Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: Ibrance, palbociclib, Abraxane, nab-paclitaxel, pancreas,
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 76
Healthy volunteers: no

Brief summary:
This is a Phase 1, open label, multi center, multiple dose, dose escalation, safety, pharmacokinetic and pharmacodynamic study of palbociclib in combination with nab-P, in sequential cohorts of adult patients with mPDAC, with MTD expansion cohort(s). Approximately 30-60 patients are expected to be enrolled in the overall study.

Detailed description:
The study has 2 parts:

• Part A (Dose-Escalation Cohorts): Consecutive cohorts of patients will receive escalating doses of oral palbociclib in combination with intravenous nab-P in 28-day cycles, in order to estimate the MTD(s) of the combination. The starting doses will be 75 mg palbociclib, and 100 mg/m2 nab-P. The observation period for dose-limiting toxicities (DLTs) will be from Day 1 to Day 28. Pharmacokinetic (PK) and pharmacodynamic (PD) properties of palbociclib and nab-P will also be assessed. Up to approximately 30 patients will be enrolled. The criteria for dose escalation will be based on a modified toxicity probability interval (mTPI) method.

• Part B \[MTD Expansion Cohort(s)\]: When the MTD(s) of palbociclib plus nab-P has been estimated with confidence, enrollment will proceed into 1 or 2 MTD expansion cohort(s) of up to 20 patients each at the MTD(s). The objective of the MTD expansion cohort(s) will be to provide additional information on safety, tolerability, biomarkers, PD activity, and PK/PD relationship for the combination regimen in order to determine the RP2D. The MTD expansion cohort(s) will only enroll patients who have not received previous treatment for their metastatic disease in order to evaluate preliminary activity of the combination in the target patient population.

All patients (in Part A and B) will receive nab-P intravenously once weekly for 3 weeks out of each 28-day cycle. Palbociclib oral dosing will be once daily on Days 1-21 of each 28-day cycle. To allow for PK evaluation of nab-P administered alone, nab-P will be administered on Day -2 for Cycle 1 only. Subsequent cycles will administer both nab-P and palbociclib on Day 1. Alternate dosing schedules for palbociclib may be explored based on emerging PK, PD, and safety data.

Patients will be treated as long as they are clinically benefiting from investigational product without unacceptable toxicity, objective disease progression, or withdrawal of consent. A modified visit schedule will be implemented for patients who are on investigational product for more than 2 years.

Arms:
arm 1: Palbociclib oral dosing on Days 1 to 21 of each 28-day cycle. Nab-paclitaxel IV dosing on Days -2, 6, and 13 of Cycle 1, and on Days 1, 8, and 15 of subsequent cycles.

Interventions: intervention 1: Palbociclib intervention 2: Nab-Paclitaxel
Intervention descriptions: intervention 1: Palbociclib oral dosing on Days 1 to 21 of each 28-day cycle. intervention 2: Nab-paclitaxel IV dosing on Days -2, 6, and 13 of Cycle 1, and on Days 1, 8, and 15 of subsequent cycles.

Protocol document:
Prot_001.pdf: 
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AN OPEN-LABEL PHASE IB STUDY OF PALBOCICLIB (ORAL CDK 4/6 
INHIBITOR) PLUS ABRAXANE(NAB-PACLITAXEL) IN PATIENTS WITH 
METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA 
Compound:
PD-0332991
Compound Name:
Palbociclib
United States (US) Investigational New
Drug (IND) Number:
122,168
European Clinical Trials Database 
(EudraCT) Number:
2015-001307-31
Protocol Number:
A5481059
Phase:
Phase 1B


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Document History
Document
Version Date
Summary of Changes 
Original protocol
20 May 2015
Not applicable (N/A)
Amendment 1
15 September 2016
Major changes include:
1. Addition of modified dose regimen 
cohorts, resulting in an increased sample 
size of the overall study.
2.
 
 
 
3. Changes to dose modification guidelines 
for hematologic toxicities and addition of 
recommendations for growth factor use.
4. Updates to the list of required laboratory 
tests (amylase/lipase are required where 
available).
5. Modifications made to prohibited 
medications and medications not 
recommended.
6. Meal information nearest PK sampling 
days will be collected.
7. PK sample processing information was 
removed and reference to the Study 
Manual was added. 
8. General spelling and grammar corrections 
throughout the document.
Amendment 2
26 October 2016
1.
 
 
 
2. Clarification was added such that the full 
physical exam including all major body 
systems should be done if clinically 
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indicated.
3. Karnofsky Performance Status and pain 
VAS are not required on Cycle 1 Day -2 if 
acceptable screening assessment is 
performed within 7 days prior to start of 
investigational product. 
4. A statement was included that will permit 
completion of dose escalation without 
determining the MTD, based on emerging 
safety data and upon agreement between 
the investigators and the sponsor. 
5. Clarification of minor discrepancies 
throughout the document.
Amendment 3
23 August 2018
1. Updated background to include a 
notification that the palbociclib + 
nab-paclitaxel combination will not be 
further developed due to emerging data.
2. Included a provision to allow remaining 
patients on investigational product to 
continue until progression, unacceptable 
toxicity or consent withdrawal, and 
remaining patients in post-treatment 
follow up will be considered to have 
completed the study after 12 months 
(365 days) have elapsed from the first 
dose of investigational product.
3. Updated the schedule of activities to allow 
flexibility for remaining patients on 
investigational product.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs). 


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
LIST OF FIGURES .................................................................................................................10
APPENDICES .........................................................................................................................10
PROTOCOL SUMMARY.......................................................................................................11
SCHEDULE OF ACTIVITIES................................................................................................17
1. INTRODUCTION ...............................................................................................................25
1.1. Mechanism of Action/Indication.............................................................................25
1.2. Background and Rationale ......................................................................................25
1.2.1. Pancreatic Ductal Adenocarcinoma............................................................25
1.2.2. Investigational Agents: Nab-Paclitaxel ......................................................27
1.2.3. Investigational Agents: Palbociclib............................................................29
1.2.3.1. Pre-Clinical Data.......................................................................29
1.2.3.3. Overview of Palbociclib Nonclinical Safety Data ....................31
1.2.3.4. Palbociclib Pharmacokinetics in Human...................................31
1.2.4. Palbociclib Clinical Data............................................................................31
1.2.5. Study Rationale...........................................................................................32
1.2.6. Rationale for Modified Dose Regimens (Amendment 1)...........................33
1.2.7. Rationale for Amendment 3........................................................................33
1.2.8. Summary of Benefit Risk Assessment .......................................................34
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................34
2.1. Objectives................................................................................................................34
2.2. Endpoints.................................................................................................................35
3. STUDY DESIGN.................................................................................................................37
3.1. Study Overview.......................................................................................................37
3.1.1. Starting Dose Level ....................................................................................39
3.1.2. Criteria for Dose Escalation........................................................................39
3.1.3. Modified Dose Regimens: Criteria for Opening MDR Expansion 
Cohort ..............................................................................................................44
3.2. Dose Limiting Toxicity Definition..........................................................................44
3.3. Maximum Tolerated Dose Definition .....................................................................45
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3.4. Recommended Phase 2 Dose (RP2D) Definition ...................................................45
4. PATIENT SELECTION......................................................................................................45
4.1. Inclusion Criteria.....................................................................................................45
4.2. Exclusion Criteria....................................................................................................47
4.3. Lifestyle Guidelines ................................................................................................49
4.3.1. Dietary Restrictions ....................................................................................49
4.3.2. Use of Contraception..................................................................................49
4.4. Sponsor’s Qualified Medical Personnel..................................................................50
5. STUDY TREATMENTS.....................................................................................................51
5.1. Allocation to Treatment ..........................................................................................51
5.2. Patient Compliance .................................................................................................51
5.3. Investigational Product Supplies.............................................................................52
5.3.1. Dosage Form(s) and Packaging..................................................................52
5.3.1.1. Palbociclib.................................................................................52
5.3.1.2. Nab-Paclitaxel ...........................................................................52
5.3.2. Preparation and Dispensing........................................................................52
5.3.2.1. Palbociclib.................................................................................52
5.3.2.2. Nab-Paclitaxel ...........................................................................53
5.3.3. Administration............................................................................................53
5.3.3.1. Nab-Paclitaxel Administration..................................................53
5.3.4. Palbociclib Administration.........................................................................54
5.3.5. Nab-Paclitaxel.............................................................................................55
5.3.6. General Recommended Dose Modifications..............................................55
5.3.6.1. Dosing Interruptions..................................................................56
5.3.6.2. Dose Delays and Retreatment Criteria......................................56
5.3.6.3. Dose Reductions........................................................................57
5.3.7. Recommended Dose Modifications for Specific Toxicities.......................58
5.3.7.1. Dose Modifications for Hematologic Toxicities.......................60
5.3.7.2. Dose Modifications for QTc Prolongation................................61
5.4. Investigational Product Storage ..............................................................................62
5.5. Investigational Product Accountability...................................................................63
5.5.1. Destruction of Investigational Product Supplies ........................................63


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5.6. Concomitant Medications and Treatment(s)...........................................................63
5.6.1. Prohibited Medications...............................................................................64
5.6.2. Medications Not Recommended.................................................................64
5.6.3. Antacids Agents..........................................................................................65
5.6.4. Use of Growth Factors................................................................................65
5.7. Other Investigational Agent(s)................................................................................65
5.8. Concomitant Radiotherapy or Surgery....................................................................65
6. STUDY PROCEDURES .....................................................................................................66
6.1. Screening.................................................................................................................66
6.2. Treatment Period.....................................................................................................67
6.3. End of Treatment Visit............................................................................................67
6.4. Follow-up Visit .......................................................................................................67
6.5. --Post-Study Patient Interview ................................................................................68
6.6. Patient Withdrawal..................................................................................................68
6.6.1. Study Treatment Discontinuation...............................................................68
6.6.2. Study Discontinuation ................................................................................69
7. ASSESSMENTS..................................................................................................................70
7.1. Efficacy Assessments..............................................................................................71
7.1.1. Tumor Assessments....................................................................................71
7.1.1.1. Screening/Baseline Tumor Assessment ....................................71
7.1.1.2. Post-Baseline Tumor Assessments............................................71
7.1.2. Overall Survival..........................................................................................72
7.1.3. Pregnancy Testing ......................................................................................72
7.2. Safety Assessments .................................................................................................73
7.2.1. Adverse Events...........................................................................................73
7.2.2. Laboratory Safety Assessment ...................................................................73
7.2.3. Vital Signs and Physical Examination........................................................74
7.2.4. (12-Lead) Electrocardiogram......................................................................74
7.2.5. Other Safety Assessments...........................................................................75
7.3. Pharmacokinetics Assessments...............................................................................75
7.3.1. Palbociclib Pharmacokinetic Assessments.................................................75
7.3.2. Nab-Paclitaxel Pharmacokinetic Assessments ...........................................77


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7.4. Biomarker Assessments ..........................................................................................78
7.4.1. Optional De Novo Tumor Tissue Biopsy for Pharmacodynamic 
Analysis............................................................................................................79
8. ADVERSE EVENT REPORTING......................................................................................82
8.1. Adverse Events........................................................................................................82
8.2. Reporting Period .....................................................................................................83
8.3. Definition of an Adverse Event...............................................................................83
8.4. Medication Errors....................................................................................................84
8.5. Abnormal Test Findings..........................................................................................85
8.6. Serious Adverse Events...........................................................................................85
8.6.1. Protocol-Specified Serious Adverse Events...............................................86
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................86
8.7. Hospitalization ........................................................................................................87
8.8. Severity Assessment................................................................................................88
8.9. Causality Assessment..............................................................................................89
8.10. Exposure During Pregnancy..................................................................................89
8.11. Occupational Exposure .........................................................................................90
8.12. Withdrawal Due to Adverse Events (see also the section on Patient 
Withdrawal)...............................................................................................................90
8.13. Eliciting Adverse Event Information ....................................................................91
8.14. Reporting Requirements........................................................................................91
8.14.1. Serious Adverse Event Reporting Requirements .....................................91
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................91
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................91
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................92
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9.1. Analysis Sets ...........................................................................................................92
9.2. Statistical Methods and Properties ..........................................................................92
9.2.1. Statistical Methods for Dose Escalation/De-Escalation .............................93
9.2.1.1. mTPI Method ............................................................................93
9.2.2. Statistical Method for Estimating the Maximum Tolerated Dose..............94
9.3. Sample Size Determination.....................................................................................95
9.4. Efficacy Analysis ....................................................................................................95
9.4.1. Analysis of Efficacy Endpoint (Expansion Cohorts)..................................95
9.5. Analysis of Other Endpoints ...................................................................................95
9.5.1. Analysis of Pharmacokinetics.....................................................................95
9.5.1.1. Palbociclib.................................................................................95
9.5.1.2. Nab-Paclitaxel ...........................................................................96
9.5.1.3. Statistical Analysis of Pharmacokinetic endpoints ...................96
9.5.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic Modeling ...............................................96
9.5.2.1. PK/PD correlation .....................................................................96
9.5.3. Biomarkers..................................................................................................97
9.5.3.1. Analysis of Biomarker Endpoints .............................................97
9.6. Safety Analysis........................................................................................................97
9.6.1. Analysis of the Primary Endpoint...............................................................98
9.6.2. Analysis of Secondary Safety Endpoints....................................................98
9.6.3. Electrocardiogram.......................................................................................98
9.7. Data Safety Monitoring Committee ........................................................................99
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................99
11. DATA HANDLING AND RECORD KEEPING ...........................................................100
11.1. Case Report Forms/Electronic Data Record .......................................................100
11.2. Record Retention.................................................................................................100
12. ETHICS............................................................................................................................101
12.1. Institutional Review Board/Ethics Committee....................................................101
12.2. Ethical Conduct of the Study ..............................................................................101
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12.3. Patient Information and Consent.........................................................................101
12.4. Patient Recruitment.............................................................................................102
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................102
13. DEFINITION OF END OF TRIAL.................................................................................103
13.1. End of Trial in a Member State...........................................................................103
13.2. End of Trial in All Other Participating Countries...............................................103
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................103
15. PUBLICATION OF STUDY RESULTS........................................................................103
15.1. Communication of Results by Pfizer ..................................................................103
15.2. Publications by Investigators ..............................................................................104
16. REFERENCES ................................................................................................................106
17. APPENDICES .................................................................................................................108
LIST OF TABLES
Table 1.
SCHEDULE OF ACTIVITIES (up to Cycle 13) .................................................17
Table 2.
Tumor Assessment Requirements Flowchart .......................................................23
Table 3.
PK Sampling and 
 Schema................................................................24
Table 4.
Potential Palbociclib and Nab-Paclitaxel Dose Combinations.............................39
Table 5.
Palbociclib Capsule Characteristics......................................................................52
Table 6.
General Criteria for Start of New Cycle...............................................................56
Table 7.
Palbociclib and Nab-Paclitaxel Dose Levels........................................................58
Table 8.
Recommended Dose Modifications for Adverse Events Associated with 
Palbociclib and/or Nab-Paclitaxel ........................................................................59
Table 9.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia (Dose Escalation and MTD Expansion Cohorts)..................60
Table 10.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia (MDR and MDR Expansion Cohorts)...................................61
Table 11.
Palbociclib Dose Modifications in the Event of QTc Prolongation .....................62
Table 12.
Laboratory Tests ...................................................................................................73
Table 13.
Summary of Biomarker Assessments...................................................................79
Table 14.
Number of Patients with DLT for Dose Escalation Decisions at a Dose 
Level .....................................................................................................................93
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LIST OF FIGURES
Figure 2.
Palbociclib and Nab-Paclitaxel Combination Dose Escalation and 
De-Escalation Sequence .......................................................................................40
Figure 3.
The General Dose Escalation and De-Escalation Schema with a Group Size 
of 3 Patients at a Given Dose Level......................................................................42
Figure 4.
Palbociclib and Nab-Paclitaxel Dose Combination Schema................................54
APPENDICES
Appendix 1. Abbreviations....................................................................................................108
Appendix 2. Karnofsky Performance Status..........................................................................112
 
Appendix 5. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines...........................................................................................................116
Appendix 6. Schedule of Activities for Patients on Investigational Product(s) Beyond 
2 Years (Not Applicable after implementation of Protocol Amendment 3).......121
Appendix 7. Dose Re-Escalation and De-Escalation Schemas for a Previous Dose 
Level (3 patients per group)................................................................................122
Appendix 8. Bone Marrow Reserve in Adults.......................................................................124
Appendix 9. List of Drugs Known to Predispose to Torsade de Pointes...............................128
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PROTOCOL SUMMARY
Metastatic pancreatic cancer is one of the most aggressive and highly lethal malignancies, 
with an estimated 5-year survival rate of less than 5%.1
KRAS mutations are a hallmark of pancreatic ductal adenocarcinoma (PDAC) with mutation 
found in more than 75% and up to 95% of tumors. Important regulatory proteins involved in 
the cell cycle transition from G1 into S-Phase are cyclin D1 (encoded by CCND1), 
p16INK4a (thereafter referred to as p16, and encoded by CDKN2A), and cyclin-dependent 
kinases (CDKs).  Deregulation of aspects of the cell-cycle, including CDKs, have been 
shown to contribute to the development of cancer.  Inactivation of p16 occurs in the majority 
of cases of metastatic PDAC (mPDAC).  Genomic characterization of PDAC identified loss 
of CDKN2A in more than 50% of tumors, most often concurrent with KRAS mutation.  In 
addition, activated MAPK pathway results in the increased expression of cyclin D1.
Palbociclib, (Ibrance®; PD-0332991) is a highly selective, reversible oral inhibitor of 
cyclin-dependent kinases 4 and 6 (CDK 4/6).  This compound prevents cellular 
deoxyribonucleic acid (DNA) synthesis by inhibiting progression of the cell cycle from 
G1 into S phase. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Nab-paclitaxel is indicated for the first-line treatment of patients with metastatic ductal 
adenocarcinoma of the pancreas (mPDAC), in combination with gemcitabine.  Median 
overall survival (OS) was extended from 6.7 months to 8.5 months when added to 
gemcitabine as first-line treatment of mPDAC (p<0.0001).2
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Single-agent data for nab-P were generated in a phase 2 clinical study evaluating
nab-P (100 mg/m2) in advanced pancreatic cancer patients who have progressed on 
gemcitabine-based therapy.3  Treatment resulted in 58 percent of patients achieving 
six-month OS, with a median survival of 7.3 months and a median progression-free survival 
(PFS) of 1.6 months.  Five patients remained alive at a median follow-up of 12.7 months, 
including one patient with stable disease (SD) on cycle 15 of therapy.  Safety results were 
generally consistent with the known safety profile of nab-P. 
 
Clinical development of palbociclib in first-line mPDAC builds upon robust pre-clinical data 
from PDX models.  
 
 
 
 
 
This current study aims to investigate the safety and tolerability, of the combination of 
palbociclib plus nab-P in patients with mPDAC.
STUDY OBJECTIVES AND ENDPOINTS
Objectives
Primary Objective: To assess the safety and tolerability of palbociclib in combination with 
nab-paclitaxel (nab-P) in patients with metastatic pancreatic ductal adenocarcinoma in order 
to estimate the maximum tolerated dose (MTD) and select the recommended Phase 2 dose 
(RP2D).
Secondary Objectives: 

To evaluate the overall safety profile of palbociclib in combination with nab-P; 

To characterize the multiple-dose pharmacokinetics of palbociclib when administered 
in combination with nab-P;

To evaluate the effect of palbociclib on pharmacokinetics of total paclitaxel when 
nab-P is administered in combination with palbociclib;

To evaluate the anti-tumor effect of palbociclib in combination with nab-P in patients 
with mPDAC;

To evaluate the pharmacodynamic effect of palbociclib and nab-P in patients with 
mPDAC;
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
To characterize candidate biomarkers of sensitivity or resistance in pre-treatment 
tumor tissue, including Rb1 and p16 expression, that may aid in the identification of 
patient subpopulations most likely to benefit from treatment.
 
 
 
 
 
 
. 
Endpoints
Primary Endpoint 

First cycle dose-limiting toxicities (DLTs).
Secondary Endpoints

Safety;

Adverse events (AEs) as characterized by type, frequency, severity [as graded by 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v.4.03], timing, seriousness, and relationship to study therapy;

Laboratory abnormalities as characterized by type, frequency, severity (as graded 
by NCI CTCAE version 4.03) and timing; 

Vital signs; 

Pharmacokinetic parameters of palbociclib and nab-P:
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
For palbociclib PK when given with nab-P: Multiple Dose (MD) (assuming 
steady-state is achieved) – Css,max, Tss,max, AUCss,, Css,trough, and CL/F as data 
permit;

For total paclitaxel when nab-P is given alone and in combination with 
palbociclib: Cmax, Tmax, AUClast, AUC∞, t1/2, CL, and Vz as data permit; 

Clinical pharmacodynamic (PD) markers associated with mPDAC (eg, Ca19-9);

Efficacy:

Objective tumor response, as assessed using the Response Evaluation Criteria in 
Solid Tumor (RECIST) version 1.1; 

Time-to-event endpoints: eg, Duration of Response (DR), Progression Free 
Survival (PFS), Six-month progression-free survival rate (6m-PFSR), Overall 
Survival (OS).

Biomarker endpoints:

Tumor tissue biomarkers (p16 and Rb1 expression by IHC). 
 
 
 
 
Study Design
This is a Phase 1, open label, multi-center, multiple dose, dose escalation, safety, 
pharmacokinetic and pharmacodynamic study of palbociclib in combination with nab-P, in 
sequential cohorts of adult patients with mPDAC, with expansion cohorts.  Approximately 
60-100 patients are expected to be enrolled in the overall study.  The study has several parts:
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
Dose Escalation Cohorts 
Consecutive cohorts of patients will receive escalating doses of oral palbociclib in 
combination with intravenous nab-P in 28-day cycles.  The starting dose of 
palbociclib will be 75 mg administered on Days 1-21 of each cycle (3/1 dosing 
schedule).  The starting dose of nab-P is 100 mg/m2 administered weekly for 3 weeks 
out of each 28-day cycle.  The observation period for dose-limiting toxicities (DLTs) 
will be from Day 1 until pre-dose Cycle 2 Day 1 (Day -2 and Day -1 will not be 
included in the DLT observation period).  Pharmacokinetic (PK) and 
pharmacodynamic (PD) properties of palbociclib and nab-P will be assessed.  Up to 
approximately 30 patients will be enrolled.
The criteria for dose escalation will be based on a modified toxicity probability 
interval (mTPI) method.
Alternate dosing schedules for palbociclib may be explored based on emerging PK, 
PD, and safety data.

Modified Dose Regimen Cohorts (Amendment 1):
Emerging data from dose levels 1, 2A and 2B have shown only 1 patient meeting the 
criteria for DLT; however, several patients have required dose reductions.  To further 
evaluate an optimal palbociclib/nab-P combination, an additional 2 cohorts of patients 
will be enrolled into alternative dose regimens at doses lower than the dose levels 
tested in dose escalation.  The following dose regimens will be tested: 

Modified Dose Regimen 1 (MDR1)-75 mg palbociclib once daily on Days 1-21 of 
each 28-day cycle, plus nab-P 125 mg/m2 biweekly in each 28-day cycle.

Modified Dose Regimen 2 (MDR2)-75 mg palbociclib continuous dosing, once 
daily, plus nab-P 100 mg/m2 biweekly in each 28-day cycle.
For patients assigned to a modified dose regimen, the use of granulocyte-colony 
stimulating factor (G-CSF) is prohibited in the first 3 cycles unless clinically 
indicated and medically unavoidable. Dose reduction and/or interruption 
should first be used to manage hematologic toxicities.
At least 6-9 patients will be enrolled into each MDR cohort. 

Expansion Cohorts 

MTD Expansion Cohort(s).


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When the MTD(s) of palbociclib plus nab-P has been estimated with confidence, 
enrollment will proceed into 1 or 2 MTD expansion cohort(s) of up to 20 patients 
each at the MTD(s).  Patients will receive the same dosing regimen as in the dose 
escalation cohorts (palbociclib 3/1 schedule and weekly nab-P for 3 weeks in each 
28-day cycle).

Modified Dose Regimen (MDR) Expansion Cohort (Amendment 3)
Based on emerging data from the MDR1 and MDR2 cohorts, enrollment into the 
MDR Expansion Cohort will be terminated. 
Patients will be treated as long as they are clinically benefiting from investigational products 
(IP) without unacceptable toxicity, objective disease progression, or withdrawal of consent. 
Protocol Amendment 3 
1. Patients who are continuing to receive IP may continue to do so as long as they are 
clinically benefiting from IP without unacceptable toxicity, objective disease 
progression, or withdrawal of consent.  Once a patient has completed Cycle 13, only 
safety data will be collected thereafter.  Patients who have completed 13 cycles of IP 
are not required to enter post-treatment follow-up upon permanent discontinuation of 
IP.  Patients who are ongoing beyond Cycle 13 will be considered to have completed 
the study upon permanent discontinuation of IP.
2. Patients who have discontinued IP before completing Cycle 13 will remain in 
post-treatment follow-up (See Schedule of Activities) until 12 months (365 days) 
have elapsed from the first dose of IP.  Once a patient has been followed for 
12 months from the first dose, the patient is considered to have completed the study 
and no further data will be collected.
Statistical Methods:
Dose escalation and de-escalation will follow a 2x3 matrix “Up-and-Down” design, with 
different dose combinations of palbociclib and nab-P using the modified toxicity probability 
interval (mTPI) method.  Approximately 60-100 patients are expected to be enrolled in the 
overall study.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities (SOA) table provides an overview of the protocol visits and procedures.  Refer to the Assessments section 
of the protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the Schedule of Activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Table 1.
SCHEDULE OF ACTIVITIES (up to Cycle 13)
Visit Identifier
Screening
Treatment Phase1
(1 cycle = 28 days)
End of 
Treatment/ 
Withdrawal2
Post-Treatment 
Follow-Up3
Cycle 1
Cycles 2-13
Study Day
Within 28 days 
prior to enrollment
Day
-24
Day
-1
Day 
1
Day 
65
Day 
13
Day
14
Day 
15
Day 16
Day 85
Day 15
Within 56 days 
of IP 
discontinuation
Monthly
Visit Time Window
1 
day
1 
day
1 
day
7 days 7 days
7 days
+7 days
28 days
Baseline Documentation
Informed Consent Process7
X
Medical / Oncological History8
X
Baseline Signs / Symptoms9
X4
Physical Examination/Vital Signs10
X
X4
X
X
X
X (C2D1 only, then as 
clinically indicated)
X
Serum/Urine Pregnancy Test11
X
X
X
X
Contraception Check12
X
Karnofsky Performance Status13
X
X
X
Laboratory Studies
Hematology14
X
X4
X
X
As clinically indicated
X
Coagulation14
X
X4
X
X
As clinically indicated
Blood Chemistry14
X
X4
X
X
As clinically indicated
X
Urinalysis14
X
X4
As clinically indicated
X
12-Lead ECG (in triplicate)15
X
X4
X
X(C2D1. C2D15, C4D1, C7D1)
X
Special Laboratory Studies 
Blood Sample for Ca 19-9
X
X
X
Blood Samples for Pharmacokinetics16
X
X
X
X
X
X
X
(C2 only)
X
(C2 only)


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Visit Identifier
Screening
Treatment Phase1
(1 cycle = 28 days)
End of 
Treatment/ 
Withdrawal2
Post-Treatment 
Follow-Up3
Cycle 1
Cycles 2-13
Study Day
Within 28 days 
prior to enrollment
Day
-24
Day
-1
Day 
1
Day 
65
Day 
13
Day
14
Day 
15
Day 16
Day 85
Day 15
Within 56 days 
of IP 
discontinuation
Monthly
Visit Time Window
1 
day
1 
day
1 
day
7 days 7 days
7 days
+7 days
28 days
Archival Tumor Tissue Specimen
X
De Novo Tumor Specimens19
X
X
Computed Tomography (CT)/ Magnetic 
Resonance Imaging (MRI); Clinical 
evaluation of superficial disease23
X
As clinically indicated. See Table 2.
Other Clinical Assessments
Drug Compliance24
X
X
X
Adverse Events25
X
Monitored and Recorded Continuously
X
Concomitant Medications/Treatments26
X
X
X
X
X
Survival 
X
Investigational Products
Enrollment29
X
Nab-paclitaxel administration (IV)30 – Dose 
escalation and MTD expansion cohorts
X
X
X
X
X
X
Nab-paclitaxel administration (IV)30 – MDR 
and MDR expansion cohorts
X
X
X
X
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Visit Identifier
Screening
Treatment Phase1
(1 cycle = 28 days)
End of 
Treatment/ 
Withdrawal2
Post-Treatment 
Follow-Up3
Cycle 1
Cycles 2-13
Study Day
Within 28 days 
prior to enrollment
Day
-24
Day
-1
Day 
1
Day 
65
Day 
13
Day
14
Day 
15
Day 16
Day 85
Day 15
Within 56 days 
of IP 
discontinuation
Monthly
Visit Time Window
1 
day
1 
day
1 
day
7 days 7 days
7 days
+7 days
28 days
Palbociclib administration (oral)– all patients 
except Modified Dose Regimen 2 (MDR2)
◄----------------------------------------------------------------►
Once daily with food on Days 1-21 of each 28-day cycle 
Palbociclib administration (oral) – Modified 
Dose Regimen 2 only
◄----------------------------------------------------------------►
Once daily (continuous dosing)
Note: After completion of Cycle 13, only safety data will be collected thereafter. Patients who have completed 13 cycles of IP are not required to enter 
post-treatment follow-up upon permanent discontinuation of IP.  Patients who are ongoing beyond Cycle 13 will be considered to have completed the study upon 
permanent discontinuation of IP.
Abbreviations: ◄--►= ongoing/continuous event; CxDy = Cycle x Day y; ECG = electrocardiogram; 
; CT = computed 
tomography; IP=investigational product; IV=intravenous; MDR=Modified Dose Regimen; MRI = magnetic resonance imaging; MTD=Maximum Tolerated 
Dose; 
; 
1.
All assessments should be performed prior to dosing with IP on the visit day unless otherwise indicated.  Acceptable time windows for performing each 
assessment are described in the column headers.  For the purposes of this trial, 1 cycle is 28 days in length.  A cycle could be longer than 28 days if 
persistent toxicity delays the initiation of the subsequent cycle.  Maximum time between visits is 30 days.
2.
End of Treatment/Withdrawal: End of Treatment/Withdrawal visit will be performed as soon as possible but no later than 8 weeks (ie, 56 days) 7 days 
from last dose of IP and prior to the initiation of any new anticancer therapy.
3.
Post Treatment Follow up: After discontinuation of IP, post study follow-up (including survival status and post study anticancer therapy therapies) will be 
collected every month (28 days) from the last dose of IP.  Telephone contact is acceptable.  Post-treatment follow up is considered complete after 
12 months (365 days) have elapsed from the first dose of IP.
4.
Cycle 1/Day -2: Blood chemistry, hematology, coagulation, urinalysis, 12-lead ECG, physical examination/vital signs, Karnofsky performance status, 
 
 and baseline signs/symptoms are not required if acceptable screening assessment is performed within 7 days prior to start of investigational product.
5.
Day 6/Day 8: Procedures on Day 6 of Cycle 1 and Day 8 of Cycle 2 are not required for patients assigned to MDR1 and MDR2 cohorts, since nab-P is 
administered biweekly in these cohorts. 
6.
Cycle 2, Day 1: In the event that the start of a new cycle is delayed due to treatment-related toxicity, procedures required on Day 1 of the given cycle will 
be performed when either investigational product is resumed. 
7.
Informed Consent: Informed consent may be obtained greater than 28 days from start of investigational product; however, it must be obtained prior to any 
protocol-required assessments being performed.
8.
Medical/Oncological History: To include information on prior anticancer treatments.
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9.
Baseline Signs/Symptoms: Baseline tumor-related signs and symptoms will be recorded at the C1D-2 visit prior to initiating nab-P and then reported as 
adverse events during the trial if they worsen in severity or increase in frequency.
10. Physical Examination/Vital Signs: A full physical examination including an examination of all major body systems (including general appearance, head, 
ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and musculoskeletal as clinically indicated), height (at screening only), weight, 
blood pressure and pulse rate, which may be performed by a physician, registered nurse or other qualified health care provider, will be required at Screening, 
C1D-2, and C2D1.  Thereafter, symptom directed physical examinations, blood pressure and pulse rate assessment will be performed as clinically indicated.
11. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL and 
assayed in a certified laboratory, will be performed on two occasions prior to starting IP, once at the start of screening, and once at the baseline visit 
immediately before investigational product administration (Cycle 1 Day -2).  Pregnancy tests will also be routinely repeated at every treatment cycle during 
the treatment period, at the End of Treatment visit, and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  Additional pregnancy tests may also be undertaken if requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  See Section 7.1.3 for further information.
12. Contraception Check: Male patients who are able to father children, and female patients who are of childbearing potential will need to affirm that they 
meet the criteria for correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to 
use 2 highly effective contraception methods consistently and correctly, and document such conversation in the patient’s chart.  In addition, the investigator 
or his or her designee will instruct the patient to call immediately if one or both selected contraception methods are discontinued, or if pregnancy is known or 
suspected in the patient or the patient’s partner.
13. Karnofsky Performance Status: See Appendix 2.  Karnofsky Performance Status is not required on Cycle 1 Day -2 if acceptable screening assessment is 
performed within 7 days prior to start of investigational product.
14. Hematology, Coagulation, Blood Chemistry, and Urinalysis: Hematology includes hemoglobin, WBC, absolute neutrophils, absolute lymphocytes, 
absolute monocytes, absolute eosinophils, absolute basophils, and platelet count.  Coagulation analysis includes PT or INR, aPTT and PTT.  Blood 
chemistry includes AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, BUN (or urea), serum creatinine, 
uric acid, phosphorus (or phosphate), albumin, glucose, and amylase/lipase (where available).  Additional blood tests should be performed where needed for 
the purpose of evaluating potential DLTs or other adverse events.  -Urinalysis will be conducted via urine dipstick for urine protein: if the result is positive, 
further diagnostic testing will be performed as clinically indicated.
15. 12-lead ECG:  to be performed pre-dose at Screening, Cycle 1 Day -2, Cycle 1 Day 13, Cycle 2 Day 1, and Cycle 2 Day 15; subsequent ECGs will be 
performed pre-dose on Day 1 of Cycles 4, and 7.  Patients should be fasted for at least 1 hour before ECGs are performed.  After Cycle 7, ECGs may be 
performed as clinically indicated.
16. Blood Sample for Pharmacokinetics: Plasma PK samples (4 mL) for total paclitaxel determination will be collected prior to nab-P IV infusion and at 
30 min (end of infusion), 1, 2, 4, 6, 8, 24, and 48 hours post the start of nab-P infusion on Day -2 and 13 of Cycle 1.  Plasma PK samples (3 mL) for 
palbociclib determination will be collected on Cycle 1 Day 13 at 0 (pre-dose), 2, 4, 6, 8, and 24 hours post palbociclib dose, and pre-dose on Cycle 2 Days 1 
and 15.  Meal information (nearest the palbociclib dose) will be collected on Cycle 1 Day 12, Cycle 1 Day 13, Cycle 2 Day 1, Cycle 2 Day 14, and Cycle 2 
Day 15.
17.
 
 
 
 
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18. Archival Tumor Tissue Specimen: A FFPE tissue block that contains sufficient tissue to generate at least 12 (preferably 15) unstained slides, each with 
tissue sections that are 5 microns thick should be collected.  If an FFPE tissue block cannot be provided, at least 12 (preferably 15) unbaked glass slides, 
each containing an unstained 5 micron FFPE tissue section will be required.  If an archival tumor tissue sample is not available, a de novo tumor biopsy 
specimen must be obtained before IPs are administered (Cycle 1 Day -2).  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE 
cell pellet material), is not adequate and should not be submitted.  Specimens will be sent to the sponsor-designated central laboratory.  Details for the 
handling of these specimens, including processing, storage, and shipment will be provided in the Study Manual. 
19. De Novo Tumor Specimens: Optional de novo tumor biopsy collection at Screening and End of Treatment.  If collected, these specimens will be provided 
in addition to the archival tumor tissue specimen that is required for eligibility purposes.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material), is not adequate and should not be submitted.  Details for handling of these specimens including processing, storage, and 
shipment will be provided in the Study Manual. 
20.
 
 
 
21.
 
 
 
23. Disease Assessments: Disease Assessments will be performed as clinically indicated.  See Table 2 for details and timing of procedures.
24. Drug Compliance: Palbociclib bottle(s), including any unused capsules, will be returned to the clinic for drug accountability.  Drug accountability will be 
performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle.
25. Adverse Events: For SAEs, the active reporting period begins from the time that the patient provides informed consent through and including 28 calendar 
days after the last administration of either investigational product.  Following the active safety reporting period, other SAEs of which the investigator 
becomes aware should be reported to Pfizer, unless the SAE is attributed by the investigator to complications of either the underlying malignancy or any 
subsequent anti cancer therapy or to the patient’s participation in a subsequent clinical study.  AEs (serious and non-serious) should be recorded on the CRF 
from the time the patient has taken at least one dose of investigational product through last patient visit.
26. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of IP and up to 28 days 
after the last dose of IP.  This includes H1 antagonists pre-medication to alleviate nab-paclitaxel infusion reactions.  Only anticancer medications will be 
collected in the post-treatment follow-up period. 
27.
28.
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29. Enrollment: A patient is considered enrolled when all screening procedures have been completed, the patient has satisfied the requirements of all 
inclusion/exclusion criteria, and the completed registration form has been approved by the sponsor. 
30. Nab-Paclitaxel Administration: Nab-paclitaxel will be administered as an intravenous infusion over 30 minutes.  For Cycle 1, nab-P will start on Days -2; 
for subsequent cycles, nab-paclitaxel will start on Day 1.


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Table 2.
Tumor Assessment Requirements Flowchart
Screeninga
Treatment Periodb
End of Treatment Visitc
CT or MRI of the 
chest and abdomen 
(including images of 
entire liver) and any 
other sites of 
disease, as clinically 
indicatedd
Requirede
Required for sites of 
disease identified at 
screening
Required for sites of disease identified at 
screening, unless disease progression has 
been confirmed elsewhere
Photographs of all 
superficial lesions as 
applicablef
Required
Required for sites of 
disease identified at 
screening
Required for sites of disease identified at 
screening, unless disease progression has 
been confirmed elsewhere
a.
Screening scans must occur within 4 weeks (ie, 28 days) prior to start of IP unless otherwise specified. 
b.
Tumor assessment are to be performedas clinically indicated during the treatment period, or until the patient meets 
criteria for investigational product discontinuation.  Tumor assessments are no longer required when the patient 
meets any of the following criteria: 1. Radiographically confirmed disease progression (PD) as per RECIST v.1.1 
(Appendix 5), 2. Initiation of new anticancer therapy, or 3. Discontinuation of patient from overall study 
participation (eg, death, patient's request, lost to follow up).  The same tumor assessment technique MUST be used 
throughout the study for a given lesion/patient. 
c.
Patients who have already demonstrated objective disease progression as per RECIST v.1.1 do not need to have 
scans repeated at the End of Treatment visit or during the post-treatment follow-up period-
d.
CT scans, including brain CT scan if applicable, should be performed with IV contrast agents unless contraindicated 
for medical reasons.  If IV contrast is medically contraindicated, the imaging modality to be used to follow the 
disease (either CT without contrast or MRI) should be the modality which best evaluates the disease, and the choice 
should be determined by the investigator in conjunction with the local radiologist.  MRI of the abdomen and pelvis 
can be substituted for CT if MRI adequately depicts the disease.  However, MRI of the chest should not be 
substituted for CT of chest even if IV contrast is contraindicated.  In such case CT will be performed without 
contrast.  If MRI is used to follow-up bone lesion(s) it should be performed a few days before any treatment that 
may affect bone-marrow cellularity (eg, G-CSF).
e.
Radiographic assessments obtained per the patient’s standard of care prior to consent is obtained do not need to be 
repeated and are acceptable to use as baseline evaluations, if (1) obtained within 28 days before start of IP, (2) they 
were performed using the method requirements outlined in RECIST v.1.1, (3) the same technique/modality can be 
used to follow identified lesions throughout the trial for a given patient, and (4) appropriate documentation 
indicating that these radiographic tumor assessments were performed as standard of care is available in the patient’s 
source notes. 
f.
Clinical assessment of superficial disease should be carried out on the same date as the imaging studies and will 
include photographs of all superficial metastatic lesions.  All lesion measurements must be recorded in the case 
report form (CRF).
Notes: 
Radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression 
at the discretion of the investigator.
If progressive disease is confirmed, patients are expected to discontinue IP and begin the follow-up phase of 
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Table 3.
PK Sampling and 
 Schema
Visit 
Identifier 
Cycle 1
Cycle 
2
Study Day
-2 
-1
1
2-5 61
7-12
13
14
15
15-21
11
151
Hours 
Pre/Post 
Dose2
01
0.5 1
2
4
6
8
24
48
01
0.5 1
2
4
6
8
24
48
Nab-paclitaxel 
Dosing
X
X3
X
X3
X
Total 
paclitaxel PK 
blood 
sampling 
X
X
X X X X X
X
X
X
X
X X X X X
X
X
Palbociclib 
Dosing
X
X
X
X4
X4,5,6
X
X
X
X5
X5
Palbociclib 
PK blood 
sampling 
X
X X X X
X
X1
X1
1.
Sample to be drawn prior to dosing of both nab-P and palbociclib. 
2.
Relative to nab-P start of infusion or palbociclib dosing, respectively.
3.
MDR and MDR expansion cohorts will not receive nab-P on Day 6/Day 8.
4.
Every attempt should be made to ensure the palbociclib was taken for the last 7 consecutive days, and the 
dose on Cycle 1 Day 12 is at least 20 hours before the pre-dose PK sample on Cycle 1 Day 13.  PK,
and 
blood sample should be rescheduled if one or more of these requirements have not been 
met. 
5.
Meal information (nearest the palbociclib dose) will be collected on Cycle 1 Day 12, Cycle 1 Day 13, 
Cycle 2 Day 1, Cycle 2 Day 14, and Cycle 2 Day 15.  Information including meal time and type (high fat, 
low fat, or standard) will be collected.
6.
On Cycle 1 Day 13, patients will be instructed to withhold administration of their palbociclib dose and 
bring it with them to their clinic visit.  Patients should be provided a meal within 30 minutes prior to 
palbociclib dosing.  After the meal is eaten, the pre-dose PK samples may be drawn just prior to palbociclib 
dosing.  Palbociclib dosing should be as close as possible to the start of the nab-P infusion.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Palbociclib (Ibrance®) is a highly selective, reversible oral inhibitor of cyclin-dependent 
kinases 4 and 6 (CDK 4/6).  The compound prevents cellular deoxyribonucleic acid (DNA) 
synthesis by prohibiting progression of the cell cycle from G1 into S phase.  Palbociclib is 
being developed in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel 
or nab-P) (Abraxane®) in patients with metastatic ductal adenocarcinoma of the pancreas 
(mPDAC).
1.2. Background and Rationale
1.2.1. Pancreatic Ductal Adenocarcinoma
Metastatic pancreatic cancer is one of the most aggressive and highly lethal malignancies, 
with an estimated 5-year survival rate of less than 5%.1
It is estimated that over 280,000 new cases of pancreatic cancer are diagnosed globally each 
year.  In the US and European Union (EU), the crude incidence rate of pancreatic cancer 
averages 15 cases per 100,000 population, which translates to approximately 38,000 incident 
cases and 34,000 deaths yearly.4
Over 95% of all malignancies of the pancreas are ductal adenocarinomas (PDAC).  Primary 
PDAC spreads and invades locally, affecting the organs of the abdominal cavity including 
the stomach, colon duodenum, and major blood vessels supplying and draining the intestinal 
tract and liver.  Regional lymph nodes are the most common site of metastasis while the liver 
is second.  Over 80% of patients present with regional or distant metastases at the time of 
diagnosis (Stage III or Stage IV) and are unsuitable for surgical resection.5  KRAS mutations 
are a hallmark of PDAC with mutations found in more than 75% and up to 95% of tumors.
PDAC was the fourth leading cause of death from cancer in Europe and the United States in 
2010.6,7  PDAC carries a grim prognosis with a median overall survival (OS) of only 
9-11 months,8,9 largely due to difficulties associated with diagnosing the disease in its early 
stages.7
Since 1997, gemcitabine (GEM) therapy has been the standard first-line treatment for 
patients with unresectable locally advanced or metastatic pancreatic cancer.  Clinical activity 
of GEM in metastatic PDAC (mPDAC) is relatively modest, as response rates are low 
(approximately 20%), and disease control rates and median OS benefits are extremely limited 
with a median progression-free survival (PFS) of approximately 3 months, and a median OS 
of 6 to 7 months.10
Given the poor response rates seen with single-agent GEM therapy, more recently clinical 
trial efforts have been undertaken to improve the efficacy of GEM while maintaining an 
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A small, but statistically significant improvement in survival among patients with advanced 
pancreatic cancer has been shown for erlotinib, a small-molecule inhibitor of the epidermal 
growth factor receptor (EGFR).11  As shown in other studies of agents targeting the EGFR, 
patients in whom drug-induced rashes developed had a better outcome.  However, the high 
frequency of KRAS-mutations in pancreatic cancer probably limits the benefits of an EGFR 
inhibitor.  As compared with erlotinib alone, the combination of gemcitabine and erlotinib 
has more toxicity, particularly gastrointestinal symptoms.  Together with the rather modest 
improvement in survival, the toxicity of this combination has limited its wide acceptance as 
the standard of care.
The FOLFIRINOX regimen (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) has gained 
favor as a first-line treatment for patients with locally-unresectable or metastatic pancreatic 
cancer.  In a Phase 3 study8 comparing FOLFIRINOX with single-agent GEM, the 
FOLFIRINOX regimen showed a median PFS of 6.4 vs. 3.3 months for GEM 
(HR =0.47; 95% confidence interval [CI], 0.37 to 0.59; P <0.001); a median OS of 11.1 vs. 
6.8 months (HR = 0.57, 95% CI, 0.45 to 0.73, P <0.001), and a 1-year survival of 48.4% vs. 
20.6%.  The Disease Control rate (CR + PR + SD) was 70.2% vs. 50.9% (P <0.001), with a 
duration of response of 5.9 vs. 4 months (p = NS).  However, while survival rates were 
improved with FOLFIRINOX, the toxicity of the regimen is significantly higher compared to 
GEM.  In this study, nearly half of the patients (45.7%) developed Grade 3/4 neutropenia 
with respect to 21% in the GEM arm, and febrile neutropenia was noted in 5.4% of patients 
treated with FOLFIRINOX compared to 1.2% of patients treated with GEM (p = 0.03).  
Patients on the FOLFIRINOX arm developed Grade 3/4 vomiting, fatigue, sensory 
neuropathy, and diarrhea at rates of 15%, 23%, 9% and 13%, respectively compared to 
8%, 18%, 0%  and 2% of patients treated with GEM.  This toxicity profile limits the use of 
FOLFIRINOX to those patients who are in good physical condition, relatively young, and 
with an excellent performance status.
Compared to FOLFIRINOX, the combination of GEM with a unique formulation of 
paclitaxel (Abraxane, nab-paclitaxel) provides a more favorable safety profile while 
maintaining similar levels of efficacy.  A Phase 3 trial confirmed the superiority of the 
combination of GEM with nab-paclitaxel (nab-P) versus GEM alone with statistically 
significant and clinically meaningful results across primary and secondary endpoints.9  
Median OS in the combination arm was superior to GEM alone (8.5 vs. 6.7 months, 
HR = 0.72, p =0.000015).  The one-year survival rate was 35% vs. 22% (p<0.001), and the 
two-year survival rate was 9% vs. 4% (p=0.02).  The median PFS was 5.5 vs. 3.7 months 
(HR = 0.69, p<0.001), and the overall response rate (ORR) was 23% compared to 
7% (p<0.001).  The safety profile of the doublet was manageable with the most common 
Grade 3 treatment-emergent AEs in the doublet vs. GEM alone being neutropenia (38% vs. 
27%), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%).  There was no significant 
difference in life-threatening toxicities between treatment arms.
However, the medical need remains high and the development of novel more efficacious and 
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1.2.2. Investigational Agents: Nab-Paclitaxel
Abraxane® (nab-paclitaxel or nab-P) is nanoparticle albumin-bound paclitaxel and therefore a 
microtubule inhibitor.  Nab-P is created by encapsulating paclitaxel within albumin 
nanoparticles.  This encapsulated formulation eliminates the need for Cremophor EL, thereby 
reducing hypersensitivity reactions during taxane infusion according to the product labeling.
Nab-paclitaxel is indicated for the first-line treatment of patients with metastatic ductal 
adenocarcinoma of the pancreas (mPDAC), in combination with gemcitabine.  Median 
overall survival (OS) was extended from 6.7 months to 8.5 months when added to 
gemcitabine as first-line treatment of mPDAC (p<0.0001).2
Single-agent data for nab-P were generated in a Phase 2 clinical study evaluating nab-P 
(100 mg/m2) in advanced pancreatic cancer patients who have progressed on 
gemcitabine-based therapy.3  Treatment resulted in 58 percent of patients achieving 
six-month OS, with a median survival of 7.3 months and a median progression-free survival 
(PFS) of 1.6 months.  Five patients remained alive at a median follow-up of 12.7 months, 
including one patient with stable disease (SD) on Cycle 15 of therapy.  Safety results were 
generally consistent with the known safety profile of nab-P.  Non-hematological toxicities 
were generally mild with Grade 1 or 2 nausea (63%), anorexia (47%), hypocalcemia 
(37%) and vomiting (26%) observed.  The most common Grade 3 and 4 adverse events that 
occurred were neutropenia (32%), neutropenic fever (11%) and anemia (11%).  There were 
no cases of Grade 3 or 4 neuropathy.  Nab-P was well-tolerated and provided clinical benefit 
in 37 percent of patients who had previously progressed on gemcitabine-based therapy.3
The results of this study demonstrated that single agent nab-paclitaxel is active in pancreatic
cancer patients who have previously progressed on gemcitabine-based therapy.  However, 
most of the safety data for single agent nab-P are have been generated in patients with 
metastatic breast cancer in a Phase 3 trial in comparison to paclitaxel.12 Mainly based on this 
study, the following adverse events describe the side effect profile for single agent nab-P:
Hematologic Disorders
Neutropenia was dose dependent and reversible.  Among patients with metastatic breast 
cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 
9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving 
paclitaxel injection at a dose of 175 mg/m2.  Pancytopenia has been observed in clinical 
trials.
Infections
Infectious episodes were reported in 24% of the patients treated with nab-P.  Oral 
candidiasis, respiratory tract infections and pneumonia were the most frequently reported 
infectious complications.


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Hypersensitivity Reactions (HSRs)
Grade 1 or 2 HSRs occurred on the day of nab-P administration and consisted of dyspnea 
(1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%).  The use of nab-P in 
patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has 
not been studied.
Cardiovascular
Hypotension, during the 30-minute infusion, occurred in 5% of patients.  Bradycardia, during 
the 30-minute infusion, occurred in <1% of patients.  These vital sign changes most often 
caused no symptoms and required neither specific therapy nor treatment discontinuation.  
Severe cardiovascular events possibly related to single-agent nab-P occurred in 
approximately 3% of patients.  These events included cardiac ischemia/infarction, chest pain, 
cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary 
thromboembolism, pulmonary emboli, and hypertension.  Cases of cerebrovascular attacks 
(strokes) and transient ischemic attacks have been reported.  Electrocardiogram (ECG) 
abnormalities were common among patients at baseline.  ECG abnormalities on study did not 
usually result in symptoms, were not dose-limiting, and required no intervention.  ECG 
abnormalities were noted in 60% of patients.  Among patients with a normal ECG prior to
study entry, 35% of all patients developed an abnormal tracing while on study.  The most 
frequently reported ECG modifications were non-specific repolarization abnormalities, sinus 
bradycardia, and sinus tachycardia.
Respiratory
Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with 
nab-P.
Neurologic
The frequency and severity of sensory neuropathy increased with cumulative dose.  Sensory 
neuropathy was the cause of nab-P discontinuation in 7/229 (3%) patients.  Twenty-four 
patients (10%) treated with nab-P developed Grade 3 peripheral neuropathy; of these 
patients, 14 had documented improvement after a median of 22 days; 10 patients resumed 
treatment at a reduced dose of nab-P and 2 discontinued due to peripheral neuropathy.  Of the 
10 patients without documented improvement, 4 discontinued the study due to peripheral 
neuropathy.  No Grade 4 sensory neuropathies were reported.  Only one incident of motor 
neuropathy (Grade 2) was observed in either arm of the controlled trial.
Vision Disorders
Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with nab-P and 
1% were severe.  The severe cases (keratitis and blurred vision) were reported in patients 
who received higher doses than those recommended (300 or 375 mg/m2).  These effects 
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Arthralgia/Myalgia
The symptoms were usually transient, occurred two or three days after nab-P administration, 
and resolved within a few days.
Hepatic
Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with nab-P and 
10% of patients treated with paclitaxel injection in the randomized trial.
Renal
Overall 11% of patients experienced creatinine elevation, 1% severe.  No discontinuations, 
dose reductions, or dose delays were caused by renal toxicities.
Other Clinical Events
Nail changes (changes in pigmentation or discoloration of nail bed) have been reported.  
Edema occurred in 10% of patients; no patients had severe edema.  Dehydration and pyrexia 
were also reported.
The Single Reference Safety Document (SRSD) for nab-P (Abraxane®) is the most recent 
version of the Summary of Product Characteristics (SPC).2
1.2.3. Investigational Agents: Palbociclib
1.2.3.1. Pre-Clinical Data 
Important regulatory proteins involved in the cell cycle transition from G1 into S-Phase are 
cyclin D1 (encoded by CCND1), p16INK4a (thereafter referred to as p16, and encoded by 
CDKN2A), and cyclin-dependent kinases (CDKs).  Deregulation of aspects of the cell-cycle, 
including CDKs, have been shown to contribute to the development of cancer.  Palbociclib 
(Molecular Weight: 447.53) is a highly selective inhibitor of CDK4/cyclin D1 kinase activity 
(IC50 = 11 nM; Ki= 2 nM).  Palbociclib has selectivity for CDK4/6, with little or no activity 
against a large panel of 274 other protein kinases including other CDKs and a wide variety of 
tyrosine and serine/threonine kinases.  CDK6, another enzyme that also complexes with 
cyclin-D subunits, is also commonly expressed in mammalian cells and tumors.  CDK6 is 
highly homologous to CDK4 and can perform the same function by phosphorylating 
retinoblastoma protein (Rb1), thus potentially creating a redundant mechanism to promote 
cell cycle progression.  Consequently, inhibition of both enzymes is necessary to ensure 
complete suppression of Rb1 phosphorylation and the greatest possible spectrum of 
antitumor activity.
Results indicate that palbociclib inhibits CDK6 with equivalent potency to CDK4.  
Palbociclib showed anti-proliferative effects on Rb1-positive cells in vitro and inhibition of 
tumor growth in several Rb-positive human breast and colon xenografts.  In these models, 
palbociclib resulted in decreased Rb1 phosphorylation and decreased Ki-67 expression, but 
did not show activity in Rb1-negative tumor xenografts.13  Additional information may be 
found in the Investigator’s Brochure (IB) for palbociclib.


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1.2.3.3. Overview of Palbociclib Nonclinical Safety Data
The nonclinical safety profile of palbociclib has been well characterized through the conduct 
of single- and repeat-dose toxicity studies up to 39 weeks in duration, and safety, 
pharmacology, genetic toxicity, reproductive and developmental toxicity, and phototoxicity 
studies.
Detailed information may be found in the IB for palbociclib.
1.2.3.4. Palbociclib Pharmacokinetics in Human
As of 01 September 2015, twenty-five clinical studies have evaluated the PK of palbociclib.  
Seven of these trials were conducted in patients with advanced malignant disease.  Detailed 
information on the PK properties of palbociclib may be found in the IB.
1.2.4. Palbociclib Clinical Data
Palbociclib has been explored in multiple clinical trials in a variety of malignancies, as single 
agent and in combination therapy.
Two Phase 1 trials evaluated single agent administration of palbociclib to patients with 
Rb-positive cancers.14,15  One of these trials determined that the dose-limiting toxicity (DLT) 
was neutropenia and the maximum tolerated dose (MTD) was 125 mg once daily when 
administered for 21 of 28 days (3 weeks on/1 week off schedule).  The most common 
non-hematologic AEs included fatigue, nausea, and diarrhea.  The mean half-life of 
palbociclib was 26.9 hours.  Patients were selected for Rb-positive cancers, based on 
immunohistochemistry (IHC) stain, defined as positive if staining intensity was 1+ or greater 
above background.  Stable disease for 4 cycles (16 weeks) occurred in 27% of evaluable 
patients and in a number of tumor types (liposarcoma, testicular, renal, ovarian, breast, 
appendiceal, peritoneal, melanoma, thymoma and lung).  Another Phase I trial of palbociclib 
using an alternative dosing plan (21 day cycles; 2 weeks on/1 week off schedule) observed a 
similar likelihood of disease control in a variety of tumor types.14  These studies demonstrate 
that palbociclib has substantial activity in Rb-positive tumors.
A randomized Phase 2 trial was initiated to determine the overall safety and efficacy of 
palbociclib (125 mg) and letrozole (2.5 mg) versus letrozole in post-menopausal women with 
ER+ HER2-negative advanced breast cancer.16  The ORR was 45% for those women who 
received palbociclib plus letrozole versus 31% for those who received letrozole (statistically 
significant).  Importantly, the median PFS was significantly different (26.2 versus 
7.5 months) favoring the combination arm. The most common adverse drug reactions of any 
grade reported in patients in the palbociclib plus letrozole arm were neutropenia, leukopenia, 
fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, 
thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and 
epistaxis.  The most frequently reported serious adverse drug reaction in patients receiving 
palbociclib plus letrozole was diarrhea (2.4%).


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Overall, neutropenia of any grade was reported in 62 (74.7%) patients in the combination 
arm, with Grade 3 neutropenia being reported in 40 (48.2%) patients, and Grade 4 
neutropenia being reported in 5 (6.0%) patients.
In the combination arm, 56.6% of patients had a maximum grade of Grade 3 neutropenia and 
4.8% of patients had a maximum grade of Grade 4 neutropenia based on laboratory data.  
The median time to first episode of neutropenia was 15 days for any grade, Grade 2, and
Grade 4 neutropenia, and 28 days for Grade 3 neutropenia in the palbociclib plus letrozole
arm.  Median duration of Grade 3 or 4 neutropenia was 7 days. Most episodes of Grade 3
neutropenia were managed by dose reduction and/or dose delay or temporary discontinuation 
and did not require permanent discontinuation of study treatment or addition of supportive 
therapy.  Grade 3-4 fatigue/asthenia, vomiting, diarrhea and peripheral neuropathy rates were 
6%, 0%, 4% and 0% respectively.
Based on these data, the US FDA approved palbociclib for the treatment of hormone receptor 
(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or 
metastatic breast cancer in combination with: 

letrozole as initial endocrine based therapy in postmenopausal women (1), or 

fulvestrant in women with disease progression following endocrine therapy. 
The indication in combination with letrozole is approved under accelerated approval based 
on progression-free survival (PFS).  Continued approval for this indication may be 
contingent upon verification and description of clinical benefit in a confirmatory trial. 
There are currently no clinical data for palbociclib in pancreatic cancer.
Complete information for palbociclib may be found in the Single Reference Safety 
Document (SRSD), which for this study is the current IB. 
1.2.5. Study Rationale
Currently FOLFIRINOX is the preferred chemotherapy combination in patients with good 
performance status.  Although the combination of GEM/nab-P represents an acceptable and 
potentially less toxic alternative to FOLFIRINOX in less fit patients, the replacement of 
GEM with palbociclib in combination with nab-P could provide additional benefits. 
Clinical development of palbociclib in mPDAC builds upon robust pre-clinical data from 
PDX models.  
 
 
 
 
 
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A number of genetic, pre-clinical in vitro and in vivo data further provide robust rationale for 
CDK4/6 inhibition in PDAC:

A recent study examining mutational patterns in PDAC using whole genome 
sequencing identified a number of alterations in the CyclinD/CDK4/RB pathway 
leading to an increased cell cycle activity through this pathway.17

PDAC is enriched for oncogenic KRAS mutations, which has been shown to be 
synthetic lethal with CDK4/6 inhibition,18 observed in up to 95% of patients.

Over 50% and up to 90% of cases reveal a loss of the tumor suppressor CDKN2A 
(p16INK4a), the endogenous inhibitor of CDK4/6.19,17

While loss of Rb1 is uncommon in PDAC,17 detection of phosphorylated Rb1 is 
reported at high frequencies suggesting that CDK4/6 signaling may be critical for the 
dysregulation of cell cycle control in PDAC. 

 
 
 
1.2.6. Rationale for Modified Dose Regimens (Amendment 1) 
Emerging data from dose levels 1, 2A and 2B have shown only 1 patient meeting the criteria 
for DLT; however, several patients have required dose reductions.  A lower or modified dose 
regimen may show better tolerability.  Biweekly regimens of the GEM/nab-P combination 
have shown comparable efficacy with an improved toxicity profile.23
1.2.7. Rationale for Amendment 3
The rationale for the study was supported on theoretical and preclinical grounds. However, 
based on emerging clinical data, the combination of palbociclib and nab-paclitaxel will not 
be further developed. 
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1.2.8. Summary of Benefit Risk Assessment
Systemic chemotherapy represents the main treatment option in patients with metastatic 
pancreatic cancer. However, mPDAC patients treated with current chemotherapy regimens 
still have a poor prognosis, and more efficacious and tolerable therapies are desirable. 
The relevance of CDK 4/6 activity in pancreatic cancer together with the efficacy observed 
with palbociclib in combination with nab-P in PDAC preclinical models support testing this 
novel combination in mPDAC patients, with the aim to improve clinical outcomes including 
survival, progression-free survival, and other health-related outcomes, such as delayed 
deterioration and/or improvement of global health status and pain.  The safety profile of the 
combination should be manageable. The most likely risk associated with a palbociclib/nab-P 
treatment regimen is neutropenia which can be managed by dose delay, dose reduction, 
temporary discontinuation, or growth factors without permanent discontinuation of treatment.  
Other potentially overlapping toxicities include anemia, neuropathy, nausea, vomiting, 
fatigue/asthenia, hypertension, and diarrhea.  In order to minimize the risk for the patients, 
safety and tolerability of the proposed combination will be carefully monitored in the 
proposed clinical protocol by means of medical visits and laboratory tests at predefined time 
points, and dose modifications for one or both drugs as well as supportive medical treatment 
may be implemented in case of emerging toxicities. 
Taken together, the potential benefits of a palbociclib/nab-P treatment outweigh the potential 
risks, supporting an overall favorable benefit/risk assessment in the treatment of patients with 
mPDAC.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objective

To assess the safety and tolerability of palbociclib in combination with nab-paclitaxel 
(nab-P) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) in 
order to estimate the maximum tolerated dose (MTD) and select the recommended 
Phase 2 dose (RP2D).
Secondary Objectives

To evaluate the overall safety profile of palbociclib in combination with nab-P; 

To characterize the multiple-dose pharmacokinetics of palbociclib when administered 
in combination with nab-P;

To evaluate the effect of palbociclib on pharmacokinetics of total paclitaxel when 
nab-P is administered in combination with palbociclib;

To evaluate the anti-tumor effect of palbociclib in combination with nab-P in patients 
with mPDAC;


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
To evaluate the pharmacodynamic effect of palbociclib and nab-P in patients with 
mPDAC;

To characterize candidate biomarkers of sensitivity or resistance in pre-treatment 
tumor tissue, including Rb1 and p16 expression, that may aid in the identification of 
patient subpopulations most likely to benefit from treatment.
 
 
 
 
 
 
 
 
2.2. Endpoints
Primary Endpoint

First cycle dose limiting toxicities (DLTs).
Secondary Endpoints

Safety: 

Adverse Events as characterized by type, frequency, severity [as graded by 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) version 4.03], timing, seriousness, and relationship to study 
therapy;

Laboratory abnormalities as characterized by type, frequency, severity (as graded 
by NCI CTCAE version 4.03), and timing;

Vital signs; 
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
Pharmacokinetic parameters of palbociclib and nab-P:

For palbociclib PK when given with nab-P: Multiple Dose (MD) (assuming 
steady-state is achieved) - Css,max, Tss,max, AUCss,, Css,trough, and CL/F, as data 
permit;

For total paclitaxel when nab-P is given alone and in combination with 
palbociclib: Cmax, Tmax, AUClast, AUC∞, t1/2, CL, and Vz as data permit; 

Clinical pharmacodynamic markers associated with mPDAC (eg, Ca19-9);

Efficacy:

Objective tumor response, as assessed using the Response Evaluation Criteria in 
Solid Tumor (RECIST) version 1.1; 

Time-to-event endpoints: eg, Duration of Response (DR), Progression Free 
Survival (PFS), Six-month progression-free survival rate (6m-PFSR), Overall 
Survival (OS);

Biomarker endpoints: 

Tumor tissue biomarkers (p16 and Rb1 expression by IHC). 
 
 
 
 
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, open label, multi-center, multiple dose, dose escalation, safety, 
pharmacokinetic and pharmacodynamic study of palbociclib in combination with nab-P, in 
sequential cohorts of adult patients with mPDAC, with expansion cohorts.  
Approximately 60-100 patients are expected to be enrolled in the overall study.  The study 
has several parts:

Dose-Escalation Cohorts:  
Consecutive cohorts of patients will receive escalating doses of oral palbociclib in 
combination with intravenous nab-P in 28-day cycles as illustrated in Figure 2, in 
order to estimate the MTD(s) of the combination.  The starting dose of palbociclib 
will be 75 mg palbociclib, administered on Days 1-21 of each cycle (3/1 dosing 
schedule).  The starting dose of nab-P is 100 mg/m2 - administered weekly for 
3 weeks out of each 28-day cycle.  The observation period for dose-limiting toxicities 
(DLTs) will be from Day 1 until pre-dose Cycle 2 Day 1 (Day -2 and -1 will not be 
included in the DLT observation period).  Pharmacokinetic (PK) and 
pharmacodynamic (PD) properties of palbociclib and nab-P will also be assessed.  Up 
to approximately 30 patients will be enrolled. 
The criteria for dose escalation will be based on a modified toxicity probability 
interval (mTPI) method. 

Modified Dose Regimen Cohorts:  
Emerging data from dose levels 1, 2A and 2B have shown only 1 patient meeting the 
criteria for DLT; however, several patients have required dose reductions.  To further 
evaluate an optimal palbociclib/nab-P combination, an additional 2 cohorts of patients 
will be enrolled into alternative dose regimens at doses lower than the dose levels 
tested in dose escalation.  The following dose regimens will be tested: 

Modified Dose Regimen 1 (MDR1)-75 mg palbociclib once daily on Days 1-21 of 
each 28-day cycle, plus nab-P 125 mg/m2 biweekly in each 28-day cycle.

Modified Dose Regimen 2 (MDR2)-75 mg palbociclib continuous dosing, once daily, 
plus nab-P 100 mg/m2 biweekly in each 28-day cycle.
For patients assigned to a modified dose regimen, the use of G-CSF is prohibited in 
the first 3 cycles, unless clinically indicated an medically unavoidable.  Dose 
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At least 6-9 patients will be enrolled into each MDR cohort.  Patients enrolled into 
MDR cohorts will also be assessed for DLTs.  If the number of patients with a DLT 
falls into the “De-escalate” category (Table 14) in one or both MDR cohorts, the 
cohort(s) will not move forward into expansion.  The MDR cohort with a DLT rate 
<0.33 in at least 9 DLT evaluable patient will be considered to move forward into 
expansion.

Expansion Cohorts:

MTD Expansion Cohort(s);
When the MTD(s) of palbociclib plus nab-P has been estimated with confidence, 
enrollment will proceed into 1 or 2 MTD expansion cohort(s) of up to 20 patients 
each at the MTD(s).  Patients will receive --the same dosing regimen as in the dose 
escalation cohorts (palbociclib 3/1 schedule and weekly nab-P for 3 weeks in each 
28-day cycle).

