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

This study is currently recruiting participants.
Verified September 2017 by Pediatric Brain Tumor Consortium
Sponsor:
ClinicalTrials.gov Identifier:
NCT02255461
First Posted: October 2, 2014
Last Update Posted: September 28, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Pediatric Brain Tumor Consortium
September 30, 2014
October 2, 2014
September 28, 2017
October 2014
December 31, 2018   (Final data collection date for primary outcome measure)
  • MTD of palbociclib isethionate defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose limiting toxicity and the next higher dose level has been determined to be too toxic [ Time Frame: 4 weeks ]
    Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.
  • Incidence of adverse events [ Time Frame: Up to 30 days ]
    Adverse event data will be summarized in tables which will incorporate dose, attribution as well as grade information.
Same as current
Complete list of historical versions of study NCT02255461 on ClinicalTrials.gov Archive Site
  • Objective responses (partial response + complete response) [ Time Frame: Up to 30 days ]
    Will be described by dose and by histology. Prolonged disease stabilizations will be reported in a descriptive fashion.
  • Individual pharmacokinetic parameters of interest, such as apparent volume of the central compartment (Vc/F), elimination rate constant (Ke), half-life (t1/2), apparent oral clearance (CL/F), and area under the plasma concentration time curve (AUC) [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 24, 48 hours after dose (day 1, course 1) and pre-dose, 1, 2, 4, 8, 10, 24 hours after dose (day 21, course 1) ]
    Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and graphical form. Pharmacokinetic parameters of interest, such as Vc/F, Ke, t1/2, CL/F, and AUC will be estimated using compartmental methods. Dose proportionality in pharmacokinetic parameters will be investigated by performing one-way analysis of variance on dose-normalized parameters.
  • Population pharmacokinetic parameters [ Time Frame: Pre-dose, 0.5, 1, 2, 4, 8, 10, 24, 48 hours after dose (day 1, course 1) and pre-dose, 1, 2, 4, 8, 10, 24 hours after dose (day 21, course 1) ]
    Will be estimated using nonlinear mixed effects modeling methods. Once the population parameters and corresponding covariance matrix are estimated, individual estimates can be obtained using post hoc analysis.
Same as current
Not Provided
Not Provided
 
Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors
Phase I Study of CDK 4-6 Inhibitor PD-0332991 (Palbociclib; IBRANCE) in Children With Recurrent, Progressive or Refractory Central Nervous System Tumors
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.

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.

Interventional
Phase 1
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • 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
  • Drug: palbociclib isethionate
    Given PO
    Other Name: 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, 827022-33-3, palbociclib, PD 0332991-0054, PD-0332991, PD-332991, PF-00080665-73
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (palbociclib isethionate)
Patients receive palbociclib isethionate PO QD on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: palbociclib isethionate
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
55
December 31, 2018
December 31, 2018   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
4 Years to 21 Years   (Child, Adult)
No
Contact: Wint M Swe, MBA, MBBS 9015955742 wint.swe@stjude.org
Contact: Stacye Richardson 9015953783 stacye.richardson@stjude.org
United States
 
 
NCT02255461
PBTC-042
U01CA081457 ( U.S. NIH Grant/Contract )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Plan to Share IPD: No
Pediatric Brain Tumor Consortium
Pediatric Brain Tumor Consortium
National Cancer Institute (NCI)
Principal Investigator: David Van Mater, MD Pediatric Brain Tumor Consortium
Pediatric Brain Tumor Consortium
September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP