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

NCT02255461 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: PBTC-042U01CA081457
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 11

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.

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

Outcome Measures

Primary Outcomes (13)

• Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I

  Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level had been determined to be too toxic. Stratum I consisted of less-heavily pre-treated patients.

  4 weeks

• Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II

  Rolling-6 design was used to estimate MTD. The MTD was empirically defined as the highest dose level at which six patients were treated with at most one patient experiencing a DLT and the next higher dose level had been determined to be too toxic. Stratum II consisted of heavily pre-treated patients.

  4 weeks

• Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)

  DLTs were defined as any of the following adverse events that were at least possibly related to palbociclib that occurred during the first 4 weeks of therapy regardless of expectedness. Hematologic DLTs included grade 3 neutropenia with fever and sepsis, grade 3 thrombocytopenia and/or requiring a platelet transfusion on 2 separate days within a 7-day period, or any grade 4 hematologic toxicity except lymphopenia. Non-hematologic DLTs included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of \< 5 days; diarrhea and/or electrolyte disturbances which have not been maximally treated; AST/ALT elevation that returns to levels meeting eligibility criteria within 7 days of study drug interruption and does not recur upon restarting drug), or any grade 2 non-hematologic toxicity that persists for \> 7 days and is considered medically significant or sufficiently intolerable by patients requires treatment interruption.

  4 weeks

• Single Dose Apparent Volume of Central Compartment (Vc/F)

  On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.

  Up to day 3

• Single Dose Elimination Rate Constant (Ke)

  On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Elimination rate constant (Ke) was estimated using a non-compartmental method.

  Up to day 3

• Single Dose Half-life (t1/2)

  On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Half-life (t1/2) was estimated using a non-compartmental method.

  Up to day 3

• Single Dose Apparent Oral Clearance (CL/F)

  On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.

  Up to day 3

• Single Dose Area Under the Plasma Concentration Time Curve (AUC)

  On day 1 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) optional, 24 (±4), 48 (±4) hours after the oral dose of palbociclib. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.

  Up to day 3

• Steady State Apparent Volume of Central Compartment (Vc/F)

  On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent volume of central compartment (Vc/F) was estimated using a non-compartmental method.

  Up to day 22

• Steady State Elimination Rate Constant (Ke)

  On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Elimination rate constant (Ke) was estimated using a non-compartmental method.

  Up to day 22

• Steady State Half-life (t1/2)

  On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Half-life (t1/2) was estimated using a non-compartmental method.

  Up to day 22

• Steady State Apparent Oral Clearance (CL/F)

  On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Apparent oral clearance (CL/F) was estimated using a non-compartmental method.

  Up to day 22

• Steady State Area Under the Plasma Concentration Time Curve (AUC)

  On day 21 of course 1, series blood samples for palbociclib pharmacokinetic studies were collected at pre-dose, 1, 2, 4, 8 (±1), 10 (±0.5) optional, and 24 (±4) hours after the dose. Area under the plasma concentration time curve (AUC) was estimated using a non-compartmental method.

  Up to day 22

Secondary Outcomes (4)

• Number of Subjects With Objective Responses

  Up to 2 years

• Association Between Neutropenia and Single Dose Palbociclib AUC

  Up to approximately 4 weeks

• Association Between Lymphopenia and Single Dose Palbociclib AUC

  Up to approximately 4 weeks

• Association Between Leukopenia and Single Dose Palbociclib AUC

  Up to approximately 4 weeks

Other Outcomes (8)

• Number of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations

  At enrollment

• Number of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations

  At enrollment

• Number of Subjects With Cyclin D1 Copy Number Variations

  At enrollment

Study Arms (1)

Treatment (palbociclib isethionate)

EXPERIMENTAL

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.

Drug: palbociclib isethionate; Other: pharmacological study; Other: laboratory biomarker analysis

Interventions

palbociclib isethionate DRUG

Given PO

Also known as: 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

Treatment (palbociclib isethionate)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (palbociclib isethionate)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (palbociclib isethionate)

Eligibility Criteria

• Age: 4 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Pediatric Brain Tumor Consortium: lead
• National Cancer Institute (NCI): collaborator

Study Sites (11)

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Lucile Packard Children Hospital Stanford University

Palo Alto, California, 94304, United States

Location

Childrens National Medical Center

Washington D.C., District of Columbia, 20010-2970, United States

Location

Lurie Childrens Hospital-Chicago

Chicago, Illinois, 60614, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cincinnati Children Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

St. Jude Children Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Childrens Hospital

Houston, Texas, 77030, United States

Location

Seattle Children Hospital

Seattle, Washington, 98105, United States

Location

Related Publications (1)

• Raetz EA, Teachey DT, Minard C, Liu X, Norris RE, Denic KZ, Reid J, Evensen NA, Gore L, Fox E, Loh ML, Weigel BJ, Carroll WL. Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: A Children's Oncology Group study (AINV18P1). Pediatr Blood Cancer. 2023 Nov;70(11):e30609. doi: 10.1002/pbc.30609. Epub 2023 Aug 8.

  PMID: 37553297 DERIVED

MeSH Terms

Conditions

Choroid Plexus Neoplasms; Astrocytoma; Oligodendroglioma; Glioblastoma; Neoplasms, Neuroepithelial; Medulloblastoma

Interventions

palbociclib

Condition Hierarchy (Ancestors)

Cerebral Ventricle Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Glioma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive

Results Point of Contact

• Title: Jie Huang
• Organization: St. Jude Children's Research Hospital

jie.huang@stjude.org

9015955750

Study Officials

• David Van Mater, MD

  Pediatric Brain Tumor Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2014
• First Posted: October 2, 2014
• Study Start: December 8, 2014
• Primary Completion: February 25, 2019
• Study Completion: February 25, 2019
• Last Updated: March 2, 2021
• Results First Posted: April 8, 2020

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (11)