Modified Dose Regimen (MDR) Expansion Cohort (Amendment 3)
Based on emerging data from the MDR1 and MDR2 cohort, enrollment into the MDR 
expansion cohort will be terminated.
For all patients, to allow for PK evaluation of nab-P administered alone, nab-P will be 
administered on Day -2 for Cycle 1 only.  Subsequent cycles will administer both nab-P and 
palbociclib on Day 1.  Alternate dosing schedules for palbociclib may be explored based on 
emerging PK, PD, and safety data. 
Patients will be treated as long as they are clinically benefiting from investigational product 
without unacceptable toxicity, objective disease progression, or withdrawal of consent. 
Patients discontinuing the treatment phase will enter a follow-up period during which 
survival and new anti-cancer therapy information will be collected every month from the last 
dose of study drug. 
Protocol Amendment 3 
1. Patients who are continuing to receive IP may continue to do so as long as they are 
clinically benefiting from IP without unacceptable toxicity, objective disease 
progression, or withdrawal of consent.  Once a patient has completed Cycle 13, only 
safety data will be collected thereafter.  Patients who have completed 13 cycles of IP 
are not required to enter post-treatment follow-up upon permanent discontinuation of 
IP.  Patients who are ongoing beyond Cycle 13 will be considered to have completed 
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2. Patients who have discontinued IP before completing Cycle 13 will remain in 
post-treatment follow-up (See Schedule of Activities) until 12 months (365 days) 
have elapsed from the first dose of IP.  Once a patient has been followed for 12 
months from the first dose, the patient is considered to have completed the study and 
no further data will be collected.  Efficacy analyses will be performed using the local 
radiologist’s/investigator’s tumor assessments as the primary data source.  Patients 
will undergo study-related safety, efficacy, and PK assessments as outlined in the 
Schedule of Activities (Table 1, Table 2, and Table 3).
Blood, tumor biopsies (optional), and/or 
 
 will be taken while on-treatment and at the end of treatment. 
 
 
 
3.1.1. Starting Dose Level 
The starting dose level (DL) for dose escalation will be 75 mg palbociclib and 
100 mg/m2 nab-P.  See Section 5.3.3 for the dosing schedules for MDR and expansion 
cohorts.
3.1.2. Criteria for Dose Escalation
Dose escalation and de-escalation will follow a 2x3 matrix “Up-and-Down” design, using 
doses of palbociclib and nab-P as shown in Table 4 and Figure 2 below.  In this dosing 
algorithm, there are up to 7 potential dose combinations (excluding DL -1):
Table 4.
Potential Palbociclib and Nab-Paclitaxel Dose Combinations
Dose Level
Palbociclib
(oral, mg/day)
Days 1-21 within a 
28-day cycle
Nab-Paclitaxel
(IV, mg/m2/day)
Weekly dose for 3 weeks 
within a 28-day cycle
-1
50
100
1 (starting dose level)
75
100
1.5
50
125
2A
100
100
2B
75
125
3A
125
100
3B
100
125
4
125
125
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The 2x3 matrix approach allows for parallel dose level cohorts consisting of different dose 
combinations.  Dose escalations and de-escalations will be called for based upon assessment 
of DLTs and other adverse events during the first treatment cycle (28 days).  See 
Section 9.2.1 for a detailed description of the mTPI dose-escalation method.
Figure 2.
Palbociclib and Nab-Paclitaxel Combination Dose Escalation and 
De-Escalation Sequence
palbociclib 75mg + 
nab-paclitaxel 
100mg/m2
palbociclib 100mg + 
nab-paclitaxel 
100mg/m2
palbociclib 75mg + 
nab-paclitaxel 
125mg/m2
palbociclib 100mg + 
nab-paclitaxel 
125mg/m2
palbociclib 125mg + 
nab-paclitaxel 
125mg/m2
palbociclib 50mg + 
nab-paclitaxel 
100mg/m2
palbociclib 125mg + 
nab-paclitaxel 
100mg/m2
Level 1 (start)
Level -1
Level 2A
Level 2B
Level 3A
Level 3B
Level 4
palbociclib 50mg + 
nab-paclitaxel 
125mg/m2
Level 1.5
Dose escalation will start from DL 1.  The sequential dose escalation scheme and the rules 
for determining dose escalation, de-escalation, or ‘stay’ (ie, enroll an additional group of 
patients to the current DL) at any given dose level are described in the following paragraph 
and are illustrated in Figure 3. 
Starting from DL 1: 

Once DL 1 has been found to be tolerable, DL 2A and DL 2B will be evaluated in 
parallel;

If dose de-escalation is required at DL 1, then DL -1 will be evaluated next. 
The following rules apply if escalation to DL 2A and DL 2B will be explored:

If both DL 2A and DL 2B are tolerated and further dose escalation is considered, then 
DL 3A and DL 3B will be evaluated in parallel;

If DL 2A is tolerated and further dose escalation is recommended, but no dose 
escalation is determined from DL 2B, then only DL 3A will be evaluated as the 
subsequent dose escalation step;


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
If DL 2B is tolerated, but no dose escalation is determined at DL 2A, then no further 
dose escalation will be performed and the current DL(s) will be expanded to
9 patients, unless already done, in order to enable a dose escalation or de-escalation 
decision;

If no dose escalation is determined at DL 2A and DL 2B, then no further dose 
escalation will be performed and the current DL(s) will be expanded to 9 patients, 
unless already done, in order to enable a dose escalation or de-escalation decision;  

If dose de-escalation is recommended after DL 2A, then DL 1 will be expanded to 
9 patients, unless already done, in order to enable a dose escalation or de-escalation 
decision;

If dose de-escalation is recommended after DL 2B, then DL 1.5 will be evaluated.
If dose escalation to DL 3A and DL 3B will be explored: 

If further dose escalations are recommended at both DL 3A and DL 3B, then DL 4 
will be evaluated;

If dose escalation is recommended only at DL 3A or DL 3B, then no further dose 
escalation will be performed and the current DL(s) will be expanded to 9 patients, 
unless already done, in order to enable a dose escalation or de-escalation decision;

If dose de-escalation is recommended after both DL 3A and DL 3B, or after DL 3B 
only, then DL 2A and DL 2B will be expanded to 9 patients, unless already done, in 
order to enable a dose escalation or de-escalation decision (the order of the evaluation 
will be determined based on the toxicities observed from DL 2A and DL 2B);

If dose de-escalation is only recommended after DL 3A (but not at DL 3B), then DL 
2A will be expanded to 9 patients, unless already done, in order to enable a dose 
escalation or de-escalation decision. 
If dose escalation to DL 3A will only be explored: 

DL 4 will not be evaluated regardless of the outcome at DL3A;

If dose de-escalation is recommended at DL 3A, then DL 2A will be expanded to 
9 patients, unless already done, in order to enable a dose escalation or de-escalation 
decision. 
If dose escalation to DL 4: 

Dose escalation will be stopped at this DL;


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
If dose de-escalation is recommended after DL 4, then DL 3A and DL 3B will be 
expanded to 9 patients, unless already done, in order to enable a dose escalation or 
de-escalation decision (the order of the evaluation will be determined based on the 
toxicities observed at DL 3A and DL 3B).
If de-escalation to DL -1: 

If dose escalation is determined from DL-1, then DL 1 will be re-evaluated;

If dose de-escalation is determined from DL -1, the study will be terminated.
Three (3) patients per group will be initially treated at any given combination DL.  Up to 
3 groups for a total of 9 patients can be treated at the same DL.  Figure 3 illustrates the 
general dose escalation and de-escalation schema with a group size of 3 patients for a given 
DL based on this method. Detailed dose re-escalation and de-escalation schemas for a 
previous DL are provided in Appendix 7.
Figure 3.
The General Dose Escalation and De-Escalation Schema with a Group Size 
of 3 Patients at a Given Dose Level
Note: In the figure, the term “DLT” means “patients with DLT”, not the actual number of DLT events.
1 pt with 
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Initially a group of 3 patients will be enrolled at the starting DL.  When all 3 patients are 
available for DLT assessment, the number of patients with DLT(s) will inform the decision 
for the next step:

If 0 patient with a DLT out of 3 evaluable patients, escalate;

If 1 patient with a DLT out of 3 evaluable patients, stay;

If 2 patients with a DLT out of 3 evaluable patients, de-escalate;

If 3 patients with a DLT out of 3 evaluable patients, stop the dose escalation.
Based on the decision above, a second group of 3 patients will be enrolled at the 
corresponding DL.  Upon completion of the second group, a decision will be made again to 
escalate, de-escalate, or stay.  Table 14 is derived from a generalized approach that extends 
the current mTPI method and preserves its decision-theoretical properties. 
There are two scenarios under the decision of de-escalation: de-escalate and revisit allowed 
or de-escalate and revisit not allowed.  The latter means that the current DL is determined to 
be unacceptably toxic; this DL and the subsequent higher DLs will be excluded from the 
study. 
The decision-making needs to consider all patients treated at the current DL under 
evaluation.  For example, if the decision is to stay at the starting DL after the first group of 
3 patients (ie, there is 1 patient with a DLT), and another group of 3 additional patients is 
enrolled at the same DL, the next decision will be made based on all 6 patients treated at that 
DL:

If 1 patient experiences a DLT out of 6 evaluable patients, escalate;

If 2 patients experience a DLT out of 6 evaluable patients, stay;

If 3 patients experience a DLT out of 6 evaluable patients, stop the dose escalation.
Dose escalation will continue until at least 9 patients have been treated at any given DL.  
Doses will not be escalated if the starting DL is deemed overly toxic, or if reaching the 
maximum sample size of approximately 30 patients is reached (ie, the number of 
DLT-evaluable patients). 
The MTD determination will be based on the observed toxicity rates among all evaluable 
patients at any given DL.  When dose escalation is stopped, the highest DL with an observed 
DLT rate <33% (in at least 9 DLT-evaluable patients) will be considered the MTD.  It is 
possible that more than one MTD will be determined, in which case a decision will be made 
to expand one or both MTDs in order to determine the RP2D. 


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The general approach to dose-finding, using the mTPI method, involves the following:

The target group size is 3.  However, patients can be enrolled in group sizes of 
2-4 patients if necessary, depending on the number of potential patients identified at 
participating sites (see Table 14);

The next group of patients can be enrolled when all patients at a given  DL have been 
evaluated for 28 days in the first treatment cycle, or any of the patients experience a 
DLT, whichever comes first;

If a patient withdraws from the study before having received >80% of the planned 
first-cycle dose for palbociclib and nab-P for reasons other than investigational 
product-related toxicity, another patient will be enrolled to replace that patient at the 
current DL.
The dose escalation portion of the study is completed when at least 9 evaluable patients have 
been treated at the highest DL associated with a DLT rate <33%.  It is estimated that 
approximately 30 ‘DLT-evaluable’ patients will be enrolled to reach n = 9 ‘DLT-evaluable’ 
patients at the estimated MTD.
Dose escalation may be completed without determining the MTD based on emerging safety 
data, and upon agreement between the investigators and the sponsor. 
The RP2D will be determined in the dose expansion cohorts, taking into account the MTD(s) 
from the dose-escalation and modified dose regimen components, and other factors related to 
safety, efficacy, and PK/PD involving all available data from all tested DLs. 
3.1.3. Modified Dose Regimens: Criteria for Opening MDR Expansion Cohort
The modified dose regimen chosen for expansion will take into account factors including 
frequency of dose reductions and/or interruptions, safety, efficacy, and PK/PD.  If the 
number of patients with a DLT falls into the “De-escalate” category (Table 14) in one or both 
MDR cohorts, the cohort(s) will not move forward into expansion.
3.2. Dose Limiting Toxicity Definition
Severity of adverse events will be graded according to NCI CTCAE version 4.03. For the 
purpose of dose escalation, any adverse events occurring in the first cycle of treatment 
(Day 1 until pre-dose Cycle 2 Day 1) which are attributable to palbociclib, nab-P, or to the 
combination of palbociclib and nab-P will be classified as DLTs.  Adverse events that occur 
between Cycle 1 Day -2 after nab-P administration and Cycle 1 Day 1 (prior to palbociclib 
dosing) will not be considered a DLT.  The following adverse events will be considered a 
DLT:

Hematologic:

Grade 4 neutropenia lasting >4 days;


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
Febrile neutropenia (defined as neutropenia Grade 3 [ANC <1000 cells/mm3] 
and a body temperature 38.5C) requiring antibiotic or antifungal treatment;

Any Grade 4 thrombocytopenia (<25,000/mm3 or <25.0 x 109/L).

Non-hematologic: Grade 3 toxicities, except those that have not been maximally 
treated (eg, nausea, vomiting, diarrhea).

Other: 

Any adverse event that causes a palbociclib treatment interruption of greater than 
7 consecutive days; or causes any combination of interruption/reduction for 
14 days;

Any adverse event that causes omission or reduction of at least 2 of the 3 weekly 
doses of nab-P.
3.3. Maximum Tolerated Dose Definition
The estimated MTD is the DL associated with <33% of 9 patients experiencing a DLT. 
3.4. Recommended Phase 2 Dose (RP2D) Definition
The Recommended Phase 2 Dose (RP2D) is the drug regimen and doses chosen for potential 
future studies based on the results of this Phase 1 study.  If the MTD proves to be clinically 
feasible for long-term administration in a reasonable number of patients, this dose usually 
becomes the RP2D.  Further experience with the MTD may result in an RP2D dose lower 
than the MTD.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study. 
Patients must meet all of the following inclusion criteria to be eligible for the study:
1. Histologically or cytologically-confirmed pancreatic ductal adenocarcinoma 
(mPDAC), with metastatic disease confirmed radiographically.

Dose-escalation and MDR cohorts: 

Prior therapy(ies) for the treatment of metastatic disease is permitted.


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
Expansion cohorts:

No prior anti-cancer therapy for the treatment of metastatic disease;

At least one measurable lesion [as defined by Response Evaluation Criteria in 
Solid Tumors (RECIST v1.1)] that has not been previously irradiated.
2. Availability of a tumor tissue specimen (ie, archived FFPE tissue [block preferred, or 
at least 12 (preferably 15) unstained slides]), which will be used for centralized, 
retrospective biomarker analysis.  If no archived tumor tissue is available, then a de 
novo biopsy is required for patient participation.
3. Age 18 years.

For dose-escalation cohorts, age must also be 75 years.
4. Karnofsky Performance Status (PS) 70 or greater (see Appendix 2). 
5. Adequate Bone Marrow Function, including:
a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 (100 x 109/L);
c.
Hemoglobin 9 g/dL (90 g/L).
6. Adequate Renal Function, including:
a.
Serum creatinine 1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance 60 mL/min as calculated using the method standard for the institution. 
7. Adequate Liver Function, including:
a.
Total serum bilirubin 1.5 x ULN unless the patient has documented Gilbert 
syndrome;
b. Aspartate and Alanine aminotransferase (AST & ALT) 2.5 x ULN; 5.0 x ULN 
if there is liver involvement secondary to tumor; 
c.
Alkaline phosphatase 2.5 x ULN; (5 x ULN in case of bone metastasis). 
8. Resolved acute effects of any prior therapy to baseline or Grade 1 severity except 
for AEs not constituting a safety risk by investigator judgment.
9. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.


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10. Male patients able to father children and female patients of childbearing potential and 
at risk for pregnancy must agree to use two highly effective methods of contraception 
throughout the study and for 1 month after the last dose of assigned treatment. 
11. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
12. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other procedures. 
4.2. Exclusion Criteria
1. Prior treatment with a CDK 4/6 inhibitor.
2. Prior treatment with nab-P for the treatment of metastatic disease (nab-P that was 
administered in the adjuvant setting is permitted).
3. Patients with known CNS metastases, carcinomatous meningitis, or leptomeningeal 
disease as indicated by clinical symptoms, cerebral edema, and/or progressive 
growth. 
4. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other 
anti-cancer therapy within 2 weeks prior to enrollment.  Patients who received prior 
radiotherapy to 25% of bone marrow (Appendix 8) are not eligible independent of 
when it was received.
5. Diagnosis of any other malignancy within 3 years prior to enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
cervix.
6. QTc >480 msec (based on the mean value of the triplicate electrocardiograms 
(ECGs), family or personal history of long or short QT syndrome, Brugada syndrome 
or known history of QTc prolongation, or Torsade de Pointes.
7. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, 
hypomagnesemia).
8. Any of the following within 6 months of enrollment: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE Grade 2, 
atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident including transient ischemic attack, 
or symptomatic pulmonary embolism.
9. Known human immunodeficiency virus infection.
10. History of interstitial lung disease or pneumonitis.


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11. Other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) or active suicidal ideation or behavior, or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study.
12. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to nab-P.
13. Difficulty swallowing capsules or requirement for a feeding tube.
14. Previous high-dose chemotherapy requiring stem cell rescue.
15. Pregnant female patients; breastfeeding female patients; male patients with partners 
currently pregnant.
16. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular 
disease or previous gastric resection or lap band.  Gastroesophageal reflux disease 
under treatment with proton pump inhibitors is allowed. 
17. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by 
hematemesis, significant hemoptysis or melena in the past 6 months.
18. Patients treated within the last 7 days prior to the start of IP with: 

Food or drugs that are known to be strong/moderate CYP3A4 inhibitors
(ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, 
diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, 
lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or 
grapefruit juice);

Drugs that are known to be strong/moderate CYP3A4 inducers (ie, 
carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, 
rifabutin, rifampin, rifapentin, and St. John’s wort);

Drugs that are known to be CYP2C8 inhibitors: including but not limited to 
deferasirox, gemfibrozil, lapatinib, trimethoprim and fluvoxamine;

Drugs that are known to be strong/moderate CYP2C8 inducers: including but not 
limited to rifampin;

Drugs that are known to prolong the QT interval (see Appendix 9).


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19. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.
20. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study entry.
4.3. Lifestyle Guidelines 
4.3.1. Dietary Restrictions
The following dietary restrictions are necessary during the treatment phase:

Palbociclib should be taken with food.  Patients must be instructed to avoid ingesting 
grapefruit, grapefruit juice, or grapefruit-containing products while taking 
palbociclib.
4.3.2. Use of Contraception 
In this study, male patients who are able to father children and female patients of 
childbearing potential and are sexually active and at risk for pregnancy will receive nab-P, 
which has been associated with teratogenic risk and/or palbociclib, a compound for which the 
teratogenic risk is currently unknown. Those who, in the opinion of the investigator, are 
sexually active and at risk for pregnancy must agree to use two (2) methods of highly 
effective contraception throughout the study and continue to do so for 1 month after the last 
dose.  The investigator or his or her designee, in consultation with the patient, will confirm 
the patient has selected 2 appropriate methods of contraception for the individual patient and 
his/her partner from the list of permitted contraception methods (see below) and instruct the 
patient in their consistent and correct use.  Patients need to affirm that they meet the criteria 
for correct use of 2 of the selected methods of contraception.  The investigator or his/her 
designee will discuss with the patient the need to use 2 highly effective contraception 
methods consistently and correctly according to the Schedule of Activities (SOA) and 
document such conversation in the patient’s chart.  In addition, the investigator or his or her 
designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued or if pregnancy is known or suspected in the patient or the patient’s 
partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
Established use of oral, inserted, injected, or implanted hormonal methods of 
contraception are allowed provided the patient plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
Correctly placed copper-containing intrauterine device (IUD).


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Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
Male sterilization with absence of sperm in the post-vasectomy ejaculate. 
Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
Female partners who meet the criteria for non-childbearing potential must meet at least 
one of the following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed by having a serum follicle-stimulating hormone 
(FSH) level within the laboratory’s reference range for postmenopausal women.
All other female patients (including females with tubal ligations) will be considered to be of 
childbearing potential.
All sexually active male patients must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for 1 month after the last dose.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list, located in the coordinator’s manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a help desk in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should only be 
used in the event that the established communication pathways between the investigational 
site and the study team are not available.  It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study.  The contact 


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number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33). 
Therefore, for purposes of this study, investigational product refers to both palbociclib and 
nab-P. 
5.1. Allocation to Treatment
Dose level allocation will be performed by the sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments. The site staff will 
email a complete Registration Form to the designated sponsor study team member.  The 
sponsor will assign a patient identification number, which will be used on all Case Report 
Form (CRF) pages and other study-related documentation or correspondence referencing that 
patient and email to the site.
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor:

Confirmation of the patient’s eligibility and permission to start IP;

Specification of the dose level for that patient and

Permission to proceed with dosing the patient.
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible investigational product start date.
5.2. Patient Compliance
Patients will be instructed to record administration of palbociclib in a patient diary provided 
by the sponsor.  Missed or changed doses and dates of all missed doses need to be recorded.  
In addition, any co-medications, especially those taken for pain, should be recorded.
Patients will be required to return all bottles of palbociclib, including any unused capsules, as 
well as the completed patient diary at the beginning of each cycle for drug accountability.  
Drug accountability will be performed on Day 1 of every cycle prior to dispensing drug 
supply for the next cycle.  The number of remaining capsules will be documented and 
recorded. 


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5.3. Investigational Product Supplies 
5.3.1. Dosage Form(s) and Packaging
5.3.1.1. Palbociclib
Palbociclib will be supplied as capsules containing 25 mg, 75 mg, 100 mg, or 125 mg 
equivalents of palbociclib free base.  The sponsor will supply the oral drug formulation to 
sites in high-density polyethylene (HDPE) bottles containing 25 mg, 75 mg, 100 mg, or 
125 mg capsules.  The capsules can be differentiated by their color, as shown in Table 5.  
Labeling will occur according to local regulatory requirements.
Table 5.
Palbociclib Capsule Characteristics
Strength
Capsule color
25 mg
Grey/Caramel
75 mg
Sunset Yellow
100 mg 
Sunset Yellow/Caramel
125 mg
Caramel
5.3.1.2. Nab-Paclitaxel
Nab-paclitaxel is commercially available as a lyophilized powder for reconstitution 
(single-use vials containing 100 mg of paclitaxel and approximately 900 mg of human 
albumin as a lyophilized powder).  Central supply or locally obtained commercial supplies of 
nab-P will be used in accordance with local regulations.  Detailed information about nab-P 
formulation can be found in the locally approved package insert.
5.3.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
palbociclib and nab-P.  Refer to the Investigational Product Manual (IP Manual) for 
additional information about the investigational products.
See the locally approved package insert for instructions on how to prepare nab-P for 
administration.  Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance.
5.3.2.1. Palbociclib
Palbociclib will be provided as capsules for oral administration.  The 25 mg, 75 mg, 100 mg, 
and 125 mg capsules will be supplied in separate bottles and labeled according to local 
regulatory requirements.  The patient number must be recorded on the bottle label in the 
spaces provided by site personnel at the time of assignment to patient.  Site personnel must 
ensure that patients clearly understand the directions for self-medication.  Patients should be 
given a sufficient supply to last until their next study visit.  All bottles must be returned to the 
site at the next study visit.  This includes unopened, empty, or partially used bottles 


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containing unused drug.  Returned, unused investigational product MUST NOT be 
re-dispensed to the patient. 
Palbociclib is an agent that must be handled and administered with care.  Patients must be 
instructed to keep their medication in the bottles provided and not transfer it to any other 
container.  Due to possible unknown hazards associated with topical and environmental 
exposure to experimental agents, capsules must not be opened and/or emptied into any 
vehicle for oral ingestion; capsules must be swallowed intact.
Only one capsule strength will be dispensed to the patient at each dispensing visit.  In the 
event of dose modification, request should be made of the patient to return all previously 
dispensed investigational product to the clinic and new capsules will be dispensed.
5.3.2.2. Nab-Paclitaxel
Nab-paclitaxel must be reconstituted before use.  Detailed information about nab-P 
reconstitution and dispensing can be found in the locally approved package insert for 
Abraxane®.
Nab-paclitaxel is a cytotoxic drug and, as with other potentially toxic paclitaxel compounds, 
caution should be exercised in handling it.  The use of gloves is recommended.  If nab-P 
(lyophilized cake or reconstituted suspension) contacts the skin, the skin must be washed 
immediately and thoroughly with soap and water.  Following topical exposure to nab-P, 
events may include tingling, burning and redness.  If nab-P contacts mucous membranes, the 
membranes should be flushed thoroughly with water.  Procedures for proper handling and 
disposal of anticancer drugs should be considered. 
The appropriate amount of reconstituted nab-P will be injected into an empty, sterile 
intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type 
intravenous bag].  The use of specialized di-ethylhexylphthalate (DEHP)-free solution 
containers or administration sets is not necessary to prepare or administer nab-P infusions.  
The use of an in-line filter is not recommended. 
5.3.3. Administration
5.3.3.1. Nab-Paclitaxel Administration
Nab-P will be administered in the clinic.
Patients will receive nab-P as an intravenous infusion over 30 minutes.  Nab-P will be 
administered based on the assigned dose regimen (either once weekly for 3 weeks, or 
biweekly in each 28-day cycle).  In Cycle 1, nab-P will start on Day -2 in order to evaluate 
the pharmacokinetics of nab-P administered alone and in combination with palbociclib 
(Figure 4).  On Day 13, nab-P and palbociclib should be dosed at approximately the same 
time.  For cycles 2, both palbociclib and nab-P administration will start on Day 1, and 
palbociclib dosing should occur as close as possible to the start of infusion of nab-P.  
Treatment with IP will continue until disease progression, unacceptable toxicity, or consent 
withdrawal. 


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Figure 4.
Palbociclib and Nab-Paclitaxel Dose Combination Schema
Dose Escalation and MTD Expansion Cohorts
Modified Dose Regimen 1 (palbociclib 3/1 schedule, biweekly nab-P)
Modified Dose Regimen 2 (continuous palbociclib, biweekly nab-P)
5.3.4. Palbociclib Administration
Palbociclib dosing will be administered orally.  The palbociclib dosing schedule is 
determined by cohort assignment, either 3/1 schedule (once a day for 21 consecutive days, 
followed by 7 days off treatment) or continuous dosing in each 28-day cycle (for MDR2 
cohort).  Each patient will receive enough palbociclib to support their treatment cycle 
duration each month.  Patients should be instructed to swallow palbociclib capsules whole 
and not to manipulate or chew them prior to swallowing.  No capsule should be ingested if it 
is broken, cracked, or otherwise not intact.  Patients should be encouraged to take their dose 
at approximately the same time each day.  Patients should be instructed to record daily 
administration of the investigational product in a patient diary provided by the sponsor.
Patients should take palbociclib with food.
To ensure consistency with PK sample analysis, patients should ensure their palbociclib dose 
on Cycle 1 Day 12 is taken at least 20 hours before the pre-dose PK sample on Cycle 1 
Day 13.  Patients must be instructed to withhold their dose of palbociclib Cycle 1 Day 13, 
Cycle 2 Day 1, and Cycle 2 Day 15 until after the pre-dose PK sample is drawn.  Patients 


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should bring their palbociclib dose with them to the clinic on these days.  Once the pre-dose 
PK sample is drawn, palbociclib may be taken with food.
Patients who miss a day’s dose entirely must be instructed NOT to “make it up” the next day.  
If a palbociclib dose is missed, and the next dose is more than 12 hours away, the patient 
should take the missed dose as soon as they remember.  If the next dose is less than 12 hours 
away, the patient should skip the missed dose and take palbociclib at the next regularly 
scheduled time.  The patient must not double or take extra doses to make up for a missed 
dose.  Patients who vomit any time after taking a dose must be instructed NOT to take 
another dose on that day.  The patient should resume treatment the next day at their regularly 
scheduled time. 
Patients who inadvertently take 1 extra dose during a day must be instructed to skip the next 
day’s dose.  Also refer to Section 8.3 for further details on medication errors and overdose.
Patients experiencing investigational product related toxicity may have their dose modified 
according to Section 5.3.6 and Section 5.3.7.
5.3.5. Nab-Paclitaxel
Nab-paclitaxel will be prepared and dispensed according to the product labeling 
information.2  
5.3.6. General Recommended Dose Modifications
Every effort should be made to administer the investigational products (palbociclib and/or 
nab-P) at the planned dose.  However, in the event of significant treatment-related toxicity, 
administration of investigational products may need to be adjusted as described in the 
following sections.  Depending on the nature of the toxicity observed, dosing adjustment may 
be required for just one or both investigational products in the combination. 
In the event of significant treatment-related toxicity, palbociclib and/or nab-P dosing may be 
interrupted or delayed and/or reduced as described below.  Except where specified 
(Section 5.3.7), if one investigational product is delayed, the other may be continued as 
scheduled.  In the event of multiple toxicities, dose modification should be based on the 
worst toxicity observed.  Patients are to be instructed to notify investigators at the first 
occurrence of any adverse sign or symptom.
Dose modifications/interruptions may occur in two ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle;

Between cycles: dosing interruptions until adequate recovery and/or dose reduction, if 
required, for the next treatment cycle.  If both palbociclib and nab-P are interrupted, 
the start of a new cycle will be delayed until one or both investigational products are 
re-started.


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5.3.6.1. Dosing Interruptions
Patients should have their treatment with the investigational products (nab-P and/or 
paclitaxel) interrupted if they experience Grade 3 or 4 toxicities, as detailed in Table 8, 
Table 9, and Table 10. 
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the investigator.  Criteria required before treatment can resume are described in 
Section 5.3.6.2.
Doses may be held as needed until toxicity resolution.  Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned 
doses within that same cycle or even to delay the initiation of the subsequent cycle. 
If an adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed.  Doses omitted for toxicity are not replaced within the 
same cycle.  The need for a dose reduction at the time of treatment resumption should be 
based on the criteria defined in Section 5.3.7 unless expressly agreed otherwise following 
discussion between the investigator and the sponsor. 
In the event of a treatment interruption for reasons other than treatment-related toxicity
(eg, non-cancer related surgery) lasting more than 2 weeks, treatment resumption will be 
decided in consultation with the sponsor.
Except where specified (Section 5.3.7), if one investigational product is interrupted, the other 
may continue as scheduled upon agreement by the sponsor and investigator (unless otherwise 
noted in the dose modification sections).
Dose re-escalation is permitted on this study.  If the dose was reduced due to neutropenia, the 
dose modification guidelines in Table 10 provide additional guidance on dose re-escalation 
with concomitant administration of granulocyte-colony stimulating factors (G-CSF). 
5.3.6.2. Dose Delays and Retreatment Criteria
Retreatment of palbociclib and/or nab-P following treatment interruption for -the start of any 
new cycle may not occur until all of the parameters in Table 6 have been met:
Table 6.
General Criteria for Start of New Cycle 
Platelet count 100,000/mm3
ANC 1500/mm3 and without fever
No fever
Other non-hematologic toxicities returned to baseline or Grade 1 severity (or, at the investigator 
discretion, Grade 2, if not considered a safety risk for the patient)
If a treatment delay results from decline in hematologic parameters, refer to Table 9 or 
Table 10.  The frequency of blood count assessments should be increased as clinically 
indicated.


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If these parameters are met within 1 week of cycle delay, investigational products may be 
resumed.  Refer to Section 5.3.6 and Section 5.3.7 for adverse events requiring dose 
reduction at the time of treatment resumption. 
If these parameters have not been met after 2 weeks of dosing interruption (including the 
scheduled 1 week off treatment for patients on a palbociclib 3/1 schedule) or 2 weeks of 
cycle delay, permanent discontinuation of investigational product(s) should be considered.  
Treatment resumption for patients recovering from treatment-related toxicity after >2 weeks 
of treatment interruption or cycle delay but deemed to be deriving obvious clinical benefit 
per the investigator’s best medical judgment is left at the investigator’s discretion.
If both investigational products are interrupted and the interruption continues beyond Day 28 
of the current cycle, then the day when either investigational product is restarted will be 
counted as Day 1 of the next cycle.
New cycle Day 1 procedures (ie, physical examination, Karnofsky performance status, ECG, 
Quality of Life questionnaire, blood chemistry, hematology) that were performed prior to 
knowing the need to delay the start of the cycle do not need to be repeated (1) if not required 
to determine whether investigational product may be resumed and (2) if performed within 
7 days prior to investigational product resumption.
5.3.6.3. Dose Reductions
Following dosing interruption or cycle delay the palbociclib or nab-P dose may need to be 
reduced when treatment is resumed.
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Step-wise dose reduction of palbociclib and/or nab-P (Table 7) (if needed, up to 3 dose 
levels) will be allowed depending on the type and severity of toxicity encountered.  Patients 
requiring palbociclib dose reductions below 50 mg or nab-P dose reductions below 60 mg/m2
should be discontinued from the respective investigational product and entered into the 
follow-up phase, unless otherwise agreed between the investigator and the sponsor.  In 
addition, if one investigational product is discontinued, the other may continue as scheduled 
(upon agreement by the sponsor and investigator).  All dose modifications/adjustments must 
be clearly documented in the patient's source notes and investigational product administration 
CRF.  Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Dose re-escalation 
is allowed if the dose was reduced due to hematologic toxicity and can be effectively 
managed with administration of growth factors (refer to Table 10).  Table 7 below shows the
available dose levels for palbociclib and nab-P.
Patients experiencing a DLT or any adverse event, laboratory abnormality or severe 
intercurrent illness presenting a substantial clinical risk to the patient will be discontinued 
based on the judgment of the investigator.


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Table 7.
Palbociclib and Nab-Paclitaxel Dose Levels
Palbociclib Dose (mg)
Nab-Paclitaxel (mg/m2)
125
125
100
100
75
75
501
602
1. Palbociclib dose de-escalation below 50 mg/day is not permitted, unless otherwise agreed between the investigator and 
the sponsor.
2. Nab-P dose de-escalation below 60 mg/m2 is not permitted, unless otherwise agreed between the investigator and the 
sponsor.
Recommended dose modifications for hematologic and non-hematologic treatment-related 
toxicities requiring treatment interruption/delay or persisting despite optimal medical 
treatment are described in the following sections.
5.3.7. Recommended Dose Modifications for Specific Toxicities
Recommendations for dose modifications are list in Table 8.  Modifications from these 
guidelines should only occur after discussion between the investigator and the sponsor. 
Appropriate follow up assessments should be performed until the investigator has determined 
the patient has adequately recovered. 


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Table 8.
Recommended Dose Modifications for Adverse Events Associated with 
Palbociclib and/or Nab-Paclitaxel
Toxicity (NCI CTCAE version 
4.03)
Proposed Action for:
Palbociclib
Nab-Paclitaxel
Hematologic
Neutropenia and/or 
thrombocytopenia
See Table 9 (dose escalation and MTD expansion cohorts)
or Table 10 (MDR cohorts)
Grade 3 Neutropenia + Fever 
38.5C and/or infection
Withhold until fever resolves and ANC 1500; resume both drugs at 
next lower dose level
Cardiovascular
QTc prolongation
See Table 11
Monitor patient carefully; no dose 
modification is required
Gastrointestinal 
Mucositis or Diarrhea, Grade 3
Withhold until symptoms resolve to Grade 1; resume at the next 
lower dose level
Mucositis or Diarrhea, Grade 4
Permanently discontinue if symptoms uncontrollable by supportive 
care
Nausea or Vomiting, Grade 3
Withhold until symptoms resolve to Grade 1; resume at the next 
lower dose level
Nausea or Vomiting, Grade 4
Permanently discontinue if symptoms uncontrollable by supportive 
care
Hepatic
AST and/or ALT
>10 - 20 x ULN
Withhold until recovery to or baseline, then resume at next lower dose 
level or discontinue
Infection
Sepsis (with or without 
neutropenia)
Withhold until resolution and ANC 1500; resume at next lower dose 
level
Lung
Pneumonitis
No action required
Permanently discontinue
Uncomplicated Pulmonary 
Embolism (Grade 3)
Withhold until recovery; then resume at next lower dose level or 
discontinue as per investigator judgment
Pulmonary Embolism (Grade 4)
Permanently discontinue
Nervous System
Peripheral Neuropathy Grade 3 
or 4
No action required
Withhold until improves to 
Grade 1; resume at next lower 
dose level
Immune System
Hypersensitivity reactions 
Grade 3 or 4(a)
Withhold until symptoms 
resolve, then resume at the same 
dose level
Immediately stop infusion, do not 
re-challenge
Other 
Any other Grade 3 
non-hematologic toxicity 
Withhold palbociclib and/or nab-P treatment until Grade 1 or Grade 2 
(if not considered a safety risk), resume investigational products at the 
next lower dose
Abbreviations: ANC=Absolute Neutrophil Count
a.
Severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or 
generalized urticaria require immediate discontinuation of study drug administration and aggressive symptomatic 
therapy.


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5.3.7.1. Dose Modifications for Hematologic Toxicities
The below tables present guidelines for dose modifications for patients who experience 
hematologic toxicities.  For patients in dose escalation and MTD expansion cohorts, the use 
of G-CSF is permitted; recommendations for use are described in Table 9.  Dose 
re-escalation to the initial dose level should be considered in subsequent cycles as long as the 
criteria for retreatment are met (See Table 6). 
For patients assigned to a modified dose regimen, the use of G-CSF is prohibited in the 
first 3 cycles unless clinically indicated and medically unavoidable.
Table 9.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia (Dose Escalation and MTD Expansion Cohorts)
Day 8 
Blood 
Counts
Day 8 
Nab-P 
Dose
Day 8 Palbo 
Dose
Day 15 
Blood Counts
Day 15 
Nab-P Dose
Day 15 
Palbo dose
ANC >1000 
and Platelets 
75,000
No modification required.
ANC >1000 and 
Platelets 75,000
No modification required.
ANC 500-1000; or 
Platelets 
50,000-74,999
Continue at same 
dose level + G-CSF1
Continue at same dose 
level + G-CSF1
ANC<500; or 
Platelets <50,000
Withhold dose + 
G-CSF1, reduce dose 
for next cycle
Reduce by 1 dose level 
from Day 8 + G-CSF1
ANC 
500-1000; 
or Platelets 
50,000-74,9
99
Continue 
dose, but 
reduce by 
1 dose 
level
Withhold until 
ANC 1000, 
AND platelet 
count 75,000; 
then 
reintroduce at 
same dose
level
ANC>1000 and 
Platelets 75,000
Return to previous 
dose level + G-CSF1
Continue at same dose 
level + G-CSF1
ANC 500-1000; or 
Platelets 
50,000-74,999
Continue at dose 
level from Day 8 
+ G-CSF1
Reduce by 1 dose level 
from Day 8  + G-CSF1
ANC<500; or 
Platelets <50,000
Withhold dose + 
G-CSF1, reduce dose 
for next cycle
Withhold dose + 
G-CSF1 until ANC 
1000, AND platelet 
count 50,000; then 
reintroduce at next 
lower dose level
ANC<500; 
or Platelets
<50,000
Withhold 
dose
Withhold until 
ANC 1000, 
AND platelet 
count 50,000; 
then 
reintroduce at 
same dose 
level
ANC>1000 and 
Platelets 75,000
Reduce by 1 dose 
level (compared to 
Day 1) + G-CSF1
Reduce dose by 1 dose 
level + G-CSF1
ANC 500-1000; or 
Platelets 
50,000-74,999
Reduce by 2 dose 
levels (compared to 
Day 1+ G-CSF1
Withhold dose + 
G-CSF1 until ANC 
1000, AND platelet 
count 75,000; then 
reintroduce at same at 
next lower dose level
ANC<500; or 
Platelets <50,000
Withhold dose + 
G-CSF1
Withhold dose + 
G-CSF1 until ANC 
1000, AND platelet 
count 50,000; then 
reintroduce at next 
lower dose level
Abbreviations: ANC=absolute neutrophil count; G-CSF=granulocyte-colony stimulating factor
1.
G-CSF should be administered according to the prescribing information until ANC 1500 cells/mm3.


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Table 10.
Recommended Dose Modifications for Neutropenia and/or 
Thrombocytopenia (MDR and MDR Expansion Cohorts)
Cycle Day
Absolute 
Neutrophil 
Count 
(ANC) 
(cells/mm3)
Platelet 
count
(cells/mm3)
Proposed Action
Nab-Paclitaxel
Palbociclib
Day -2 
(Cycle 1) 
or Day 1 
(Cycles 2)
<1500
OR
<100,000
Delay dose until recovery (ANC 1500 AND platelet 
count 100,000
Day 13 
(Cycle 1) 
or Day 15 
(Cycles 2)
500 to <1000
OR
50,000 to 
<75,000
Continue dose, but 
reduce by 1 dose level 
(compared to Day 8)
Withhold dose until ANC 
1000, then reintroduce 
at same dose level
<500
OR
<50,000
Withhold dose 
Withhold dose until ANC 
1000 AND platelet 
count 50,000, then 
reintroduce at next lower 
dose level
Abbreviations: ANC=absolute neutrophil count 
1.
In the first 3 cycles, G-CSF use in the MDR cohorts is prohibited unless clinically indicated and medically 
unavoidable.
5.3.7.2. Dose Modifications for QTc Prolongation 
Patients experiencing QTc prolongation (QTc 501 msec on at least two separate ECGs) 
should have their palbociclib treatment interrupted/delayed. 
In the event of QTc prolongation, possible alternative reversible causes such as serum 
electrolytes abnormalities, or usage of concomitant medications with the potential to prolong 
the QTc interval should be evaluated. 
If such reversible causes are identified, then they should be corrected accordingly 
(ie, correction of electrolyte abnormalities with supplements to within normal limits and/or 
discontinuation (if possible) of concomitant medications known to prolong the QT interval). 
Recommended dose modifications in the event of QTc prolongation are provided in 
Table 11.


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Table 11.
Palbociclib Dose Modifications in the Event of QTc Prolongation
Toxicity (NCI CTCAE Grade, Version 4.03)
Grade 2 QTc prolongation
Grade 3 QTc prolongation
Grade 4 QTc 
prolongation
Reversible 
cause 
identified 
Treat reversible cause 
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc 480 msec 
Continue at the same dose level1
Treat reversible cause 
Withhold treatment until QTc <501 msec 
Resume treatment at the same dose level.
Monitor ECG more frequently as per 
investigator’s best medical judgment until 
QTc 480 msec.  
Permanently 
discontinue
No reversible 
cause 
identified
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc 480 msec 
Continue at the same dose level1
Withhold treatment until QTc <501 msec 
Resume treatment at the next lower dose
level2
Monitor ECG more frequently as per 
investigator’s best medical judgment until 
QTc 480 msec.
Permanently 
discontinue
1.
If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the absence of other 
alternative causes or despite correction of alternative causes, then dose adjustment and/or discontinuation should be 
considered in consultation with a cardiologist and the sponsor, taking into account the emerging safety data from 
palbociclib trials and the investigator’s best medical judgment.
2.
If the Grade 3 QTc prolongation occurs again after one DL reduction, further dose adjustment and/or discontinuation 
should be discussed with the sponsor in consultation with a cardiologist, taking into consideration the emerging safety 
data from palbociclib trials and the investigator’s best medical judgment.
5.4. Investigational Product Storage 
The investigator, or an approved representative (eg, pharmacist) will ensure that all IP, 
including any comparative agents and/or marketed products are stored in a secured area with 
controlled access under required storage conditions and in accordance with applicable 
regulatory requirements.
Investigational product must be stored in its original container and in accordance with the 
label.  See the locally approved package insert for storage conditions of nab-P once it is 
reconstituted. 
Storage conditions stated in the Study Reference Safety Document (SRSD) (ie, IB or SPC) 
will be superseded by the storage conditions stated in the product label information.  The IP 
Manual must be referenced for any additional guidance on storage conditions and actions to 
be taken when conditions are outside the specified range.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This must be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be documented.  The operation of the temperature monitoring device 
and storage unit (for example, refrigerator), as applicable, should be regularly inspected to 
ensure it is maintained in working order. 


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Any excursions from the product label storage conditions must be reported upon discovery. 
The site must actively pursue options for returning the product to that storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion. Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation. Specific details regarding 
information the site should report for each excursion will be provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered excursions.
More specific details will be provided to the sites separately.
Site staff will instruct patients on the storage requirements for take home medications. 
5.5. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.
Medication should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements.  Returned medication should be stored separately from 
medication that needs to be dispensed.
To ensure adequate records, palbociclib capsules will be accounted for as instructed by the 
sponsor.  Patients are requested to return previously dispensed containers as well as their 
completed patient diary to the clinic at each visit for accountability purposes even if no new 
investigational product will be issued at that visit.
5.5.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer and all destruction must be adequately documented.
5.6. Concomitant Medications and Treatment(s)
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the investigator.  Any medications 
including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior 
to the start of IP and up to 28 days following the last dose, including the reason for their 
administration, must be recorded on the CRF, which includes pre-medications to alleviate 
nab-P infusion reactions.


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Routine postoperative care, such as dressing changes, suture removal, drain removal, or 
venous access (central or peripheral), does not need to be recorded.  Anesthetics used for any 
surgical procedures performed during the patient’s participation in the study must be 
recorded on the CRF; it is not necessary to list the specific anesthetics.  Palliative and 
supportive care for cancer-related symptoms will be offered to all patients in this study.
5.6.1. Prohibited Medications
The following treatments are prohibited throughout the duration of the treatment phase: 

Anticancer agents: No additional investigational or commercial anticancer agents 
such as chemotherapy, targeted therapy, or biological response modifiers, will be 
permitted during the treatment phase. 

Strong/Moderate CYP3A inhibitors: including but not limited to amprenavir, 
atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, 
erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
suboxone, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit, 
grapefruit juice or any product containing grapefruit.

Strong/Moderate CYP3A inducers: including but not limited to carbamazepine, 
felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifampin, rifabutin, 
rifapentin, and St. John’s wort.

Dexamethasone is considered a weak to moderate CYP3A inducer depending on the 
dose regimen.  The use of dexamethasone as a premedication is prohibited on days 
where PK samples are drawn.  Sponsor approval must be obtained if dexamethasone 
is needed to prevent adverse reactions to nab-P.

Strong/Moderate CYP2C8 inhibitors: including but not limited to deferasirox, 
gemfibrozil, lapatinib, trimethoprim, and fluvoxamine.

Strong/Moderate CYP2C8 inducers: including but not limited to rifampin.

Drugs known to cause QT interval prolongation Refer to Appendix 9 for a list of 
drugs known to predispose to Torsade de Pointes.
5.6.2. Medications Not Recommended 
The following treatments are not recommended throughout the duration of the treatment 
phase.  Alternative therapies should be considered whenever possible.  If usage of the 
following treatments is deemed necessary, consultation and agreement with the sponsor is
required prior to treatment initiation. 

The concurrent use of dexamethasone is not recommended. 


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
Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids.  Steroids given for physiological replacement, as anti-emetics or 
inhaled as well as short course of oral/topical steroids given for allergic reactions or 
asthma flares are allowed.

