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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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 Summary:

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.


Sponsor: Pediatric Brain Tumor Consortium

Current Primary Outcome:

  • 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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.


Original Secondary Outcome: Same as current

Information By: Pediatric Brain Tumor Consortium

Dates:
Date Received: September 30, 2014
Date Started: October 2014
Date Completion: December 31, 2018
Last Updated: April 3, 2017
Last Verified: April 2017