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TerminatedNCT02255461Updated Mar 2, 2021Results posted

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

A Phase 1 interventional study of palbociclib isethionate and pharmacological study in Childhood Choroid Plexus Tumor, Childhood Ependymoblastoma and Childhood Grade III Meningioma, sponsored by Pediatric Brain Tumor Consortium. Terminated at 11 sites in United States. Open to participants aged 4 Years to 21 Years. Per ClinicalTrials.gov, last updated 2021-03-02.

Sponsored by Pediatric Brain Tumor Consortium · Phase 1, Interventional, and Treatment

Why this study was terminated
Data for the primary objectives is complete and the MTD identified in Stratum II.
Phase
Phase 1
Study type
Interventional
Enrollment
35
Allocation
Not applicable
Ages
4 Years to 21 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • 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
03

Who can participate

Ages eligible
4 Years to 21 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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
04

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
35 participants (actual)

Study arms

  • 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.

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

Interventions

  • Drugpalbociclib isethionate

    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

  • Otherpharmacological study

    Correlative studies

    Also known as: pharmacological studies

  • Otherlaboratory biomarker analysis

    Correlative studies

05

What researchers measure

Primary outcomes

  1. 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.

    Time frame: 4 weeks

  2. 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.

    Time frame: 4 weeks

  3. 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.

    Time frame: 4 weeks

  4. 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.

    Time frame: Up to day 3

  5. 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.

    Time frame: Up to day 3

  6. 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.

    Time frame: Up to day 3

  7. 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.

    Time frame: Up to day 3

  8. 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.

    Time frame: Up to day 3

  9. 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.

    Time frame: Up to day 22

  10. 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.

    Time frame: Up to day 22

  11. 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.

    Time frame: Up to day 22

  12. 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.

    Time frame: Up to day 22

  13. 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.

    Time frame: Up to day 22

Secondary outcomes

  1. Number of Subjects With Objective Responses

    Objective responses included complete response (CR) and partial response (PR).

    Time frame: Up to 2 years

  2. Association Between Neutropenia and Single Dose Palbociclib AUC

    Neutrophil count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between neutrophil count decreased and single dose palbociclib AUC for all participants was examined.

    Time frame: Up to approximately 4 weeks

  3. Association Between Lymphopenia and Single Dose Palbociclib AUC

    Lymphocyte count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between Lymphocyte count decreased and single dose palbociclib AUC for all participants was examined.

    Time frame: Up to approximately 4 weeks

  4. Association Between Leukopenia and Single Dose Palbociclib AUC

    White blood cell count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between white blood cell count decreased and single dose palbociclib AUC for all participants was examined.

    Time frame: Up to approximately 4 weeks

Other outcomes

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

    CDK4 is a key component in signaling pathways inside normal cells and cancer cells. CDK4 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

    Time frame: At enrollment

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

    CDK6 is a key component in signaling pathways inside normal cells and cancer cells. CDK6 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

    Time frame: At enrollment

  3. Number of Subjects With Cyclin D1 Copy Number Variations

    Cyclin D1 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D1 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

    Time frame: At enrollment

  4. Number of Subjects With Cyclin D2 Copy Number Variations

    Cyclin D2 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D2 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

    Time frame: At enrollment

  5. Number of Subjects With Cyclin D3 Copy Number Variations

    Cyclin D3 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D3 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

    Time frame: At enrollment

  6. Number of Subjects With Ink4a-ARF Loss Copy Number Variations

    Ink4a-ARF is a key component in signaling pathways inside normal cells and cancer cells. Ink4a-ARF loss copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

    Time frame: At enrollment

  7. Polymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1)

    Polymorphisms in ABCB1 encode for efflux-transporter proteins P-glycoprotein (P-gp), for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCB1 polymorphisms.

    Time frame: At enrollment

  8. Polymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2)

    Polymorphisms in ABCG2 encode for BCRP, for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCG2 polymorphisms.

    Time frame: At enrollment

06

Results

Posted Apr 8, 2020

Participant flow

Patients between 4 and 21 years of age with histologically confirmed retinoblastoma protein (Rb1) positive, primary recurrent, progressive, or refractory central nervous system tumors were enrolled at Pediatric Brain Tumor Consortium member institutions. The first patient was enrolled on 12/8/2014 and the last patient was enrolled on 10/10/2018.

Participant flow — Overall Study
MilestoneStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Started3126410
Completed310548
Not completed02102
Withdrew: Adverse event01001
Withdrew: Withdrawal by subject00101
Withdrew: Not meet dose reduction bsa requirement01000

Outcome measures

PrimaryMaximum 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.

Time frame:
4 weeks
Reported as:
Number · mg/m2/day
Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I
mg/m2/dayStratum I
Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I75
PrimaryMaximum 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.

Time frame:
4 weeks
Reported as:
Number · mg/m2/day
Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II
mg/m2/dayStratum II
Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II75
PrimaryNumber 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.

Time frame:
4 weeks
Reported as:
Count of participants · Participants
Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)
ParticipantsStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)02201
PrimarySingle 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.

Time frame:
Up to day 3
Reported as:
Median · L/m^2
Single Dose Apparent Volume of Central Compartment (Vc/F)
L/m^2Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Single Dose Apparent Volume of Central Compartment (Vc/F)672 (622 to 1189)741 (562 to 1856)708 (601 to 819)847 (373 to 1153)850 (398 to 3653)
PrimarySingle 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.

Time frame:
Up to day 3
Reported as:
Median · per hour
Single Dose Elimination Rate Constant (Ke)
per hourStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Single Dose Elimination Rate Constant (Ke)0.053 (0.045 to 0.055)0.053 (0.030 to 0.070)0.048 (0.023 to 0.083)0.051 (0.031 to 0.070)0.051 (0.014 to 0.097)
PrimarySingle 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.

Time frame:
Up to day 3
Reported as:
Median · hour
Single Dose Half-life (t1/2)
hourStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Single Dose Half-life (t1/2)13.0 (12.5 to 15.5)13.0 (9.9 to 22.8)14.6 (8.4 to 29.8)13.8 (10.0 to 22.0)13.5 (7.1 to 48.7)
PrimarySingle 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.

Time frame:
Up to day 3
Reported as:
Median · L/h/m^2
Single Dose Apparent Oral Clearance (CL/F)
L/h/m^2Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Single Dose Apparent Oral Clearance (CL/F)35.8 (34.4 to 53.1)38.4 (29.3 to 72.0)33.7 (17.3 to 63.3)37.2 (16.9 to 64.3)24.4 (11.7 to 355.0)
PrimarySingle 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.

Time frame:
Up to day 3
Reported as:
Median · h*ng/mL
Single Dose Area Under the Plasma Concentration Time Curve (AUC)
h*ng/mLStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Single Dose Area Under the Plasma Concentration Time Curve (AUC)1156 (810 to 1164)1743 (892 to 2537)2407 (1485 to 3252)1289 (747 to 2834)2538 (189 to 2951)
PrimarySteady 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.

Time frame:
Up to day 22
Reported as:
Median · L/m^2
Steady State Apparent Volume of Central Compartment (Vc/F)
L/m^2Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Steady State Apparent Volume of Central Compartment (Vc/F)491 (465 to 517)449 (282 to 1560)442 (383 to 501)705 (250 to 1308)458 (247 to 919)
PrimarySteady 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.

Time frame:
Up to day 22
Reported as:
Median · per hour
Steady State Elimination Rate Constant (Ke)
per hourStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Steady State Elimination Rate Constant (Ke)0.052 (0.041 to 0.066)0.050 (0.017 to 0.110)0.062 (0.054 to 0.071)0.032 (0.024 to 0.049)0.039 (0.032 to 0.074)
PrimarySteady 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.

Time frame:
Up to day 22
Reported as:
Median · hour
Steady State Half-life (t1/2)
hourStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Steady State Half-life (t1/2)13.7 (10.5 to 16.9)13.7 (6.5 to 41.6)11.3 (9.8 to 12.8)23.1 (14.2 to 29.4)17.9 (9.4 to 21.4)
PrimarySteady 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.

Time frame:
Up to day 22
Reported as:
Median · L/h/m^2
Steady State Apparent Oral Clearance (CL/F)
L/h/m^2Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Steady State Apparent Oral Clearance (CL/F)26.6 (19.0 to 34.2)25.8 (12.3 to 101.0)28.1 (20.8 to 35.3)17.0 (9.7 to 64.0)16.1 (12.1 to 62.4)
PrimarySteady 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.

Time frame:
Up to day 22
Reported as:
Median · h*ng/mL
Steady State Area Under the Plasma Concentration Time Curve (AUC)
h*ng/mLStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Steady State Area Under the Plasma Concentration Time Curve (AUC)1211 (972 to 1450)2143 (521 to 4070)2193 (1520 to 3168)1410 (559 to 3301)2359 (952 to 4253)
SecondaryNumber of Subjects With Objective Responses

Objective responses included complete response (CR) and partial response (PR).

Time frame:
Up to 2 years
Reported as:
Count of participants · Participants
Number of Subjects With Objective Responses
ParticipantsStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Number of Subjects With Objective Responses00000
SecondaryAssociation Between Neutropenia and Single Dose Palbociclib AUC

Neutrophil count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between neutrophil count decreased and single dose palbociclib AUC for all participants was examined.

Time frame:
Up to approximately 4 weeks
Reported as:
Mean · h*ng/mL
Association Between Neutropenia and Single Dose Palbociclib AUC
h*ng/mLAll Patients
No neutropenia1424.4 ± 966.3
Grade 1 or 2 neutropenia2166.3 ± 797.8
Grade 3 or 4 neutropenia1937.6 ± 621.8
Statistical analysis
  • All Patients · Odds ratio (or): 1.06 · 95% CI 0.97 to 1.15
SecondaryAssociation Between Lymphopenia and Single Dose Palbociclib AUC

Lymphocyte count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between Lymphocyte count decreased and single dose palbociclib AUC for all participants was examined.

Time frame:
Up to approximately 4 weeks
Reported as:
Mean · h*ng/mL
Association Between Lymphopenia and Single Dose Palbociclib AUC
h*ng/mLAll Patients
No lymphopenia1727.5 ± 882.6
Grade 1 or 2 lymphopenia1837.9 ± 592.7
Grade 3 or 4 lymphopenia2159.0 ± 793.7
Statistical analysis
  • All Patients · Odds ratio (or): 1.05 · 95% CI 0.97 to 1.15
SecondaryAssociation Between Leukopenia and Single Dose Palbociclib AUC

White blood cell count decreased adverse events observed in course 1 that were at least possibly attributable to palbociclib were included in analysis. Based on the highest toxicity grade reported, all participants, irrespective of their dose level or stratum, were combined and classified into three categories: 0 = no toxicity reported, 1 = grade 1 or 2, and 2 = grade 3 or 4. Association between white blood cell count decreased and single dose palbociclib AUC for all participants was examined.

Time frame:
Up to approximately 4 weeks
Reported as:
Mean · h*ng/mL
Association Between Leukopenia and Single Dose Palbociclib AUC
h*ng/mLAll Patients
No leukopenia1420.3 ± 955.1
Grade 1 or 2 leukopenia1879.6 ± 682.6
Grade 3 or 4 leukopenia2171.6 ± 712.9
Statistical analysis
  • All Patients · Odds ratio (or): 1.10 · 95% CI 1.01 to 1.20
Other pre-specifiedNumber of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations

CDK4 is a key component in signaling pathways inside normal cells and cancer cells. CDK4 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

Time frame:
At enrollment

Results for this outcome have not been posted.

Other pre-specifiedNumber of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations

CDK6 is a key component in signaling pathways inside normal cells and cancer cells. CDK6 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

Time frame:
At enrollment

Results for this outcome have not been posted.

Other pre-specifiedNumber of Subjects With Cyclin D1 Copy Number Variations

Cyclin D1 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D1 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

Time frame:
At enrollment

Results for this outcome have not been posted.

Other pre-specifiedNumber of Subjects With Cyclin D2 Copy Number Variations

Cyclin D2 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D2 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

Time frame:
At enrollment

Results for this outcome have not been posted.

Other pre-specifiedNumber of Subjects With Cyclin D3 Copy Number Variations

Cyclin D3 is a key component in signaling pathways inside normal cells and cancer cells. Cyclin D3 copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

Time frame:
At enrollment

Results for this outcome have not been posted.

Other pre-specifiedNumber of Subjects With Ink4a-ARF Loss Copy Number Variations

Ink4a-ARF is a key component in signaling pathways inside normal cells and cancer cells. Ink4a-ARF loss copy number variations were to be assessed by array comparative genomic hybridization in available tumor tissues from consenting patients.

Time frame:
At enrollment

Results for this outcome have not been posted.

Other pre-specifiedPolymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1)

Polymorphisms in ABCB1 encode for efflux-transporter proteins P-glycoprotein (P-gp), for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCB1 polymorphisms.

Time frame:
At enrollment

Results for this outcome have not been posted.

Other pre-specifiedPolymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2)

Polymorphisms in ABCG2 encode for BCRP, for which palbociclib has been shown as a substrate. Genomic DNA was to be isolated from peripheral blood samples from consenting patients to determine ABCG2 polymorphisms.

Time frame:
At enrollment

Results for this outcome have not been posted.

