Palbociclib Isethionate in Treating Younger Patients With... | NCT02255461

ID	Type	Description	Link
U01CA081457	U.S. NIH Grant/Contract		View source

Name	Class
National Cancer Institute (NCI)	NIH

Description Module

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.

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
palbociclib isethionate	Drug	Given PO	Treatment (palbociclib isethionate)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.

Secondary Outcomes

Measure	Description	Time Frame
Number of Subjects With Objective Responses	Objective responses included complete response (CR) and partial response (PR).	Up to 2 years
Association Between Neutropenia and Single Dose Palbociclib AUC

Other Outcomes

Measure	Description	Time Frame
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.	At enrollment

Eligibility Module

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

Name	Affiliation	Role
David Van Mater, MD	Pediatric Brain Tumor Consortium	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Childrens Hospital Los Angeles		Los Angeles	California	90027	United States
Lucile Packard Children Hospital Stanford University

PubMed Identifier	Type	Citation	Retractions
37553297	Derived	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.

ID	Title	Description
FG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
FG001	Stratum I, Dose Level 2 (75 mg/m2)

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
ICF	No	No	Yes	Informed Consent Form	Jun 28, 2018	Feb 12, 2020

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Patients who were enrolled on stratum I and were evaluable for dose finding assessment were used to determine the MTD for stratum I.

Posted

Number

mg/m2/day

4 weeks

ID	Title	Description
OG000	Stratum I	Of 21 patients enrolled on stratum I, 2 patients were not evaluable for dose finding assessment due to receiving less than required dose of study drug. The remaining 19 patients were used to determine the MTD for stratum I.

Units	Counts
Participants	OG00019

Title

Denominators

Categories

Title	Measurements
	OG00075

Primary

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.

Patients who were enrolled on stratum II and were evaluable for dose finding assessment were used to determine the MTD for stratum II.

Posted

Number

mg/m2/day

4 weeks

ID	Title	Description
OG000	Stratum II	Of 14 patients enrolled on stratum II, 3 patients were not evaluable for dose finding assessment: 2 patients due to receiving less than required dose of study drug and 1 due to withdrawal consent prior to beginning protocol therapy. The remaining 11 patients were used to determine the MTD for stratum II.

Units	Counts
Participants	OG000

Primary

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.

Patients who received at least one dose of palbociclib were included in the analysis. One patient in stratum II dose level 2 who withdrew prior to beginning protocol therapy was excluded.

Posted

Count of Participants

Participants

4 weeks

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.

Posted

Median

Full Range

L/m^2

Up to day 3

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.

Posted

Median

Full Range

per hour

Up to day 3

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.

Posted

Median

Full Range

hour

Up to day 3

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.

Posted

Median

Full Range

L/h/m^2

Up to day 3

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 1-3 of course 1 were included.

Posted

Median

Full Range

h*ng/mL

Up to day 3

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.

Posted

Median

Full Range

L/m^2

Up to day 22

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.

Posted

Median

Full Range

per hour

Up to day 22

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.

Posted

Median

Full Range

hour

Up to day 22

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.

Posted

Median

Full Range

L/h/m^2

Up to day 22

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Primary

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.

Patients with blood samples collected for pharmacokinetic studies on days 21-22 of course 1 were included.

Posted

Median

Full Range

h*ng/mL

Up to day 22

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Secondary

Number of Subjects With Objective Responses

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

Patients who received at least one dose of palbociclib were included in the analysis. One patient in stratum II dose level 2 who withdrew prior to beginning protocol therapy was excluded.

Posted

Count of Participants

Participants

Up to 2 years

ID	Title	Description
OG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
OG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.

Secondary

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.

It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between neutropenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.

Posted

Mean

Standard Deviation

h*ng/mL

Up to approximately 4 weeks

ID	Title	Description
OG000	All Patients	All 34 patients who had course 1 single dose palbociclib AUC data available were included in analysis. Patients were classified into no neutropenia (n = 9), grade 1 or 2 neutropenia (n = 7), and grade 3 or 4 neutropenia (n = 18).

Units	Counts
Participants

Secondary

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.

It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between lymphopenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.

Posted

Mean

Standard Deviation

h*ng/mL

Up to approximately 4 weeks

ID	Title	Description
OG000	All Patients	All 34 patients who had course 1 single dose palbociclib AUC data available were included in analysis. Patients were classified into no lymphopenia (n = 17), grade 1 or 2 lymphopenia (n = 10), and grade 3 or 4 lymphopenia (n = 7).

Units	Counts
Participants

Secondary

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.

It was pre-specified that data from all participants from different dose levels and strata were combined to calculate an association between leukopenia and single dose AUC for all participants. Of 35 patients enrolled, one patient in stratum II withdrew prior to protocol therapy and was excluded.

Posted

Mean

Standard Deviation

h*ng/mL

Up to approximately 4 weeks

ID	Title	Description
OG000	All Patients	All 34 patients who had course 1 single dose palbociclib AUC data available were included in analysis. Patients were classified into no leukopenia (n = 8), grade 1 or 2 leukopenia (n = 17), and grade 3 or 4 leukopenia (n = 9).

Units	Counts
Participants

Other Pre-specified

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.

Not Posted

At enrollment

Participants

Other Pre-specified

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.

Not Posted

At enrollment

Participants

Other Pre-specified

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.

Not Posted

At enrollment

Participants

Other Pre-specified

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.

Not Posted

At enrollment

Participants

Other Pre-specified

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.

Not Posted

At enrollment

Participants

Other Pre-specified

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.

Not Posted

At enrollment

Participants

Other Pre-specified

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.

Not Posted

At enrollment

Participants

Other Pre-specified

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.

Not Posted

At enrollment

Participants

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Anemia	Blood and lymphatic system disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0016 events5 affected12 at risk EG0023 events2 affected6 at risk EG0038 events4 affected4 at risk EG00411 events6 affected9 at risk
Sinus bradycardia	Cardiac disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0021 events1 affected6 at risk EG003
Eye disorders - other, specify	Eye disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0012 events2 affected12 at risk EG0020 events0 affected6 at risk EG003
Abdominal pain	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Constipation	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0016 events4 affected12 at risk EG0021 events1 affected6 at risk EG003
Diarrhea	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0013 events2 affected12 at risk EG0020 events0 affected6 at risk EG003
Dyspepsia	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Dysphagia	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Flatulence	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Gastrointestinal disorders - other, specify	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Mucositis oral	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG00110 events3 affected12 at risk EG0020 events0 affected6 at risk EG003
Nausea	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0014 events3 affected12 at risk EG0020 events0 affected6 at risk EG003
Oral pain	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Stomach pain	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Vomiting	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0014 events2 affected12 at risk EG0020 events0 affected6 at risk EG003
Fatigue	General disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0015 events5 affected12 at risk EG0021 events1 affected6 at risk EG003
Pain	General disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Mucosal infection	Infections and infestations	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0021 events1 affected6 at risk EG003
Alanine aminotransferase increased	Investigations	Systematic Assessment	EG0001 events1 affected3 at risk EG0013 events3 affected12 at risk EG0020 events0 affected6 at risk EG003
Alkaline phosphatase increased	Investigations	Systematic Assessment	EG0001 events1 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Aspartate aminotransferase increased	Investigations	Systematic Assessment	EG0001 events1 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Blood bilirubin increased	Investigations	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Electrocardiogram qt corrected interval prolonged	Investigations	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0021 events1 affected6 at risk EG003
Investigations - other, specify	Investigations	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Lymphocyte count decreased	Investigations	Systematic Assessment	EG0003 events2 affected3 at risk EG00144 events8 affected12 at risk EG0023 events3 affected6 at risk EG003
Neutrophil count decreased	Investigations	Systematic Assessment	EG0003 events1 affected3 at risk EG00154 events10 affected12 at risk EG0026 events3 affected6 at risk EG003
Platelet count decreased	Investigations	Systematic Assessment	EG0001 events1 affected3 at risk EG00123 events6 affected12 at risk EG0024 events3 affected6 at risk EG003
Weight loss	Investigations	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
White blood cell decreased	Investigations	Systematic Assessment	EG0003 events2 affected3 at risk EG00157 events10 affected12 at risk EG00210 events5 affected6 at risk EG003
Anorexia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0012 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Dehydration	Metabolism and nutrition disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0013 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Hypercalcemia	Metabolism and nutrition disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Hyperglycemia	Metabolism and nutrition disorders	Systematic Assessment	EG0002 events2 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Hyperkalemia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Hypermagnesemia	Metabolism and nutrition disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Hypoalbuminemia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Hypokalemia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0013 events2 affected12 at risk EG0021 events1 affected6 at risk EG003
Hyponatremia	Metabolism and nutrition disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0012 events2 affected12 at risk EG0020 events0 affected6 at risk EG003
Hypophosphatemia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0012 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0021 events1 affected6 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - other, specify	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Ataxia	Nervous system disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Dizziness	Nervous system disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Headache	Nervous system disorders	Systematic Assessment	EG0001 events1 affected3 at risk EG0014 events1 affected12 at risk EG0021 events1 affected6 at risk EG003
Paresthesia	Nervous system disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Proteinuria	Renal and urinary disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0020 events0 affected6 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected12 at risk EG0021 events1 affected6 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0013 events3 affected12 at risk EG0020 events0 affected6 at risk EG003
Rash acneiform	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0012 events2 affected12 at risk EG0020 events0 affected6 at risk EG003
Hypertension	Vascular disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0012 events1 affected12 at risk EG0020 events0 affected6 at risk EG003
Hypotension	Vascular disorders	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected12 at risk EG0020 events0 affected6 at risk EG003

ID	Title	Description
BG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
BG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
BG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
BG003	Stratum II, Dose Level 1 (50 mg/m2)	Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
BG004	Stratum II, Dose Level 2 (75mg/m2)	Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.
BG005	Total	Total of all reporting groups

ID	Term
D016545	Choroid Plexus Neoplasms
D001254	Astrocytoma
D009837	Oligodendroglioma
D005909	Glioblastoma
D018302	Neoplasms, Neuroepithelial
D008527	Medulloblastoma

ID	Term
D002551	Cerebral Ventricle Neoplasms
D001932	Brain Neoplasms
D016543	Central Nervous System Neoplasms
D009423	Nervous System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D005910	Glioma
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type
D009375	Neoplasms, Glandular and Epithelial
D009380	Neoplasms, Nerve Tissue
D018242	Neuroectodermal Tumors, Primitive

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Stratum I, Dose Level 1 (50 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.	0	3	0	3	3	3
EG001	Stratum I, Dose Level 2 (75 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.	3	12	1	12	12	12
EG002	Stratum I, Dose Level 3 (95 mg/m2)	Less-heavily pre-treated patients received oral palbociclib daily at 95 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.	1	6	1	6	5	6
EG003	Stratum II, Dose Level 1 (50 mg/m2)	Heavily pre-treated patients received oral palbociclib daily at 50 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.	1	4	0	4	4	4
EG004	Stratum II, Dose Level 2 (75mg/m2)	Heavily pre-treated patients received oral palbociclib daily at 75 mg/m2/day for 21 days followed by a week rest (one course = 28 days) for up to 26 courses in the absence of disease progression or unacceptable toxicity.	1	9	0	9	9	9