The use of herbal medicine is not recommended during the treatment phase. 
5.6.3. Antacids Agents
Proton-pump inhibitors (PPIs): The concomitant use of PPIs with palbociclib is prohibited 
7 days before the scheduled palbociclib PK sample collection (eg, C1D13) until the last 
palbociclib PK sample is drawn. 
H2-receptor antagonists: If H2-receptor antagonists are used, staggered dosing relative to 
palbociclib dosing is recommended on palbociclib PK sample collection days.  The evening 
dose of H2-receptor antagonist should be given 10 hours before the palbociclib dose, and the 
morning dose of H2-receptor antagonist should be given 2 hours after the palbociclib dose.
Local antacids: The staggered dosing of local antacid relative to palbociclib dosing is 
recommended on palbociclib PK sample collection days.  Local antacids should be given at 
least 2 hours before or after palbociclib administration. 
5.6.4. Use of Growth Factors
In the dose-escalation and MTD expansion cohorts, the use of G-CSF to manage neutropenia 
is permitted at the discretion of the investigator.  Dose modification guidelines in Table 9
provide recommendations on G-CSF administration.  Growth factors should be used in 
accordance with the prescribing information.
For patients assigned to a modified dose regimen, growth factors should not be used during 
the first 3 cycles unless clinically indicated and medically unavoidable.
5.7. Other Investigational Agent(s)
While on IP, patients will not be permitted to participate in another study involving 
investigational drug(s) (Phases 1-4). 
5.8. Concomitant Radiotherapy or Surgery
Any concurrent radiotherapy (except palliative radiotherapy as specified below) or 
cancer-related surgery are prohibited throughout the duration of the treatment phase of the 
study.  Patients requiring any of these procedures will be discontinued from the treatment 
phase and will enter the follow-up phase.
Palliative radiotherapy is permitted for the treatment of painful bony lesions provided that the 
lesions were known to be present at the time of study entry and the investigator clearly 
documents that the need for palliative radiotherapy is not indicative of disease progression.  
In view of the current lack of data about the interaction of palbociclib with radiotherapy, 
palbociclib treatment should be interrupted during palliative radiotherapy, stopping 1 day 


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before and resuming treatment 1 week after.  For patients with bone involvement, it is 
suggested to institute palliative radiotherapy before study initiation if possible and clinically 
appropriate (eg, lesions at risk for spontaneous micro-fractures or painful lesions).  Palliative 
radiotherapy during the treatment phase will be considered alternative cancer therapy and 
will result in censoring of the PFS endpoint.  The dates on which palliative radiotherapy is 
administered must be recorded on the appropriate CRFs. 
Caution is advised on theoretical grounds for any non-cancer related surgical procedures 
during the study.  The appropriate interval of time between surgery and palbociclib required 
to minimize the risk of impaired wound healing and bleeding has not been determined.  
Based on the available pharmacokinetic data, stopping palbociclib is recommended at least 
7 days prior to elective surgery.  Postoperatively, the decision to reinitiate palbociclib 
treatment should be based on a clinical assessment of satisfactory wound healing and 
recovery from surgery.
6. STUDY PROCEDURES 
6.1. Screening
For details on screening/baseline procedures, see the Schedule of Activities tables.
Voluntary, written, dated, and signed informed consent must be obtained before any study 
specific procedures are performed (with the exception of certain imaging assessments if 
meeting the criteria defined in this section); however, it may be obtained more than 28 days 
before enrollment.  See Section 4 for detailed inclusion and exclusion criteria.
Medical and oncological history must include information on prior anticancer treatments.
Date of enrollment is defined as the day the patient has satisfied all inclusion and exclusion 
criteria and is considered eligible for the study. 
Baseline tumor related signs and symptoms will be recorded at the C1D-2 visit prior to 
initiating treatment and then reported as adverse events during the trial if they worsen in 
severity or increase in frequency. 
Radiographic tumor assessments (as documented on the Tumor Assessments flowchart) that 
were performed before the signing of the informed consent form as routine procedures (but 
within 28 days prior to the start of IP) do not need to be repeated and may be used as baseline 
assessments, as long as:

The tests were performed per the method requirements outlined in the Tumor 
Assessments flowchart and, Section 7.1.
and

Appropriate documentation indicating that these radiographic tumor assessments 
were performed as standard of care is available in the patient’s source notes. 


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6.2. Treatment Period
For details on procedures during the treatment phase, see the Schedule of Activities tables. 
On C1D-2, blood chemistry, hematology, coagulation, urinalysis, 12-lead ECG,  physical 
examination/vital signs, and baseline signs/symptoms are not required if acceptable screening 
assessment is performed within 7 days prior to start of IP.
Patients who are sexually active and at risk for pregnancy must agree to use two methods of 
highly effective contraception throughout the treatment period and continue for 1 month after 
the last dose of IP.  See Section 4.3 for further information. 
The start of a new cycle may be delayed when both palbociclib and nab-P are withheld due to 
treatment-related toxicity.  In the event that the start of a new cycle is delayed, procedures 
required on Day 1 of the given cycle will be performed when either investigational product is 
resumed.  New cycle Day 1 procedures (ie, physical examination, Karnofsky performance 
status, ECG, questionnaire, blood chemistry, hematology, coagulation) that were performed 
prior to knowing the need to delay the start of the cycle do not need to be repeated (1) if not 
required to determine whether investigational product may be resumed and (2) if performed 
within 7 days prior to investigational product resumption.  Maximum time between visits is 
30 days.
Procedures on Day 6 of Cycle 1 and Day 8 of Cycle 2 are not required for patients assigned 
to MDR1 and MDR2 cohorts, since nab-P is administered biweekly in these cohorts.
If only one investigational product (either palbociclib or nab-P) is delayed, the next cycle 
may begin as scheduled. 
6.3. End of Treatment Visit
For details on procedures to be performed at the End of Treatment visit, see the Schedule of 
Activities tables.
The End of Treatment visit will be performed as soon as possible but no later than 8 weeks 
(ie, 56 days) 7 days from last dose of investigational product and prior to the initiation of 
any new anticancer therapy.
Patients who are sexually active and at risk for pregnancy must continue to use two methods 
of highly effective contraception for 1 month after the last dose of investigational product.
Patients who discontinue nab-P treatment due to treatment-related toxicity may continue 
palbociclib treatment as scheduled.  Similarly, patients who discontinue palbociclib treatment 
due to treatment-related toxicity may continue nab-P therapy as scheduled (agreement by the 
sponsor and investigator is required in either case).
6.4. Follow-up Visit
For details on follow-up visit procedures, see the Schedule of Activities tables.


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Approximately every month (28 days) after discontinuation of IP, post-treatment follow-up 
visit procedures will be collected until 12 months (365 days) have elapsed from the first dose 
of IP.  Telephone contact is acceptable.  Patients who have discontinued IP within 12 months 
(365 days) since the first dose will remain in post-treatment follow-up (See Schedule of 
Activities) until 12 months have elapsed from the first dose of IP.  Anticancer medications 
will be collected in the post-treatment follow-up period.
6.5. Post-Study Patient Interview
Upon implementation of Amendment 3, this assessment is no longer required.
6.6. Patient Withdrawal
6.6.1. Study Treatment Discontinuation
The term "interruption" refers to a patient stopping the investigational products during the 
course of the study, but then re-starting it at a later time in the study.  The reason for dosing 
interruption will be collected on the appropriate CRF. 
The term "discontinuation" refers to a patient's withdrawal from the study treatment.  The 
reason for discontinuation from treatment will be collected on the appropriate CRF. 
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator or sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression; 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity; 

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Death.


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If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  Lost to follow-up is defined by the inability to reach the patient after a minimum of 
three documented phone calls, faxes, or emails as well as lack of response by the patient to 
one registered mail letter.  All attempts should be documented in the patient’s medical 
records.  If it is determined that the patient has died, the site will use permissible local 
methods to obtain the date and cause of death.  If investigator’s use of third-party 
representative to assist in the follow-up portion of the study has been included in the patient’s 
informed consent, then the investigator may use a sponsor retained third-party representative 
to assist site staff with obtaining patient’s contact information or other public vital status data 
necessary to complete the follow-up portion of the study.  The site staff and representative 
will consult publicly available sources, such as public health registries and databases, in 
order to obtain updated contact information.  If after all attempts, the patient remains lost to 
follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the patient’s medical records.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow-up with 
the patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Patients who request to discontinue IP will remain in the study and must continue to be 
followed for protocol specified follow-up procedures.  The only exception to this is when a 
patient specifically withdraws consent for any further contact with him/her or persons 
previously authorized by patient to provide this information.  Patients should notify the 
investigator of the decision to withdraw consent from future follow-up in writing, whenever 
possible.  The withdrawal of consent should be explained in detail in the medical records by 
the investigator, as to whether the withdrawal is from further treatment with investigational 
product only or also from study procedures and/or post treatment study follow-up, and 
entered on the appropriate CRF page.  In the event that vital status (whether the patient is 
alive or dead) is being measured, publicly available information should be used to determine 
vital status only as appropriately directed in accordance with local law.
6.6.2. Study Discontinuation
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol required schedule of study 
visits or procedures at a given study site.
Patients will be withdrawn from study in the case of:


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
Withdrawal of consent (ie, refuses tumor assessments or survival status after end of 
treatment);

Lost to follow-up;

Death; 

Administrative study closure by sponsor. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  If after three unsuccessful attempts to contact the patient, one of which is by 
registered letter, the patient should be considered “lost to follow-up”.  Steps taken to contact 
the patient (eg, dates of telephone calls, registered letters, etc.) must be clearly documented in 
the source documents. In any circumstance, every effort should be made to document patient 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request the patient to return all unused investigational product(s), request the patient to return
for a final visit, if applicable, and follow-up with the patient regarding any unresolved 
adverse events (AEs).
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7. ASSESSMENTS
All study procedures are described in the Schedule of Activities table and footnotes.  Every 
effort should be made to ensure that the protocol-required tests and procedures are completed 
as described.  However, it is anticipated that from time to time there may be circumstances, 
outside of the control of the investigator, that may make it unfeasible to perform the test.  In 
these cases the investigator will take all steps necessary to ensure the safety and well-being 
of the patient.  When a protocol-required test cannot be performed, the investigator will 
document the reason for this and any corrective and preventive actions that he or she has 
taken to ensure that normal processes are adhered to as soon as possible.  The study team will 
be informed of these incidents in a timely fashion.
All assessments should be performed prior to dosing with IP on the visit day unless otherwise 
indicated.  Acceptable time windows for performing each assessment are described in the 
column headers.  For the purposes of this trial, the first cycle is 30 days in length; subsequent 
cycles are 28 days in length.  A cycle could be longer than 28 days if persistent toxicity 
delays the initiation of the subsequent cycle.


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7.1. Efficacy Assessments
7.1.1. Tumor Assessments
The importance of timely and complete disease assessments in this study cannot be 
understated.  Disease assessments must be performed as scheduled according to the calendar, 
regardless of treatment delays resulting from toxicity, to prevent the introduction of bias into 
the assessment of efficacy.  Failure to perform any of the required disease assessments will 
result in the inability to determine disease status for that time point.  A series of incomplete 
disease assessments will result in censoring of the exploratory endpoint of PFS back to the 
time of the last full assessment that did not show progression.  Frequent off schedule or 
incomplete disease assessments have the potential to weaken the conclusion of this clinical 
trial.
Objective tumor response will be measured using the Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1(Appendix 5).  All measurements should be recorded in metric 
notation using a ruler or calipers.
MRI of the abdomen and pelvis can be substituted for CT if MRI adequately depicts the 
disease.  However, MRI of the chest should not be substituted for CT of chest even if IV 
contrast is contraindicated.  In such case, CT will be performed without contrast.  If MRI is 
used to follow-up bone lesion(s) it should be performed a few days before any treatment that 
may affect bone-marrow cellularity [eg, granulocyte-colony stimulating factor (G-CSF)].
Refer to Table 2 and the Schedule of Activities for timing of disease assessments.
7.1.1.1. Screening/Baseline Tumor Assessment
Screening/baseline tumor assessment will be carried out within 28 days before start of IP 
(unless otherwise specified below). 
Disease assessment for all patients at baseline will include computed tomography (CT) or 
magnetic resonance imaging (MRI) scan of all sites of disease as clinically indicated. 
Clinical assessment of superficial disease which will include photographs of all superficial 
metastatic lesions.  All lesion measurements must be recorded in the CRF.
7.1.1.2. Post-Baseline Tumor Assessments
Post-baseline tumor assessments will be performed as clinically indicated from start of 
investigational product until radiographically and/or clinically (ie, for photographed or 
palpable lesions) documented PD as per RECIST v.1.1, initiation of new anticancer therapy, 
or discontinuation of patient from overall study participation (eg, death, patient's request, lost 
to follow-up). Imaging assessments are to be scheduled using the investigational product 
start date (Cycle 1 Day -2) as the reference date for all time points and are NOT to be 
scheduled based on the date of the previous imaging time point.  Imaging assessment delay to 
conform to treatment delay is not permitted.


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Post-baseline tumor assessments will include clinical assessment of sites of superficial 
disease identified at baseline.  Clinical assessment of superficial disease should coincide with 
the imaging studies and will include photographs of all superficial metastatic lesions.  All 
lesion measurements must be recorded in the CRF.

CT or MRI scan of any other sites of disease identified at baseline, including brain 
CT scan if applicable.  CTs should be performed with contrast agents unless 
contraindicated for medical reasons.  If IV contrast is medically contraindicated, the 
imaging modality to be used to follow the disease (either CT without contrast or 
MRI) should be the modality which best evaluates the disease, and the choice should 
be determined by the investigator in conjunction with the local radiologist.
The same method and technique should be used to characterize each lesion identified and 
reported at baseline, during the study treatment period and during follow-up.  The use of 
plain-film X-rays is discouraged.  The use of positron emission tomography (PET) imaging 
as the only imaging modality is not permitted.
7.1.2. Overall Survival
Following the End of Treatment Visit, survival status will be collected in all patients 
(telephone contact is acceptable) every 28 days (28 days) until 12 months (365 days) have 
elapsed from the first dose of IP.  Information on subsequent anticancer therapy will also be 
collected.
Patients who have completed 13 cycles of IP are not required to enter post-treatment 
follow-up upon permanent discontinuation of IP. Patients who are ongoing beyond Cycle 13 
will be considered to have completed the study upon permanent discontinuation of IP.
Patients who have discontinued IP before completing Cycle 13 will remain in post-treatment 
follow-up (See Schedule of Activities) until 12 months (365 days) have elapsed from the first 
dose of IP.  Once a patient has been followed for 12 months from the first dose, the patient is 
considered to have completed the study and no further data will be collected.
7.1.3. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting study treatment, once at the start of screening and once at the 
baseline visit, immediately before investigational product administration (Cycle 1 Day -2).  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and another negative pregnancy test result will then be required at the baseline 
visit before the patient may receive IP.  Pregnancy tests will also be routinely repeated at 
every treatment cycle during the treatment period, at the end of study treatment, and 
additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  In the case of a positive hCG test, the patient will be withdrawn from treatment 
and will be withdrawn from the study.  Additional pregnancy tests may also be undertaken if 
requested by institutional review boards (IRBs)/ethics committees (EC) or if required by 
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7.2. Safety Assessments
Safety assessments will include collection of adverse events (AEs), serious adverse events 
(SAEs), vital signs and physical examination, electrocardiogram [ECG (12-lead)], laboratory 
assessments, including pregnancy tests and verification of concomitant treatments.
7.2.1. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the NCI 
CTCAE version 4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study, including baseline signs and symptoms, will be 
recorded on the adverse events CRF page.
7.2.2. Laboratory Safety Assessment
Haematology, blood chemistry, coagulation, and urinalysis will be drawn as indicated in the 
Schedule of Activities and analyzed at local laboratories.
Blood tests will include the following:
Table 12.
Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy Test
Hemoglobin
ALT
PT or INR
Urine dipstick for 
urine protein: If 
positive, further 
diagnostic testing 
will be performed as 
clinically indicated -
For female patients 
of childbearing 
potential, serum or 
urine 
Platelets
AST
PTT
WBC
Alk Phosphatase
aPTT
Absolute Neutrophils
Sodium
Absolute Lymphocytes
Potassium
Absolute Monocytes
Magnesium
Urine dipstick for 
urine blood: If 
positive collect a 
microscopic (Reflex 
Testing)
Absolute Eosinophils
Chloride
Absolute Basophils
Total Calcium
Total Bilirubin*
BUN or Urea
Creatinine
Uric Acid
Glucose 
(non-fasted)
Albumin
Phosphorous or 
Phosphate
Amylase (if 
available)
Lipase (if available)
*For potential Hy’s Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/INR, and alkaline phosphastase.  In addition, acetaminophen levels should be considered.


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Blood tests will be drawn as described in the Schedule of Activities table, and analyzed at 
local laboratories.  Additional blood tests should be performed where needed for the purpose 
of evaluating potential DLTs or other adverse events. 
Urinalysis will be conducted via urine dipstick for urine protein: if the result is positive, a 
24-hour collection and microscopic reflex testing will be conducted.
7.2.3. Vital Signs and Physical Examination
Patients will have a physical exam to include weight, vital signs (pulse rate and blood 
pressure), assessment of Karnofsky (see Appendix 2) performance status, and height; height 
will be measured at screening only.
7.2.4. (12-Lead) Electrocardiogram
All ECGs will be performed using a 12-lead (with a 10-second rhythm strip) tracing.  ECG 
measurements will include PR interval, QT interval, RR interval, and QRS complex.  It is 
preferable that the machine used has a capacity to calculate the standard intervals 
automatically. 
ECG interval readings by the ECG recorder’s algorithm will be read and interpreted at the 
investigational site for eligibility determination and patient safety monitoring and 
documentation stored in the source documents. 
Triplicate ECGs will be performed for all patients. 

All ECGs should be obtained after a fast of at least 1 hour.  When scheduled at the 
same nominal time/visit, triplicate ECGs should be collected prior to any blood draws 
for PK, biomarkers, or safety labs and prior to placement of the IV line for nab-P 
administration.

Triplicate ECGs will be obtained for safety monitoring at Screening, and 0 hour 
(pre-dose) on C1D-2, C1D13, C2D1 and C2D15, then on Day 1 of Cycles 4 and 7.  
ECGs will be obtained at the time of End of Treatment or Withdrawal.  ECGs beyond 
Cycle 7 will be performed as clinically indicated.
Additional ECGs may be performed as clinically indicated at any time.
For the purpose of the study, triplicate ECGs are defined as three consecutive ECGs 
performed approximately 2 minutes apart but within 10 minutes for all 3 ECGs at the 
protocol specified timepoints (see Schedule of Activities table for details) to determine the 
mean QTc interval. 
If at any time during the course of treatment, the mean QTc is prolonged (501 msec on at 
least two separate ECGs, ie, CTCAE Grade 3), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including 
verification that the machine reading is accurate (and manual calculation of QTcF).  If 
manual reading confirms a QTcF of 501 msec, immediate search for reversible causes 
(including electrolyte abnormalities, hypoxia and concomitant medications for drugs with the 


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potential to prolong the QTc interval) should be performed.  In addition, repeat ECGs should 
be immediately performed hourly for at least 3 hours until the QTc interval falls below 
501 msec. 

If QTcF interval reverts to less than 501 msec, and in the judgment of investigator(s) 
in consultation with the sponsor the cause is determined to be other than 
investigational product, treatment may be continued with regular ECG monitoring 
under hospital supervision. 

If in that timeframe the QTc intervals remain above 501 msec the investigational 
product (palbociclib) will be held until the QTc interval decreases to <501 msec. 

Patients will then restart investigational product at the next lowest dose level.  If the 
QTcF interval has still not decreased to 480 msec after 2 weeks, or if at any time a 
patient has a QTcF interval >515 msec or becomes symptomatic, the patient will need 
to discontinue IP.  Additional triplicate ECGs may be performed as clinically 
indicated. 
Prior to concluding that an episode of prolongation of the QTc interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event. 
When matched with PK sampling, ECG must be carried out before PK sample drawing such 
that the PK samples are collected at the nominal time (ie, the timing of the PK collections 
overrides the timing of the ECG collections.
7.2.5. Other Safety Assessments
A full physical examination including an examination of all major body systems (including 
general appearance, head, ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, 
abdomen, and musculoskeletal), height (at Screening only), weight, blood pressure and pulse 
rate which may be performed by a physician, registered nurse or other qualified health care 
provider, will be required at screening, and Cycle 1 Day -2 and Cycle 2 Day 1. 
Symptom directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits according to the Schedule of Activities.
7.3. Pharmacokinetics Assessments
7.3.1. Palbociclib Pharmacokinetic Assessments
Plasma PK samples for palbociclib determination will be collected on Day 13 of Cycle 1 at 
0 (pre-dose), 2, 4, 6, 8 and 24 hours post palbociclib dose, and on Cycle 2 Days 1 and 
15 (pre-dose)  as described in Schedule of Activities.  Patients must have received at least 


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7 consecutive days of palbociclib before PK assessments on Cycle 1 Day 13 and Cycle 2 
Day 15. 
Additional instructions for serial PK sampling on Cycle 1 Day 13 include the following:

The palbociclib dose that is taken on C1D12 should be at least 20 hours from the time 
the pre-dose PK sample is drawn on C1D13.  Patients should record the time of their 
C1D12 palbociclib dose in the patient diary.

Patients must not take their palbociclib dose on C1D13 until after the pre-dose PK 
sample is drawn.  Patients must be instructed to bring their palbociclib dose with 
them to the clinic.

Because patients must take palbociclib with food, the investigator must provide the 
patient with a structured meal on C1D13.  The total nutritional composition should be 
approximately 50% carbohydrate, 35% fat and 15% protein.  The caloric intake per 
for the meal should be approximately 500-700 kcal.  The meal should be eaten within 
30 minutes prior to administration of palbociclib, and the patient should consume at 
least 80% of the meal provided before palbociclib dosing. 

Palbociclib must be administered as close as possible to the start of infusion of nab-P.
Other PK sampling days (C2D1, C2D15) - On the days where trough PK samples are drawn, 
patients must not take their palbociclib dose until after the predose PK sample is drawn.  
Once the predose PK sample is drawn, patients should take their palbociclib dose (with any 
food the patient prefers) as close as possible to the start of nab-P infusion.  The investigator 
should plan to provide the patient with a meal on these days. 
Meal information (nearest the palbociclib dose) will be collected on Cycle 1 Day 12, Cycle 1 
Day 13, Cycle 2 Day 1, Cycle 2 Day 14, and Cycle 2 Day 15.  Information including meal 
time and type (high fat, low fat, or standard) will be collected.
In the event nab-P is not dosed on Day 13, PK samples for palbociclib determination can be 
collected on the day the second or third dose of nab-P is administered as long as there is no 
dose interruption, reduction or delay of palbociclib dosing within 7 days of the intended 
nab-P dosing and PK sampling.  In the event PK samples cannot be collected (or is not 
collected) on Day 13 of Cycle 1 or the day of third nab-P dosing, every effort should be made 
to collect makeup samples on Day 8 or 15 of Cycle 2 or the day when the second or third 
dose of nab-P in Cycle 2 (or later cycles) is administered using the same criteria.  The 
Day 13, 24-hour PK sample should collected prior to the administration of the Day 14 
palbociclib dose.  The exact time of the sample collection and the most recent dosing time 
before and after PK sample collection will be recorded on the CRF.  The date of missing dose 
should also be recorded in the CRF.  
 and
blood sample on Day 13 should 
also be rescheduled to coincide with PK assessments.
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During all study periods, blood samples (3 mL) to provide approximately 1 mL of plasma for 
pharmacokinetic analysis will be collected into appropriately labeled tubes containing 
dipotassium ethylenediaminetetraacetic acid (K2EDTA) at times specified in the Study 
Procedures section of the protocol. 
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the pharmacokinetic samples at the exact nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60 minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF/DCT).
Refer to the Study Manual for details on PK sample collection, processing and shipping 
procedures.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.  As part of understanding the PK of the palbociclib, blood 
samples may be used for metabolite identification and/or evaluation of the bioanalytical 
method.  
 
7.3.2. Nab-Paclitaxel Pharmacokinetic Assessments 
Plasma PK samples for total paclitaxel determination will be collected on Days -2 to Day 1 
and Days 13 to 15 of Cycle 1 at 0 (pre-dose), 0.5 (end of infusion), 1, 2, 4, 6, 8, 24 and 
48 hours post the start of nab-P IV infusion as described in SOA.  The pre-dose samples 
should be collected just before the start of the nab-P infusion.  On Day 13, nab-P and 
palbociclib should be dosed at approximately the same time.  The PK samples should be 
drawn from the opposite arm of the IV infusion.  For Day 13 and 14 PK samples, the PK 
samples will only be collected for patients who have received at least 7 consecutive days of 
palbociclib dosing.  For patients who had a palbociclib dose interruption, reduction or delays 
within 7 days of the third nab-P dose, PK samples collection can be made up in later cycles.  
In the event nab-P is not dosed on Day 13, PK samples for total paclitaxel determination can 
be collected on Day 8 or 15 (the day the second or third nab-P dose is administered), as long 
as there is no dose interruption, reduction or delay of palbociclib dosing within 7 days of the 
intended nab-P dosing and PK sampling.  The exact date and time of the sample collection 
and the exact start and stop time of the nab-P infusion will be recorded on the CRF.  The date 
of missing dose(s) should also be recorded in the CRF. 
During all study periods, blood samples (4 mL) to provide approximately 1.5 mL of plasma 
for pharmacokinetic analysis will be collected into appropriately labeled tubes containing 
sodium heparin at times specified in the Study Procedures section of the protocol.
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the pharmacokinetic samples at the exact nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60 minute sample) from dosing will not be captured as a protocol deviation, as long as the 
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exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF/DCT).
Additional blood samples may be requested from patients experiencing unexpected or serious 
adverse events, or adverse events that lead to discontinuation.
Refer to the Study Manual for detailed PK sample collection, processing and shipping 
procedures.
As part of understanding the PK of total paclitaxel following nab-P administration, blood 
samples may be used for evaluation of the bioanalytical method.  
 
7.4. Biomarker Assessments 
An archival tumor tissue sample (or de novo tumor biopsy tissues) is required from all 
patients for study participation. 
Specifically, an FFPE tissue block that contains sufficient tissue to generate at least 
12 (preferably 15) unstained slides, each with tissue sections that are 5 microns thick, should 
be collected.  If an FFPE tissue block cannot be provided, at least 12 (preferably 15) unbaked 
glass slides, each containing an unstained 5 micron FFPE tissue section, is required.  If an 
archival tumor tissue sample is not available, a de novo tumor biopsy specimen must be 
obtained before investigational products are administered (Cycle 1 Day -2).  Tumor tissue 
from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is 
not adequate and should not be submitted.  Specimens will be sent to the sponsor-designated 
central laboratory.  Results from the Rb1 and p16 expression testing by IHC will be used for 
sensitivity analyses. 
 
 

 
 
 
 
 
 
 
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
 
 
 
 
Detailed information about biomarker sample collection, preparation, storage, labeling, and 
shipment is indicated in the Study Manual.  Refer to the Schedule of Activities for details 
pertaining to specific days of sample collection.  Table 13 summarizes the biomarker 
assessments currently planned for the study.
These analyses may also lead to the identification of potential biomarkers of response to the 
combination treatment, ultimately leading to the development of a patient selection strategy 
for further clinical investigation.
Table 13.
Summary of Biomarker Assessments
Assay
Source
p16 and Rb1 status
Archival tumor specimen and/or 
de novo tumor biopsies
7.4.1. Optional De Novo Tumor Tissue Biopsy for Pharmacodynamic Analysis
For patients who consent, the optional de novo tumor biopsy collection should be collected at 
Screening and End of Treatment.  If collected, these specimens will be provided in addition 
to the archival tumor tissue specimen that is required for eligibility purposes.  Tumor tissue 
from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is 
not adequate and should not be submitted.  Details for handling of these specimens including 
processing, storage, and shipment will be provided in the Study Manual.
De novo tumor core biopsy collection is strongly encouraged unless it poses a safety risk to 
the patient, in the opinion of the investigator.  The tumor tissue will be used for 
pharmacodynamic assessment and to further determine possible mechanisms of 
sensitivity/resistance to study treatment. 
 
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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
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For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of investigational product (either nab-P or palbociclib) through the 
patient’s last visit.
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs 
ends at the time the new treatment is started.  Death must be reported if it occurs during the 
SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;


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
Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page. 
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the safety reporting 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
safety reporting period, then the event leading to death must be recorded as an AE and as an 
SAE with CTCAE Grade 5 (see the section on Severity Assessment).


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values ≥3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value ≥2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value ≤2 × ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with preexisting AST or ALT baseline values above the normal 
range, AST or ALT value 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller);
Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN; or 
if the value reaches 3 × ULN (whichever is smaller).


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The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug, 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for LFT abnormalities identified at the time, should be considered potential Hy’s 
Law cases irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs.  Such potential Hy’s Law cases should be 
reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 


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
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.


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8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE [ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly (in a 
live-born baby, a terminated fetus, an intrauterine fetal demise or a neonatal death)], the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (see also the section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.


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When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Analysis Sets 
1. Safety analysis set. 
The safety analysis set includes all enrolled patients who receive at least one dose of either 
investigational product.  The safety analysis set will also be used for efficacy analyses.
2. Per protocol analysis set evaluable for MTD.
The per protocol analysis set includes all enrolled patients who receive at least one dose of 
investigational product and who do not have major treatment deviations during the first cycle 
of treatment.  Patients with major treatment deviations in the first cycle are not evaluable for 
the MTD assessment and will be replaced as needed to permit MTD estimation.  Major 
treatment deviations include administration of less than 80% of the planned dose of 
palbociclib, or less than 2 doses of nab-P for reasons other than treatment-related toxicity in 
Cycle 1. 
3. PK analysis sets.
The PK parameter analysis population is defined as all enrolled patients treated who have 
sufficient information to estimate at least 1 of the PK parameters of interest and have no 
major protocol deviations affecting PK assessment.
The PK concentration population is defined as all enrolled patients who are treated and have 
at least 1 analyte concentration.
4. Biomarker analysis sets.
The biomarker analysis set is defined as all patients who have received at least one dose 
of investigational product and who have at least one baseline biomarker assessment.  
Analysis sets will be defined separately for serum, plasma, archival tumor tissue, 
 
 and de novo tumor biopsies.
9.2. Statistical Methods and Properties
Due to the exploratory nature of this study, no confirmatory inferential analyses are planned 
since the primary objectives of this study are to assess the safety and tolerability MTD(s), of 
palbociclib in combination with nab-P in patients with mPDAC in order to estimate the MTD 
and select the RP2D.
CCI


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Dose escalation and de-escalation will follow a 2x3 matrix “Up-and-Down” design, with 
different dose combinations of palbociclib and nab-P using the modified toxicity probability 
interval (mTPI) method.  Approximately 60-100 patients are expected to be enrolled in the 
overall study.
9.2.1. Statistical Methods for Dose Escalation/De-Escalation
9.2.1.1. mTPI Method 
The rules for dose escalation/de-escalation will follow a modified toxicity probability 
interval (mTPI) method.20  The mTPI method relies upon a statistical probability algorithm 
which is calculated using all patients treated at the same dose level.  Upon completion of a 
group (ie, all patients in that cohort are evaluable for DLT), a decision to escalate, 
de-escalate, or stay (ie, enroll an additional group at the current dose level) will be made. 
Many alternative designs have been proposed to the standard 3+3 design for Phase 1 dose 
escalation studies that improve its accuracy, efficiency and statistical validity. 
The modified toxicity probability interval (mTPI) design uses a Bayesian statistics 
framework and a beta/binomial hierarchical model to compute the posterior probability of 
three dosing intervals that reflect the relative difference between the toxicity rate of each 
dose level to the target rate (pT = 0.28).  If the toxicity rate of the currently used dose level is 
far smaller than pT, the mTPI will recommend escalating the dose level; if it is close to target 
probability (pT), the mTPI will recommend continuing at the current dose; if it is far greater 
than pT, the mTPI will recommend de-escalating the dose level.  These rules are 
conceptually similar to those used by the 3+3 design, except the decisions of an mTPI design 
are based on posterior probabilities calculated under a coherent probability model. 
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different studies with different toxicity parameters.  More 
importantly, all the dose-escalation decisions for a given study can be pre-calculated under 
the mTPI design and presented in a two-way table below.  Thus, compared to other advanced 
model-based designs published in the literature, the mTPI design is logistically less 
complicated and easier to implement.  Recently, a Phase 1 study based on the mTPI design 
has been published.21
Table 14.
Number of Patients with DLT for Dose Escalation Decisions at a Dose Level
Total Number of DLT Evaluable Patients
2
3
4
5
6
7
8
9
10
Escalate
0
0
0
0
0-1
0-1
0-1
0-2
0-2
Stay
1
1
1
1-2
2
2
2
3
De-Escalate & revisit 
allowed
2
2
3
3-4
3-4
4-5
De-Escalate & revisit not 
allowed 
2
3
3-4
3-4
3-5
4-5
5
5
6


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Decision rules are based on calculating unit probability mass (UPM) of three dosing intervals 
corresponding to under, proper, and overdosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0; pT-e1), the overdosing interval (pT+e2), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of palbociclib as a single-agent in Study A5481001, e1 is selected as 0.03, and 
e2 is selected as 0.045.  Therefore, the target interval for the DLT rate is (0.25, 0.325).
The three dosing intervals are associated with three different dose-escalation decisions.  The 
underdosing interval corresponds to a dose escalation (E), overdosing corresponds to a dose 
de-escalation (D), and proper-dosing corresponds to remaining at the current dose (R).  
Given a dosing interval and a probability distribution, the unit probability mass (UPM) of 
that dosing interval is defined as the probability of a patient belonging to that dosing interval 
divided by the length of the dosing interval. The mTPI design calculates the UPMs for the 
three dosing intervals, and the one with the largest UPM informs the corresponding 
dose-finding decision, which is the dose level to be used for future patients.  For example, if 
the underdosing interval has the largest UPM, the decision will be to escalate, and the next 
cohort of patients will be treated at the next higher dose level.  Ji et al. (2010)20 have 
demonstrated that the decision based on UPM is optimal in that it minimizes a posterior 
expected loss (ie, minimizes the chance of making a wrong dosing decision). 
The dose-finding portion of the study is terminated when either approximately 30 DLT 
evaluable patients have been enrolled or when at least 9 evaluable patients have been treated 
at the highest dose with DLT rate <33%, whichever comes first.
9.2.2. Statistical Method for Estimating the Maximum Tolerated Dose
As previously described, the estimated MTD is the highest tested dose level with DLT rate 
<0.33 in at least 9 DLT evaluable patients.  It is assumed that higher doses of either 
palbociclib or nab-P result in higher toxicity rates.  But, due to the relatively low number of 
patients that may be potentially allocated to any dose combination, this assumption may be 
violated.
For example, at the end of the study, the dose combination palbociclib 100 mg and nab-P
125 mg/m2 may have a higher proportion of observed toxicities than, say, palbociclib 
125 mg, nab-P 125 mg/m2, and this variability may be simply related to small cohort size 
alone.  To overcome this potential problem, a bivariate isotonic regression is used to smooth 
the resulting toxicity surface to a monotonically increasing one.  The determination of the 
MTD contour is accomplished using the Dykstra-Roberston algorithm.22  Once a 
monotonically increasing toxicity surface is obtained (either observed or smoothed according 
to the bivariate isotonic regression algorithm), the MTD combinations closest to the targeted 
DLT rate of 0.28 but still <0.33 are calculated.  Clinical judgment will be exercised in taking 
forward combinations to the expansion cohorts in case no clear choice exists between more 
than 1 competing MTD combination.  While the limited sample size may result in up to 
2 dose combinations of equal potential anti-tumor activity, under the circumstances of this 
study, it is possible that 2 MTD expansion cohorts will be explored.  This decision will be 
based upon the combination of data related to safety, PK, PD, anti-tumor activity, and 
clinical judgment of the investigators and the sponsor.


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9.3. Sample Size Determination
Due to the dynamic nature of the Bayesian allocation procedure, the sample size of the 
Up-and-Down matrix design using the mTPI approach cannot be determined in advance.  It 
is estimated that approximately 30 DLT evaluable patients will be enrolled in the dose 
escalation stage in order to have a reliable and accurate estimate of the MTD(s).  The 
expansion cohorts will enroll up to approximately 20 response evaluable patients at the 
estimated MTD(s).
Based on probability theory, a sample size of approximately 20 patients per expansion cohort 
at the MTD(s) will ensure the estimates of any binary variable (eg, ORR) have a 
95% confidence interval of width 0.45.  A sample size of approximately 60 patients (at any 
dose) also enables detection of any unexpected toxicity that occurs at 5% rate (in a 
non-dose-dependent fashion) with a probability of 0.95, and that occurs at 10% rate with a 
probability of 0.998.
9.4. Efficacy Analysis
In this study, anti-tumor activity is a secondary objective in the dose-finding component and 
in the expansion component.  The analyses of endpoints dependent on disease assessments 
will be based on results of the investigator assessment of disease response and progression.
9.4.1. Analysis of Efficacy Endpoint (Expansion Cohorts)
PFS, duration of response (DR), and OS will be summarized using the Kaplan-Meier method 
and displayed graphically.  The median event time and 2-sided 95% confidence interval for 
the median will be provided for each endpoint.  ORR will be reported along with its 2- sided 
95% confidence interval.  OS will also be summarized based on all treated patients.
Six-month progression-free survival rate (6m-PFSR) will be summarized as a product limit 
estimator based on the Kaplan-Meier method to account for censored events, together with 
the corresponding 2-sided 95% confidence interval (CI).  The 2-sided 95% CI for the 
log[-log(6-month PFS probability)] will be calculated using normal approximation and then 
back transformed to give the CI for the 6m-PFSR itself.  Analysis results will be included in 
the table for the PFS analysis.
9.5. Analysis of Other Endpoints
9.5.1. Analysis of Pharmacokinetics
9.5.1.1. Palbociclib
PK samples for palbociclib determination will be collected on Day 13 of Cycle 1 when 
palbociclib is given in combination with nab-P for all patients at all dose levels studied.  
Plasma pharmacokinetic parameters including maximum plasma concentration at steady state 
(Css,max), time for Css,max (Tss,max), trough plasma concentration at steady state (Css,trough), area 
under the plasma concentration-time curve for dosing interval at steady state (AUCss,τ), and 
apparent clearance (CL/F) for palbociclib will be estimated using non-compartmental 
analysis.  The effect of nab-P on steady-state palbociclib exposure will be evaluated by 
comparing palbociclib PK parameters, including Cmax and AUCobtained on Day 13 of 
Cycle 1 with historical data.


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9.5.1.2. Nab-Paclitaxel
PK samples for total paclitaxel determination will be collected on Days -2 to 1 when nab-P is 
given alone and on Days 13-15 when nab-P is given in combination with multiple doses of 
palbociclib.  Plasma PK parameters including maximum plasma concentration (Cmax), time 
for Cmax (Tmax), area under the plasma concentration-time curve from time 0 to last 
quantifiable concentration (AUClast), area under the plasma concentration-time curve from 
time 0 extrapolated to infinite time (AUCinf), terminal plasma elimination half-life (t1/2), 
clearance (CL), and volume of distribution (Vz) will be estimated using non-compartmental 
analysis if data permit.  The effect of palbociclib on total paclitaxel PK will be evaluated by 
determining the ratios of adjusted geometric means (nab-P in combination with 
palbociclib/nab-P alone) and 90% CIs for the ratios (AUCinf and Cmax). 
9.5.1.3. Statistical Analysis of Pharmacokinetic endpoints
For both palbociclib and nab-P concentrations, concentrations will be summarized 
descriptively (n, mean, SD, coefficient of variation (CV), median, minimum, maximum, 
geometric mean and its associated CV) by dose/cohort, cycle, day, and nominal time.  
Individual patient and median profiles of the concentration-time data will be plotted by 
dose/cohort, cycle, and day (using nominal times.  Median profiles will be presented on both 
linear-linear and log-linear scales.
For both palbociclib and total paclitaxel, PK parameters will be summarized descriptively by 
treatment day.  For total paclitaxel, statistical summary of treatment comparison (nab-P given 
in combination with palbociclib vs. nab-P given alone) will also be provided. 
For both palbociclib and total paclitaxel, dose normalized AUCτ (AUCinf for total paclitaxel), 
and Cmax will be plotted against dose (using a logarithmic scale) by day.  These plots will 
include individual patient values and the geometric means for each dose.  These plots will be 
used to help understand the relationship between the PK parameters and dose.
9.5.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
Modeling
Pharmacokinetic (PK) and pharmacodynamic (PD) data from this study may be analyzed 
using modeling approaches and may also be pooled with data from other studies to 
investigate any association between palbociclib exposure and biomarkers or significant safety 
endpoints.  The results of these analyses, if performed, may be reported separately.
 
 
CCI


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9.5.3. Biomarkers
9.5.3.1. Analysis of Biomarker Endpoints
Biomarkers will be assessed separately for serum, plasma, archival tumor tissue, de novo 
tumor biopsies and 
.  In each case, summaries of baseline levels, changes from 
baseline (where appropriate), expression and mutation will be reported.  For continuous 
variables, summary statistics may include the mean, ratio to baseline, standard deviation, 
25th median, and 75th quartile, % CV, and minimum/maximum levels of biomarker measures; 
for categorical variables, summary may include number and percentage, odds ratio as 
appropriate. 
For p16 and Rb1 expression, sensitivity analysis may be performed.
Data from biomarker assays will be analyzed using graphical methods and descriptive 
statistics such as linear regression, t test, and analysis of variance (ANOVA).  The statistical 
approach may examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy.
 
 
 
 
 
 
 
 
 
9.6. Safety Analysis
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set.
CCI
CCI
CCI
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9.6.1. Analysis of the Primary Endpoint
Dose Limiting Toxicity (DLT) is the primary endpoint of the dose escalation component of 
the study.  The occurrence of DLTs observed in the dosing cohorts is used to estimate the 
MTD(s) as described in the Study Design section.  Adverse Events constituting DLTs will be 
listed per dose level.
9.6.2. Analysis of Secondary Safety Endpoints
Adverse Events
Adverse Events (AEs) will graded by the investigator according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on Treatment Emergent Adverse Events, those with initial onset or increasing in severity 
after the first dose of investigational product.  The number and percentage of patients who 
experienced any AE, serious AE (SAE), treatment related AE, and treatment related SAE 
will be summarized according to worst toxicity grades.  The summaries will present AEs 
both on the entire study period and by cycle (Cycle 1 and cycles beyond 1). 
Laboratory Test Abnormalities
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each lab assay.  The analyses will 
summarize laboratory tests both on the entire study period and by cycle (Cycle 1 and cycles 
beyond 1).  Shift tables will be provided to examine the distribution of laboratory toxicities.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal or not done. 
9.6.3. Electrocardiogram
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data.  Baseline is defined as Cycle 1 Day -2.
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, 
QTcF (and other correction factors, eg, QTcB as appropriate), and dose.  Individual QT (all 
evaluated corrections) intervals will be listed by time and dose.  The most appropriate 
correction factor will be selected and used for the following analyses of central tendency and 
outliers and used for the study conclusions.  Descriptive statistics (n, mean, median, standard 


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deviation, minimum, and maximum) will be used to summarize the absolute corrected QT 
interval and changes from baseline in corrected QT after treatment by dose and time point.  
For each patient and by treatment, the maximum change from baseline will be calculated as 
well as the maximum post-baseline interval across time points.  Categorical analysis will be 
conducted for the maximum change from baseline in corrected QT and the maximum 
post-baseline QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction method will be used) using maximum CTCAE Grade.  Shift tables will also be 
provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: (n, %)).  
Patients experiencing clinically-relevant morphological ECG changes will be summarized 
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
9.7. Data Safety Monitoring Committee 
An external Data Safety Monitoring Committee will not be established for the study.  For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases.  Procedures include:

Surveillance for serious adverse events (SAEs) according to regulatory guidelines;

Discussions between the investigators and the sponsor of AEs and laboratory tests 
alterations seen at each dose level in an ongoing manner at regular teleconferences 
and/or meetings to determine the safety profile and risk/benefit ratio and decide if 
further enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.


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The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 


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be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
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When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients. Note that 
the use of initials should be avoided in compliance with Pfizer CT08-GSOP.  The study site 
will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  Radiologic 
assessments performed as standard of care prior to informed consent is obtained may be used 
for the study provided they were performed within the protocol guidelines.  The investigator 
will retain the original of each patient's signed consent document.
12.4. Patient Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA)) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as last patient last visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
palbociclib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within one week of notification.  As directed by Pfizer, 
all study materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.


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Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicentre study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.


