosis Cerebri
Recurrent Childhood Gliosarcoma
Recurrent Childhood Medulloblastoma
Recurrent Childhood Pineoblastoma
Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
Lead sponsor: Pediatric Brain Tumor Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2014-10-02
Enrollment: 35
Sex: ALL
Minimum age (years): 4
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I trial studies the side effects and best dose of palbociclib isethionate in treating younger patients with central nervous system tumors that have grown, come back, or not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description: 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, 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I
timeFrame: 4 weeks
measure: Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II
timeFrame: 4 weeks
measure: Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)
timeFrame: 4 weeks
measure: Single Dose Apparent Volume of Central Compartment (Vc/F)
timeFrame: Up to day 3
measure: Single Dose Elimination Rate Constant (Ke)
timeFrame: Up to day 3
measure: Single Dose Half-life (t1/2)
timeFrame: Up to day 3
measure: Single Dose Apparent Oral Clearance (CL/F)
timeFrame: Up to day 3
measure: Single Dose Area Under the Plasma Concentration Time Curve (AUC)
timeFrame: Up to day 3
measure: Steady State Apparent Volume of Central Compartment (Vc/F)
timeFrame: Up to day 22
measure: Steady State Elimination Rate Constant (Ke)
timeFrame: Up to day 22
measure: Steady State Half-life (t1/2)
timeFrame: Up to day 22
measure: Steady State Apparent Oral Clearance (CL/F)
timeFrame: Up to day 22
measure: Steady State Area Under the Plasma Concentration Time Curve (AUC)
timeFrame: Up to day 22
Secondary outcomes:
measure: Number of Subjects With Objective Responses
timeFrame: Up to 2 years
measure: Association Between Neutropenia and Single Dose Palbociclib AUC
timeFrame: Up to approximately 4 weeks
measure: Association Between Lymphopenia and Single Dose Palbociclib AUC
timeFrame: Up to approximately 4 weeks
measure: Association Between Leukopenia and Single Dose Palbociclib AUC
timeFrame: Up to approximately 4 weeks
Other outcomes:
measure: Number of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations
timeFrame: At enrollment
measure: Number of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations
timeFrame: At enrollment
measure: Number of Subjects With Cyclin D1 Copy Number Variations
timeFrame: At enrollment
measure: Number of Subjects With Cyclin D2 Copy Number Variations
timeFrame: At enrollment
measure: Number of Subjects With Cyclin D3 Copy Number Variations
timeFrame: At enrollment
measure: Number of Subjects With Ink4a-ARF Loss Copy Number Variations
timeFrame: At enrollment
measure: Polymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1)
timeFrame: At enrollment
measure: Polymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2)
timeFrame: At enrollment
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children Hospital Stanford University
state: California
city: Washington
country: United States
facility: Childrens National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Lurie Childrens Hospital-Chicago
state: Illinois
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children Hospital Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Children Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Childrens Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle Children Hospital
state: Washington
Study officials:
affiliation: Pediatric Brain Tumor Consortium
name: David Van Mater, MD
role: PRINCIPAL_INVESTIGATOR
References: