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

• Sponsor: Pediatric Brain Tumor Consortium (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02255461
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 35
• Locations: 11
• Arm: 1
• Actual Duration (Months): 50.6
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: palbociclib isethionate; Other: pharmacological study; Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. To determine plasma pharmacokinetics of PD-0332991 in children with Rb1positive recurrent, progressive or refractory primary CNS tumors.

SECONDARY OBJECTIVES:

1. To record preliminary evidence of efficacy of PD-0332991 in children with recurrent CNS tumors.

2. 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).

3. 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).

4. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of CDK 4-6 Inhibitor PD-0332991 (Palbociclib; IBRANCE) in Children With Recurrent, Progressive or Refractory Central Nervous System Tumors
• Actual Study Start Date: Dec 8, 2014
• Actual Primary Completion Date: Feb 25, 2019
• Actual Study Completion Date: Feb 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
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; Given PO; Other Names: 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 ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

Secondary Outcome Measures

1. Number of Subjects With Objective Responses [Up to 2 years]

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

2. 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.

3. 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.

4. 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.

Other Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 21 Years
• Sexes Eligible for Study: 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:

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
2	Lucile Packard Children Hospital Stanford University	Palo Alto	California	United States	94304
3	Childrens National Medical Center	Washington	District of Columbia	United States	20010-2970
4	Lurie Childrens Hospital-Chicago	Chicago	Illinois	United States	60614
5	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
6	Duke University Medical Center	Durham	North Carolina	United States	27710
7	Cincinnati Children Hospital Medical Center	Cincinnati	Ohio	United States	45229
8	Children Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
9	St. Jude Children Research Hospital	Memphis	Tennessee	United States	38105
10	Texas Childrens Hospital	Houston	Texas	United States	77030
11	Seattle Children Hospital	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Pediatric Brain Tumor Consortium
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: David Van Mater, MD, Pediatric Brain Tumor Consortium

Study Documents (Full-Text)

• Informed Consent Form - Jun 28, 2018
• Study Protocol and Statistical Analysis Plan - Jun 28, 2018

More Information

Publications

None provided.

• Responsible Party: Pediatric Brain Tumor Consortium
• ClinicalTrials.gov Identifier: NCT02255461
• Other Study ID Numbers: PBTC-042; U01CA081457
• First Posted: Oct 2, 2014
• Last Update Posted: Mar 2, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Additional relevant MeSH terms: Neoplasms; Glioblastoma; Astrocytoma; Meningioma; Gliosarcoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Medulloblastoma; Oligodendroglioma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Choroid Plexus Neoplasms; Pinealoma; Neoplasms, Neuroepithelial; Recurrence; Palbociclib

Study Results

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 Detail	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.

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Period Title: Overall Study
STARTED	3	12	6	4	10
COMPLETED	3	10	5	4	8
NOT COMPLETED	0	2	1	0	2

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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.	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.	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.	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.	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.	Total of all reporting groups
Overall Participants	3	12	6	4	10	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	16.6	12.6	9.3	16.5	10.5	12.7
Sex: Female, Male (Count of Participants)
Female	1 33.3%	5 41.7%	3 50%	0 0%	3 30%	12 34.3%
Male	2 66.7%	7 58.3%	3 50%	4 100%	7 70%	23 65.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	3 25%	2 33.3%	0 0%	3 30%	8 22.9%
Not Hispanic or Latino	3 100%	6 50%	4 66.7%	2 50%	5 50%	20 57.1%
Unknown or Not Reported	0 0%	3 25%	0 0%	2 50%	2 20%	7 20%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	1 25%	0 0%	1 2.9%
Asian	1 33.3%	1 8.3%	1 16.7%	0 0%	0 0%	3 8.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	2 16.7%	0 0%	0 0%	2 20%	4 11.4%
White	2 66.7%	7 58.3%	4 66.7%	3 75%	7 70%	23 65.7%
More than one race	0 0%	0 0%	1 16.7%	0 0%	0 0%	1 2.9%
Unknown or Not Reported	0 0%	2 16.7%	0 0%	0 0%	1 10%	3 8.6%
Region of Enrollment (participants) [Number]
United States	3 100%	12 100%	6 100%	4 100%	10 100%	35 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Palbociclib in Stratum I
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stratum I
Arm/Group Description	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.
Measure Participants	19
Number [mg/m2/day]	75

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Palbociclib in Stratum II
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Stratum II
Arm/Group Description	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.
Measure Participants	11
Number [mg/m2/day]	75

3. Primary Outcome

Title	Number of Patients Who Experienced Dose Limiting Toxicities (DLTs)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	3	12	6	4	9
Count of Participants [Participants]	0 0%	2 16.7%	2 33.3%	0 0%	1 10%

4. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	3	12	6	4	9
Median (Full Range) [L/m^2]	672	741	708	847	850

5. Primary Outcome

Title	Single Dose Elimination Rate Constant (Ke)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	3	12	6	4	9
Median (Full Range) [per hour]	0.053	0.053	0.048	0.051	0.051

6. Primary Outcome

Title	Single Dose Half-life (t1/2)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	3	12	6	4	9
Median (Full Range) [hour]	13.0	13.0	14.6	13.8	13.5

7. Primary Outcome

Title	Single Dose Apparent Oral Clearance (CL/F)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	3	12	6	4	9
Median (Full Range) [L/h/m^2]	35.8	38.4	33.7	37.2	24.4

8. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	3	12	6	4	9
Median (Full Range) [h*ng/mL]	1156	1743	2407	1289	2538

9. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	2	10	3	4	8
Median (Full Range) [L/m^2]	491	449	442	705	458

10. Primary Outcome

Title	Steady State Elimination Rate Constant (Ke)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	2	10	3	4	8
Median (Full Range) [per hour]	0.052	0.050	0.062	0.032	0.039

11. Primary Outcome

Title	Steady State Half-life (t1/2)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	2	10	3	4	8
Median (Full Range) [hour]	13.7	13.7	11.3	23.1	17.9

12. Primary Outcome

Title	Steady State Apparent Oral Clearance (CL/F)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	2	10	3	4	8
Median (Full Range) [L/h/m^2]	26.6	25.8	28.1	17.0	16.1

13. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	2	10	3	4	8
Median (Full Range) [h*ng/mL]	1211	2143	2193	1410	2359

14. Secondary Outcome

Title	Number of Subjects With Objective Responses
Description	Objective responses included complete response (CR) and partial response (PR).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

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/Group Title	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)
Arm/Group Description	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.	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.	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.	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.	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.
Measure Participants	3	12	6	4	9
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%

15. Secondary Outcome

Title	Association Between Neutropenia and Single Dose Palbociclib AUC
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	All Patients
Arm/Group Description	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).
Measure Participants	34
No neutropenia	1424.4 (966.3)
Grade 1 or 2 neutropenia	2166.3 (797.8)
Grade 3 or 4 neutropenia	1937.6 (621.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum I
	Comments
	Type of Statistical Test	Other
	Comments	Ordinal logistic regression model was built for outcome neutropenia (0/1/2). Explanatory variable AUC was transformed by dividing by 100.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Association Between Lymphopenia and Single Dose Palbociclib AUC
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	All Patients
Arm/Group Description	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).
Measure Participants	34
No lymphopenia	1727.5 (882.6)
Grade 1 or 2 lymphopenia	1837.9 (592.7)
Grade 3 or 4 lymphopenia	2159.0 (793.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum I
	Comments
	Type of Statistical Test	Other
	Comments	Ordinal logistic regression model was built for outcome lymphopenia (0/1/2). Explanatory variable AUC was transformed by dividing by 100.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.97 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Association Between Leukopenia and Single Dose Palbociclib AUC
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	All Patients
Arm/Group Description	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).
Measure Participants	34
No leukopenia	1420.3 (955.1)
Grade 1 or 2 leukopenia	1879.6 (682.6)
Grade 3 or 4 leukopenia	2171.6 (712.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum I
	Comments
	Type of Statistical Test	Other
	Comments	Ordinal logistic regression model was built for outcome leukopenia (0/1/2). Explanatory variable AUC was transformed by dividing by 100.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 1.01 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Other Pre-specified Outcome

Title	Number of Subjects With Cyclin D1 Copy Number Variations
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

21. Other Pre-specified Outcome

Title	Number of Subjects With Cyclin D2 Copy Number Variations
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

22. Other Pre-specified Outcome

Title	Number of Subjects With Cyclin D3 Copy Number Variations
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

23. Other Pre-specified Outcome

Title	Number of Subjects With Ink4a-ARF Loss Copy Number Variations
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

24. Other Pre-specified Outcome

Title	Polymorphisms in Efflux-transporter Proteins P-glycoprotein (P-gp; ABCB1)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

25. Other Pre-specified Outcome

Title	Polymorphisms in Breast Cancer Resistance Protein (BCRP; ABCG2)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 2 years after starting treatment
Adverse Event Reporting Description	Adverse events (AEs) were graded using CTCAE v4.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to palbociclib and b) all grade 3+ AEs on treatment and within 30 days off treatment. AEs that were at least possibly attributable to palbociclib were summarized in SAE and Other AE tables below. All mortality on this study were due to disease. One patient in stratum II dose level 2 withdrew prior to protocol therapy and was not at risk.
Arm/Group Title	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)
Arm/Group Description	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.		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.		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.		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.		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.
All Cause Mortality
	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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		3/12 (25%)		1/6 (16.7%)		1/4 (25%)		1/9 (11.1%)
Serious Adverse Events
	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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/12 (8.3%)		1/6 (16.7%)		0/4 (0%)		0/9 (0%)
Investigations
Neutrophil count decreased	0/3 (0%)	0	0/12 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/9 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	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)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		12/12 (100%)		5/6 (83.3%)		4/4 (100%)		9/9 (100%)
Blood and lymphatic system disorders
Anemia	0/3 (0%)	0	5/12 (41.7%)	6	2/6 (33.3%)	3	4/4 (100%)	8	6/9 (66.7%)	11
Cardiac disorders
Sinus bradycardia	0/3 (0%)	0	0/12 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/9 (0%)	0
Eye disorders
Eye disorders - other, specify	0/3 (0%)	0	2/12 (16.7%)	2	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	4
Constipation	1/3 (33.3%)	1	4/12 (33.3%)	6	1/6 (16.7%)	1	1/4 (25%)	1	1/9 (11.1%)	1
Diarrhea	1/3 (33.3%)	1	2/12 (16.7%)	3	0/6 (0%)	0	1/4 (25%)	1	0/9 (0%)	0
Dyspepsia	0/3 (0%)	0	0/12 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	0/9 (0%)	0
Dysphagia	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Flatulence	1/3 (33.3%)	1	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Gastrointestinal disorders - other, specify	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Mucositis oral	0/3 (0%)	0	3/12 (25%)	10	0/6 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	1
Nausea	0/3 (0%)	0	3/12 (25%)	4	0/6 (0%)	0	1/4 (25%)	1	0/9 (0%)	0
Oral pain	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Stomach pain	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Vomiting	1/3 (33.3%)	1	2/12 (16.7%)	4	0/6 (0%)	0	1/4 (25%)	1	2/9 (22.2%)	4
General disorders
Fatigue	1/3 (33.3%)	1	5/12 (41.7%)	5	1/6 (16.7%)	1	1/4 (25%)	1	3/9 (33.3%)	3
Pain	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Infections and infestations
Mucosal infection	0/3 (0%)	0	0/12 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/9 (0%)	0
Investigations
Alanine aminotransferase increased	1/3 (33.3%)	1	3/12 (25%)	3	0/6 (0%)	0	0/4 (0%)	0	2/9 (22.2%)	3
Alkaline phosphatase increased	1/3 (33.3%)	1	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Aspartate aminotransferase increased	1/3 (33.3%)	1	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	2/9 (22.2%)	2
Blood bilirubin increased	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Electrocardiogram qt corrected interval prolonged	0/3 (0%)	0	1/12 (8.3%)	1	1/6 (16.7%)	1	1/4 (25%)	2	1/9 (11.1%)	1
Investigations - other, specify	0/3 (0%)	0	0/12 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	1
Lymphocyte count decreased	2/3 (66.7%)	3	8/12 (66.7%)	44	3/6 (50%)	3	2/4 (50%)	10	4/9 (44.4%)	8
Neutrophil count decreased	1/3 (33.3%)	3	10/12 (83.3%)	54	3/6 (50%)	6	4/4 (100%)	13	7/9 (77.8%)	25
Platelet count decreased	1/3 (33.3%)	1	6/12 (50%)	23	3/6 (50%)	4	2/4 (50%)	10	5/9 (55.6%)	13
Weight loss	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
White blood cell decreased	2/3 (66.7%)	3	10/12 (83.3%)	57	5/6 (83.3%)	10	4/4 (100%)	15	7/9 (77.8%)	22
Metabolism and nutrition disorders
Anorexia	1/3 (33.3%)	1	1/12 (8.3%)	2	0/6 (0%)	0	3/4 (75%)	3	0/9 (0%)	0
Dehydration	0/3 (0%)	0	1/12 (8.3%)	3	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Hypercalcemia	0/3 (0%)	0	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1
Hyperglycemia	2/3 (66.7%)	2	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Hyperkalemia	1/3 (33.3%)	1	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1
Hypermagnesemia	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Hypoalbuminemia	1/3 (33.3%)	1	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Hypokalemia	1/3 (33.3%)	1	2/12 (16.7%)	3	1/6 (16.7%)	1	0/4 (0%)	0	2/9 (22.2%)	2
Hyponatremia	0/3 (0%)	0	2/12 (16.7%)	2	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Hypophosphatemia	1/3 (33.3%)	1	1/12 (8.3%)	2	0/6 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1
Myalgia	0/3 (0%)	0	0/12 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/9 (0%)	0
Pain in extremity	0/3 (0%)	0	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - other, specify	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Nervous system disorders
Ataxia	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Dizziness	0/3 (0%)	0	0/12 (0%)	0	0/6 (0%)	0	1/4 (25%)	1	1/9 (11.1%)	2
Headache	1/3 (33.3%)	1	1/12 (8.3%)	4	1/6 (16.7%)	1	0/4 (0%)	0	0/9 (0%)	0
Paresthesia	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Renal and urinary disorders
Proteinuria	0/3 (0%)	0	0/12 (0%)	0	0/6 (0%)	0	0/4 (0%)	0	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Alopecia	0/3 (0%)	0	0/12 (0%)	0	1/6 (16.7%)	1	0/4 (0%)	0	0/9 (0%)	0
Dry skin	0/3 (0%)	0	3/12 (25%)	3	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Rash acneiform	0/3 (0%)	0	2/12 (16.7%)	2	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Vascular disorders
Hypertension	0/3 (0%)	0	1/12 (8.3%)	2	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0
Hypotension	0/3 (0%)	0	1/12 (8.3%)	1	0/6 (0%)	0	0/4 (0%)	0	0/9 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.