Adverse events

Collected over Up to 2 years after starting treatment. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Stratum I, Dose Level 1 (50 mg/m2)0/3 (0%)0/3 (0%)3/3 (100%)
Stratum I, Dose Level 2 (75 mg/m2)3/12 (25%)1/12 (8.3%)12/12 (100%)
Stratum I, Dose Level 3 (95 mg/m2)1/6 (16.7%)1/6 (16.7%)5/6 (83.3%)
Stratum II, Dose Level 1 (50 mg/m2)1/4 (25%)0/4 (0%)4/4 (100%)
Stratum II, Dose Level 2 (75mg/m2)1/9 (11.1%)0/9 (0%)9/9 (100%)
Most frequent serious events
Most frequent serious events
EventStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
Neutrophil count decreasedInvestigations0/30/121/60/40/9
DehydrationMetabolism and nutrition disorders0/31/120/60/40/9
Most frequent other events
Showing 10 of 53
Most frequent other events
EventStratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)
AnemiaBlood and lymphatic system disorders0/35/122/64/46/9
Neutrophil count decreasedInvestigations1/310/123/64/47/9
White blood cell decreasedInvestigations2/310/125/64/47/9
AnorexiaMetabolism and nutrition disorders1/31/120/63/40/9
Lymphocyte count decreasedInvestigations2/38/123/62/44/9
HyperglycemiaMetabolism and nutrition disorders2/30/120/60/40/9
Platelet count decreasedInvestigations1/36/123/62/45/9
FatigueGeneral disorders1/35/121/61/43/9
ConstipationGastrointestinal disorders1/34/121/61/41/9
DiarrheaGastrointestinal disorders1/32/120/61/40/9

Baseline characteristics

Summary statistics for baseline characteristics are shown for all enrolled patients (n = 35).

Age, Continuous
Age, Continuous(years)Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)Total
Median16.6 (9.7 to 16.6)12.6 (7.0 to 21.1)9.3 (4.9 to 19.3)16.5 (13.3 to 17.2)10.5 (6.3 to 21.6)12.7 (4.9 to 21.6)
Sex: Female, Male
Sex: Female, Male(Participants)Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)Total
Female1530312
Male2734723
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)Total
Hispanic or Latino032038
Not Hispanic or Latino3642520
Unknown or Not Reported030227
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)Total
American Indian or Alaska Native000101
Asian111003
Native Hawaiian or Other Pacific Islander000000
Black or African American020024
White2743723
More than one race001001
Unknown or Not Reported020013
Region of Enrollment
Region of Enrollment(participants)Stratum I, Dose Level 1 (50 mg/m2)Stratum I, Dose Level 2 (75 mg/m2)Stratum I, Dose Level 3 (95 mg/m2)Stratum II, Dose Level 1 (50 mg/m2)Stratum II, Dose Level 2 (75mg/m2)Total
United States312641035
07

Study locations

11 sites
  • Childrens Hospital Los Angeles
    Los Angeles, California 90027, United States
  • Lucile Packard Children Hospital Stanford University
    Palo Alto, California 94304, United States
  • Childrens National Medical Center
    Washington, District of Columbia 20010-2970, United States
  • Lurie Childrens Hospital-Chicago
    Chicago, Illinois 60614, United States
  • Memorial Sloan Kettering Cancer Center
    New York, New York 10065, United States
  • Duke University Medical Center
    Durham, North Carolina 27710, United States
  • Cincinnati Children Hospital Medical Center
    Cincinnati, Ohio 45229, United States
  • Children Hospital of Pittsburgh of UPMC
    Pittsburgh, Pennsylvania 15224, United States
  • St. Jude Children Research Hospital
    Memphis, Tennessee 38105, United States
  • Texas Childrens Hospital
    Houston, Texas 77030, United States
  • Seattle Children Hospital
    Seattle, Washington 98105, United States
08

References and documents

Study documents

  • Informed consent form · Jun 28, 2018
  • Protocol and statistical analysis plan · Jun 28, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT02255461
Lead sponsor
Pediatric Brain Tumor Consortium
Collaborators
National Cancer Institute (NCI)
Responsible party
Sponsor
First posted
Oct 2, 2014
Start date
Dec 8, 2014
Primary completion
Feb 25, 2019
Completion
Feb 25, 2019
Results posted
Apr 8, 2020
Last update
Mar 2, 2021

Study contacts

David Van Mater, MD
principal investigator · Pediatric Brain Tumor Consortium

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
View the source record on ClinicalTrials.gov ↗

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