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

Phase I Study of CDK 4-6 Inhibitor PD-0332991 (Palbociclib; IBRANCE) in Children With Recurrent, Progressive or Refractory Central Nervous System Tumors

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02255461

Enrollment

Registered

2014-10-02

Start date

2014-12-08

Completion date

2019-02-25

Last updated

2021-03-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Childhood Choroid Plexus Tumor, Childhood Ependymoblastoma, Childhood Grade III Meningioma, Childhood High-grade Cerebellar Astrocytoma, Childhood High-grade Cerebral Astrocytoma, Childhood Medulloepithelioma, Recurrent Childhood Anaplastic Astrocytoma, Recurrent Childhood Anaplastic Oligoastrocytoma, Recurrent Childhood Anaplastic Oligodendroglioma, Recurrent Childhood Brain Stem Glioma, Recurrent Childhood Cerebellar Astrocytoma, Recurrent Childhood Cerebral Astrocytoma, Recurrent Childhood Giant Cell Glioblastoma, Recurrent Childhood Glioblastoma, Recurrent Childhood Gliomatosis Cerebri, Recurrent Childhood Gliosarcoma, Recurrent Childhood Medulloblastoma, Recurrent Childhood Pineoblastoma, Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor

Brief summary

This phase I trial studies the side effects and best dose of palbociclib isethionate in treating younger patients with central nervous system tumors that have grown, come back, or not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed 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.

Interventions

DRUGpalbociclib isethionate

Given PO

OTHERpharmacological study

Correlative studies

OTHERlaboratory biomarker analysis

Correlative studies

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

4 Years to 21 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Steady State Area Under the Plasma Concentration Time Curve (AUC)	Up to day 22	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.
Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I	4 weeks	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.
Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II	4 weeks	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.
Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)	4 weeks	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.
Single Dose Apparent Volume of Central Compartment (Vc/F)	Up to day 3	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.
Single Dose Elimination Rate Constant (Ke)	Up to day 3	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.
Single Dose Half-life (t1/2)	Up to day 3	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.
Single Dose Apparent Oral Clearance (CL/F)	Up to day 3	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.
Single Dose Area Under the Plasma Concentration Time Curve (AUC)	Up to day 3	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.
Steady State Apparent Volume of Central Compartment (Vc/F)	Up to day 22	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.
Steady State Elimination Rate Constant (Ke)	Up to day 22	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.
Steady State Half-life (t1/2)	Up to day 22	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.
Steady State Apparent Oral Clearance (CL/F)	Up to day 22	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.

Secondary

Measure	Time frame	Description
Association Between Neutropenia and Single Dose Palbociclib AUC	Up to approximately 4 weeks	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.
Association Between Lymphopenia and Single Dose Palbociclib AUC	Up to approximately 4 weeks	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.
Association Between Leukopenia and Single Dose Palbociclib AUC	Up to approximately 4 weeks	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.
Number of Subjects With Objective Responses	Up to 2 years	Objective responses included complete response (CR) and partial response (PR).

Other

Measure	Time frame	Description
Number of Subjects With Ink4a-ARF Loss Copy Number Variations	At enrollment	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.
Polymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1)	At enrollment	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.
Polymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2)	At enrollment	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.
Number of Subjects With Cyclin-dependent Kinase-6 (CDK6) Copy Number Variations	At enrollment	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.
Number of Subjects With Cyclin-dependent Kinase-4 (CDK4) Copy Number Variations	At enrollment	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.
Number of Subjects With Cyclin D1 Copy Number Variations	At enrollment	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.
Number of Subjects With Cyclin D2 Copy Number Variations	At enrollment	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.
Number of Subjects With Cyclin D3 Copy Number Variations	At enrollment	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.

Countries

United States

Participant flow

Recruitment details

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.

Pre-assignment details

All 35 eligible patients enrolled were included. The 'Completed' row included patients who completed all protocol therapy or who experienced a protocol endpoint which took them off therapy. These included dose limiting toxicities and progression/relapse events. Adverse events not related to study agent were included in the 'Not Completed' row.

Participants by arm

Arm	Count
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.	3
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.	12
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.	6
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.	4
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.	10
Total	35

Withdrawals & dropouts

Period	Reason	FG001	FG002	FG004
Overall Study	Adverse Event	1	0	1
Overall Study	Not meet dose reduction BSA requirement	1	0	0
Overall Study	Withdrawal by Subject	0	1	1

Baseline characteristics

Characteristic	Stratum I, Dose Level 1 (50 mg/m2)	Total	Stratum II, Dose Level 2 (75mg/m2)	Stratum II, Dose Level 1 (50 mg/m2)	Stratum I, Dose Level 3 (95 mg/m2)	Stratum I, Dose Level 2 (75 mg/m2)
Age, Continuous	16.6 years	12.7 years	10.5 years	16.5 years	9.3 years	12.6 years
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	8 Participants	3 Participants	0 Participants	2 Participants	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants	20 Participants	5 Participants	2 Participants	4 Participants	6 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	7 Participants	2 Participants	2 Participants	0 Participants	3 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	3 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	4 Participants	2 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	3 Participants	1 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) White	2 Participants	23 Participants	7 Participants	3 Participants	4 Participants	7 Participants
Region of Enrollment United States	3 participants	35 participants	10 participants	4 participants	6 participants	12 participants
Sex: Female, Male Female	1 Participants	12 Participants	3 Participants	0 Participants	3 Participants	5 Participants
Sex: Female, Male Male	2 Participants	23 Participants	7 Participants	4 Participants	3 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 3	3 / 12	1 / 6	1 / 4	1 / 9
other Total, other adverse events	3 / 3	12 / 12	5 / 6	4 / 4	9 / 9
serious Total, serious adverse events	0 / 3	1 / 12	1 / 6	0 / 4	0 / 9

Outcome results

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.

Time frame: 4 weeks

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

Arm	Measure	Value (NUMBER)
Stratum I	Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I	75 mg/m2/day

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.

Time frame: 4 weeks

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

Arm	Measure	Value (NUMBER)
Stratum I	Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II	75 mg/m2/day

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.

Time frame: 4 weeks

Population: 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.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Stratum I	Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)	0 Participants
Stratum I, Dose Level 2 (75 mg/m2)	Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)	2 Participants
Stratum I, Dose Level 3 (95 mg/m2)	Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)	2 Participants
Stratum II, Dose Level 1 (50 mg/m2)	Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)	0 Participants
Stratum II, Dose Level 2 (75mg/m2)	Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)	1 Participants

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.

Time frame: Up to day 3