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For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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16. REFERENCES
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Thota R, Pauff JM, Berlin JD. Treatment of metastatic pancreatic adenocarcinoma: a 
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Hosein PJ, Lopes Jr Gd, Gomes CM, Pastorini VH, Macintyre J, et al. A phase II trial of 
nab-paclitaxel (NP) in patients with advanced pancreatic cancer (PC) who have 
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Jemal A, Siegel R, Ward E, Hao Y, et al. Cancer Statistics, 2008. CA Cancer J Clin. 
2008; 58: 71-96.
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De Vita VT et al. (2011) DeVita, Hellman, and Rosenberg's Cancer: Principles and 
Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins.
6.
Cancer facts and figures 2013. Atlanta: American Cancer Society, 2013.
7.
Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality 
predictions for the year 2013. Ann Oncol 2013;24:792-800.
8.
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, et al. FOLFIRINOX versus 
gemcitabine for metastatic pancreatic cancer. New Engl J Med. 2011; 364:1817-25.  
9.
Von Hoff DD, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. New Engl J Med. 2013; 369:1691-1703.
10.
Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, et al. Improvements in 
survival and clinical benefit with gemcitabine as first-line therapy for patients with 
advanced pancreatic cancer: a randomized trial. J Clin Onc.1997; 15:2403-2413.
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Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with 
gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the 
National Cancer Institute of Canada Clinical Trials Group.  J Clin Oncol 2007; 
25:1960-6.
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Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle 
albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in 
women with breast cancer. J Clin Oncol 2005;23(31):7794-803.
13.
Fry D, Harvey PJ, Keller PR, Elliott WL, Meade MA, Trachet E, Albassam M, Zheng 
XX, Leopold WR, Pryer NK, Toogood PL. Specific Inhibition of cyclin-dependent 
kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. 
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14.
Schwartz GK, LoRusso PM, Dickson MA, Randolph SS, Shiak MN, et al. Phase I study
of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles 
(Schedule 2/1). Brit J Cancer 2011;104:1862-68.
15.
Flaherty KT, LoRusso PM, DeMichele A, Abramson VG, Courtney R, et al. Phase I, 
Dose-Escalation Trial of the Oral Cyclin-Dependent Kinase 4/6 Inhibitor PD 0332991, 
Administered Using a 21-Day Schedule in Patients with Advanced Cancer. Clin Cancer 
Res 2012;18(2):568-76.
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Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The 
cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus 
letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, 
advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet 
Oncol. 2015 Jan;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3.
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Waddell G, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whoe 
genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 
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18.
Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P,  et al. A Synthetic Lethal 
Interaction between K-Ras Oncogenes and Cdk4 Unveils a Therapeutic Strategy for 
Non-small Cell Lung Carcinoma. Cancer Cell, 2010; 18(1):63-73.
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Schutte M, Hruban RH, Geradts J, Maynard R, Werner H, et al.  Abrogation of the 
Rb/p16 Tumor-suppressive Pathway in Virtually All Pancreatic Carcinomas.  Cancer 
Research 1997; 57:3126-3130.
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Ji Y, Liu P, Li Y, and Bekele BN. A modified toxicity probability interval method for 
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Fanale M , Fayad L , Pro B et al. Phase I study of bortezomib plus ICE(BICE) for the 
treatment of relapsed/refractory Hodgkin lymphoma. Br. J. Hematol. 2011; 154, 271–
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Dykstra R, Robertson T. An algorithm for isotonic regression for two or more variables. 
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17. APPENDICES
Appendix 1. Abbreviations
Abbreviation
Term
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice daily
BP
blood pressure
BUN
blood urea nitrogen
C
Cycle
C
Concentration
C
degrees Celsius
CHF
congestive heart failure
CI
confidence interval
CL
Clearance
CLIA
Clinical Laboratory Improvement Amendments
CNS
central nervous system
CR
complete response
CRF
case report form
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
D
day
DAI
dosage and administration instructions
DCT
data collection tool
DDI
drug-drug interaction
DEHP
di-ethylhexylphthalate
DL
dose level
DLT
dose limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DR
Duration of Response
EC
ethics committee
ECG
electrocardiogram


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Abbreviation
Term
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
eg
for example
ESoE
Early Signs of Efficacy
etc
‘and other things’ or ‘and so forth’
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United 
States)
FFPE
formalin-fixed paraffin-embedded 
FSH
follicle-stimulating hormone
g
gravity
GCP
Good Clinical Practice
GEM
gemcitabine
G-CSF
granulocyte-colony stimulation factor
HBV
hepatitis B virus
HCV
hepatitis C virus
HDPE
high-density polyethylene
HER2
Human epidermal growth factor receptor 2
Hgb
hemoglobin
HIV
human immunodeficiency virus
HR
hazard ratio
IB
investigator’s brochure
IC50
concentration of an inhibitor where the response (or binding) 
is reduced by half
ICH
International Conference on Harmonisation
ID
identification
ie
that is
IHC
immunohistochemistry
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IP
investigational product
IV
intravenous
K2EDTA
dipotassium ethylene diamine tetraacetic acid
KPS
Karnofsky performance status
KRAS
Kirsten rat sarcoma viral oncogene homolog
LFT
liver function test
mTPI
modified toxicity probability interval
MAPK
Mitogen-activated protein kinase
CCI


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Abbreviation
Term
MD
multiple dose
MDR
Modified Dose Regimen
MedDRA
Medical Dictionary for Regulatory Activities
MFD
maximum feasible dose
MID
minimally important difference
mPDAC
Metastatic Pancreatic Ductal Adenocarcinoma
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
N/A
not applicable
Nab-P
nanoparticle albumin-bound Paclitaxel
NCI 
National Cancer Institute 
NS
not significant
ORR
overall response rate
OS
overall survival
pT
target probability
PCD
primary completion date
PD
pharmacodynamics
PD
progressive disease
PDAC
Pancreatic ductal adenocarcinoma
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PPI
Proton-pump inhibitor
PR
partial response
p-Rb1
Phosphorylated retinoblastoma protein
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
PVC
plasticized polyvinyl chloride
QD
every day
QT
time between the start of the Q wave and the end of the 
T wave
R
ratio
RECIST
Response Evaluation Criteria in Solid Tumors
RFS
Relapse-Free Survival
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SIB
suicidal ideation and behavior
CCI
CCI
CCI


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Abbreviation
Term
SOA
Schedule of Activities
SPC
Summary of Product Characteristics
SRSD
single reference safety document
T
Time
T1/2
terminal elimination half-life
TBR
tumor background ratio
TTD
time to deterioration
ULN
upper limit of normal
UPM
unit probability mass
US
United States
USPI
United States Package Insert
V
volume of distribution
Vz/F
WBC
white blood cell 


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Appendix 2. Karnofsky Performance Status


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f 
CCI


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CCI


Palbociclib
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CCI


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Appendix 5. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247 
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions
Lesions that can be accurately measured in at least one dimension.
a.
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).
b. Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
c.
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
d. Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, leptomeningeal disease, lymphangitic involvement of 
skin or lung, clinical lesions that cannot be accurately measured with calipers, abdominal 
masses identified by physical exam that are not measurable by reproducible imaging 
techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.


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Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.

Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 


Palbociclib
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Final Protocol Amendment 3, 23 August 2018
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single item on the case report form (eg, multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 
Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed. 

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate.  Progression has not been documented, and 

one or more target measurable lesions have not been assessed; 

or assessment methods used were inconsistent with those used at baseline;

or one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);

or one or more target lesions were excised or irradiated and have not reappeared 
or increased. 
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).


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
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 


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Table 1. Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing 
No
PR
PR
Non-CR/Non-PD, Indeterminate, 
or Missing
No
PR
SD
Non-CR/Non-PD, Indeterminate, 
or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target 
Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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Appendix 6. Schedule of Activities for Patients on Investigational Product(s) Beyond 
2 Years (Not Applicable after implementation of Protocol Amendment 3)


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Appendix 7. Dose Re-Escalation and De-Escalation Schemas for a Previous Dose Level 
(3 patients per group)
Figure A. Dose de-escalation schema to a previous dose level where 3 patients have been 
treated with 0 DLT
Figure B. Dose de-escalation schema to a previous dose level where 6 patients have been 
treated with 1 DLT
De-escalate to 
6 patients 
with ≤1 DLT
9 patients
(3 groups)
≥3 DLTs
≤2 DLTs
Re-Escalate 
to the next 
dose level
De-escalate to 
the previous 
dose level


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Figure C. Dose re-escalation schema from a previous dose level where 3 patients have 
been treated with 2 DLTs
Escalate from 
3 patients 
with 2 DLTs
6 patients
(2 groups)
2 DLTs
≥3 DLTs
9 patients
(3 groups)
≥3 DLTs
2 DLTs
Re-Escalate 
to the next 
dose level
De-escalate to 
the previous 
dose level
Figure D. Dose re-escalation schema from a previous dose level where 6 patients have 
been treated with 3 DLTs


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Appendix 8. Bone Marrow Reserve in Adults 
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol.  5, 255-258, 1961
Marrow Distribution of the Adult
SITE
MARROW
wt. (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head :
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle :
86.7
HUMERI,
SCAPULAE,
2 Humerus, 
head & neck
26.5
0.75
20.0
8.3
8.3
CLAVICLES
2 Scapulae 
67.4
0.75
50.5
2 Clavicles
21.6
0.75
16.2
Sternum
39.0
0.6
23.4
2.3
Ribs : 
82.6
1 pair
10.2
All 0.4
4.1
2 
12.6
5.0
3
16.0
6.4
STERNUM
4
18.6
7.4
AND
5
23.8
9.5
7.9
10.2
RIBS
6
23.6
9.4
7
25.0
10.0
8
24.0
9.6
9
21.2
8.5
10
16.0
6.4
11
11.2
4.5
12
4.6
1.8


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SITE
MARROW
wt. (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head :
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle :
86.7
Sacrum 
194.0
0.75
145.6
13.9
PELVIC 
BONES
2 os coxae
310.6
0.75
233.0
22.3
36.2
FEMUR
2 Femoral head 
and neck
53.0
0.75
40.0
3.8


Palbociclib
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Marrow Distribution of the Adult (cont’d)
SITE
MARROW
wt. (g)
FRACTION RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Cervical):
35.8
1
6.6
All 0.75
5.0
2
8.4
6.3
3
5.4
4.1
3.4
4
5.7
4.3
5
5.8
4.4
6
7.0
5.3
7
8.5
6.4
Vertebrae
(Thoracic):
147.9
1 pair
10.8
All 0.75
8.1
2
11.7
8.8
3
11.4
8.5
4
12.2
9.1
VERTEBRAE
5
13.4
10.1
14.1
28.4
6
15.3
11.5
7
16.1
12.1
8
18.5
13.9
9
19.7
14.8
10
21.2
15.9
11
21.7
16.3
12
25.0
18.8


Palbociclib
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SITE
MARROW
wt. (g)
FRACTION RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Lumbar) :
114.1
1 pair
27.8
All 0.75
20.8
2
29.1
21.8
10.9
3
31.8
23.8
4
32.1
24.1
5
31.4
23.6
TOTAL
1497.7
1045.7
100.0
100.0


Palbociclib
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Final Protocol Amendment 3, 23 August 2018
Page 128
Appendix 9. List of Drugs Known to Predispose to Torsade de Pointes
Generic Name
Brand Name(s)
Amiodarone
Cordarone, Pacerone
Arsenic trioxide
Trisenox
Astemizole
Hismanal
Azithromycin
Zithromax
Bepridil
Vascor
Chloroquine
Aralen
Chlorpromazine
Thorazine
Cisapride
Propulsid
Citalopram
Celexa
Clarithromycin
Biaxin
Disopyramide
Norpace
Dofetilide
Tikosyn
Domperidone
Motilium
Droperidol
Inapsine
Erythromycin
Erythrocin, E.E.S. 
Flecainide
Tambocor
Halofantrine
Halfan
Haloperidol
Haldol
Ibutilide
Corvert
Levomethadyl
Orlaam
Mesoridazine
Serentil
Methadone
Dolophine, Methadose
Moxifloxacin
Avelox
Ondansetron*
Zofran
Pentamidine
Pentam, NebuPent
Pimozide
Orap
Probucol
Lorelco
Procainamide
Pronestyl, Procan
Quinidine
Cardioquin, Quinaglute
Sotalol
Betapace
Sparfloxacin
Zagam
Terfenadine
Seldane
Thioridazine
Mellaril
Vandetanib
Caprelsa
*when administered intravenously at high dose (32 mg).
Adapted from the University of Arizona Cancer Center for Education and Research on Therapeutics: "Torsades 
List: Drugs with a Risk of Torsades de Pointes," drugs that are generally accepted by the QTdrugs.org Advisory 
Board to carry a risk of Torsades de Pointes on the University of Arizona CERT website: 
http://www.crediblemeds.org/.  This list is not meant to be considered all inclusive.  See website for current list.

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Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 2 
Document History 
Document Version 
Date 
Summary of Changes 
Original SAP 
July 29, 2015 
Not applicable (N/A) 
Version 2 
Nov 27, 2017 
Incorporate the changes from protocol Amendment 
1 and Amendment 2. 
Major changes include: 
1. Addition of modified dose regimen 
cohorts, resulting in an increased sample size of 
the overall study. 
2. A statement was included that will permit 
completion of dose escalation without 
determining the MTD, based on emerging 
safety data and upon agreement between the 
investigators and the sponsor. 
3. Adding BOR detail definition. 
4. Modify RDI detail definition. 
5. Add in subgroup analysis for Ca19a-9. 
6. Add in endpoint - Clinical Benefit Response 
7. Add in RDI calculation rules for MDR1 and 
MDR2.  
8. Provide details for dosing RDI calculation  
9. Clarification of minor discrepancies throughout 
the document. 
10. Modifications on Biomarkers, PRO, PK   
Version 3 
May 8, 2018 
1. Revise Biomarker population 
2. Add analysis on endpoint-CBR 
3. Add analysis on combined treatment group - 
DL3B (MTD cohort) + MTD 
4. Remove QTcS 
 
Version 4 
December 6 
2018 
1. Remove 
MDR 
expansion 
cohort, 
per 
Protocol Amendment 3 
2. Remover 3-tier AE summary 
 
 
 
 
 
 


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1.AMENDMENTS FROM PREVIOUS VERSION(S) 
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2.INTRODUCTION 
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2.1.Study Design 
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2.1.1.Dose Escalation Cohorts  
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Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 7 
Table 2.1 Potential Palbociclib and Nab-Paclitaxel Dose Combinations 
Dose Level 
Palbociclib 
(oral, mg/day) 
Days 1-21 within a 
28-day cycle 
Nab-Paclitaxel 
(IV, mg/m2/day) 
Weekly dose for 3 weeks 
within a 28-day cycle 
-1 
50 
100 
1 (starting dose level) 
75 
100 
1.5 
50 
125 
2A 
100 
100 
2B 
75 
125 
3A 
125 
100 
3B 
100 
125 
4 
125 
125 
 
Alternate dosing schedules for palbociclib may be explored based on emerging PK, PD, and 
safety data. 
The 2x3 matrix approach allows for parallel dose level cohorts consisting of different dose 
combinations. Dose escalations and de-escalations will be called for based upon assessment 
of DLTs and other adverse events during the first treatment cycle (28 days). See Section 
8.1.1. for a detailed description of the mTPI dose-escalation method. 
Figure 2.1 Palbociclib and Nab-Paclitaxel Combination Dose Escalation and De-
Escalation Sequence 
palbociclib 75mg + 
nab-paclitaxel 
100mg/m2
palbociclib 100mg + 
nab-paclitaxel 
100mg/m2
palbociclib 75mg + 
nab-paclitaxel 
125mg/m2
palbociclib 100mg + 
nab-paclitaxel 
125mg/m2
palbociclib 125mg + 
nab-paclitaxel 
125mg/m2
palbociclib 50mg + 
nab-paclitaxel 
100mg/m2
palbociclib 125mg + 
nab-paclitaxel 
100mg/m2
Level 1 (start)
Level -1
Level 2A
Level 2B
Level 3A
Level 3B
Level 4
palbociclib 50mg + 
nab-paclitaxel 
125mg/m2
Level 1.5
 
The sequential dose escalation scheme and the rules for determining dose escalation, de-
escalation, or ‘stay’ (i.e. enroll an additional group of patients to the current DL) at any given 
dose level are described in Appendix 10.2.   


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 8 
2.1.2. Modified Dose Regimen (MDR) Cohort(s) 
 Per Protocol Amendment 1, additional 2 cohorts of patients will be enrolled into alternative 
dose regimens at doses lower than the dose levels tested in dose escalation. The following 
dose regimens will be tested: 
 Modified Dose Regimen 1 (MDR1)-75 mg palbociclib once daily on Days 1-21 of 
each 28-day cycle, plus nab-P 125 mg/m2 biweekly in each 28-day cycle. 
 Modified Dose Regimen 2 (MDR2)-75 mg palbociclib continuous dosing, once daily, 
plus nab-P 100 mg/m2 biweekly in each 28-day cycle. 
 
At least 6-9 patients will be enrolled into each MDR cohort. Patients enrolled into MDR 
cohorts will also be assessed for DLTs. If the number of patients with a DLT falls into the 
mTPI “De-escalateescalate,” category for one or both MDR cohorts, cohort(s) will not 
move forward into expansion. The MDR cohort with a DLT rate <0.33 in at least 9 DLT 
evaluable patientspatients will be considered to move forward into expansion. 
 
2.1.3. Expansion Cohort(s) 
 MTD Expansion Cohort(s) 
When the MTD(s) of palbociclib plus nab-paclitaxel has been estimated with 
confidence, enrollment will proceed into 1 or 2 MTD expansion cohort(s) of up to 20 patients 
each at the MTD(s). Patients will receive the same dosing regimen as in the dose escalation 
cohorts (palbociclib 3/1 schedule and weekly nab-P for 3 weeks in each 28-day cycle). 
 
 
The objective of the expansion cohort(s) are to provide additional information on safety, 
tolerability, biomarkers, PD activity and PK/PD relationship for the combination regimen in 
order to determine the recommended phase 2 dose (RP2D).  The expansion cohort(s) will 
only enroll patients who have not received previous treatment for their metastatic disease in 
order to evaluate preliminary activity of the combination in patients in the target patient 
population.  
 
 
2.1.4. Study Treatments 
All patients will receive nab-paclitaxel and palbociclib.   
2.1.4.1. Nab-Paclitaxel Administration 
To allow for PK evaluation of nab-paclitaxel administered alone, nab-paclitaxel will be 
administered on Day -2 for Cycle 1 only.  Subsequent cycles will administer both nab-
paclitaxel and palbociclib on Day 1.  Alternate dosing schedules for palbociclib may be 
explored based on emerging PK, PD, and safety data. 
Nab-P will be administered in the clinic. Patients will receive nab-P as an intravenous 
infusion over 30 minutes. Nab-P will be administered based on the assigned dose regimen 
(either once weekly for 3 weeks, or biweekly in each 28-day cycle). In Cycle 1, nab-P will 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 9 
start on Day -2 in order to evaluate the pharmacokinetics of nab-P administered alone and in 
combination with palbociclib (Figure 2.2). On Day 13, nab-P and palbociclib should be 
dosed at approximately the same time. For cycle ≥2, both palbociclib and nab-P 
administration will start on Day 1, and palbociclib dosing should occur as close as possible to 
the start of infusion of nab-P. Treatment with IP will continue until disease progression, 
unacceptable toxicity, or consent withdrawal. 
Figure 2.2 Palbociclib and Nab-Paclitaxel Dose Combination Schema  
Dose Escalation and MTD Expansion Cohorts 
 
Modified Dose Regimen 1 (palbociclib 3/1 schedule, biweekly nab-P) 
 
Modified Dose Regimen 2 (continuous palbociclib, biweekly nab-P) 
 
2.1.4.2. Palbociclib Administration 
Palbociclib dosing will be administered orally. The palbociclib dosing schedule is determined 
by cohort assignment, either 3/1 schedule (once a day for 21 consecutive days, followed by 7 
days off treatment) or continuous dosing in each 28-day before starting the next cycle (for 
MDR2 cohort). Each patient will receive enough palbociclib to support their treatment cycle 
duration each month. Patients should be instructed to swallow palbociclib capsules whole 
and not to manipulate or chew them prior to swallowing. No capsule should be ingested if it 
is broken, cracked, or otherwise not intact. Patients should be encouraged to take their dose at 
approximately the same time each day. Patients should be instructed to record daily 
administration of the investigational product in a patient diary provided by the sponsor. 


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3.INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
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4.HYPOTHESES AND DECISION RULES 
4.1.Statistical Hypotheses 
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4.2.Sample Size Determination and Statistical Decision Rules 
4.2.1.Sample Size Determination 
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Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 12 
Based on probability theory, a sample size of approximately 20 patients per expansion cohort 
at the MTD(s) will ensure the estimates of any binary variable have a 95% confidence 
interval of maximum width 0.45. A sample size of approximately 60 patients (at any dose) 
also enables detection of any unexpected toxicity that occurs at 5% rate (in a non-dose-
dependent fashion) with a probability of 0.95, and that occurs at 10% rate with a probability 
of 0.998.   
4.2.2. Statistical Decision Rules 
Dose Escalation Cohorts 
The dose escalation/de-escalation rules will follow the mTPI method (see Section 8.1 for a 
detailed description). Briefly, the mTPI method relies upon a statistical probability algorithm, 
calculated using data from all patients treated at the same dose level (and not simply those in the 
current cohort) to determine whether future cohorts should involve dose escalation, no change in 
dose, or dose de-escalation. 
The MTD determination will be based on the observed toxicity rates among all evaluable 
patients at any given DL.  When dose escalation is stopped, the highest DL with an observed 
DLT rate <33% (in at least 9 DLT-evaluable patients) will be considered the MTD.  It is 
possible that more than one MTD will be determined, in which case a decision will be made 
to expand one or both MTDs in order to determine the RP2D. 
The dose escalation portion of the study is completed when at least 9 evaluable patients have 
been treated at the highest DL associated with a DLT rate <33%. It is estimated that 
approximately 30 ‘DLT-evaluable’ patients will be enrolled to reach n = 9 ‘DLT-evaluable’ 
patients at the estimated MTD. 
Dose escalation may be completed without determining the MTD based on emerging safety 
data, and upon agreement between the investigators and the sponsor. 
Modified Dose Regimen Cohorts 
Patients enrolled into MDR cohorts will also be assessed for DLTs. If the number of patients 
with a DLT falls into the “De-escalate” category in one or both MDR cohorts, the cohort(s) 
will not move forward into expansion. The MDR cohort with a DLT rate <0.33 in at least 9 
DLT evaluable patient will be considered to move forward into expansion. 
 
Expansion Cohorts 
 
MTD Expansion Cohort(s): 
Once the MTD for the combination has been defined in the dose-escalation cohorts, up to 20 
patients who have not received previous treatment for their metastatic disease will be enrolled 
and treated in the MTD expansion cohort. Patients will receive the same dosing regimen as in 
the dose escalation cohorts (palbociclib 3/1 schedule and weekly nab-P for 3 weeks in each 
28-day cycle). 
 


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5.ANALYSIS SETS 
5.1.Safety Analysis Set (Full Analysis Set) 
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5.4.Pharmacokinetic Analysis Sets 
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5.5.Biomarker Analysis Sets 
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Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 14 
5.7. Treatment Misallocations  
Not applicable. 
5.8. Protocol Deviations 
All deviations will be described when they appear and relate to the statistical analyses or 
analysis populations. 
6. ENDPOINTS AND COVARIATES 
6.1. Safety Endpoints 
6.1.1. Primary Endpoint  
First cycle DLTs 
Severity of adverse events will be graded according to NCI CTCAE version 4.03.  For the 
purpose of dose escalation, any adverse events occurring in the first cycle of treatment (Day 
1 until pre-dose Cycle 2 Day 1) which are attributable to palbociclib, nab-paclitaxel, or to the 
combination of palbociclib and nab-paclitaxel will be classified as DLTs.  Adverse events 
that occur between Cycle 1 Day -2 after nab-paclitaxel administration and Cycle 1 Day 1 
(prior to palbociclib dosing) will not be considered a DLT.  The following adverse events 
will be considered a DLT: 
 Hematologic: 
o Grade 4 neutropenia lasting > 4 days; 
o Febrile neutropenia (defined as neutropenia Grade ≥3 [ANC <1000 cells/mm3] 
and a body temperature ≥38.5°C) requiring antibiotic or antifungal treatment; 
o Any Grade 4 thrombocytopenia (<25,000/mm3 or <25.0 x 109/L). 
 Non-hematologic: Grade 3 toxicities, except those that have not been maximally 
treated (e.g., nausea, vomiting, diarrhea).  
 Other:  
o Any adverse event that causes a palbociclib treatment interruption of greater than 
7 consecutive days; or causes any combination of interruption/reduction for ≥14 
days; 
o Any adverse event that causes omission or reduction of at least 2 of the 3 weekly 
doses of nab-P 
 
6.1.2. Secondary Endpoints  
6.1.2.1. Safety  
Safety assessment will consist of monitoring of all AEs, including SAEs, regular monitoring 
of hematology, serum chemistry, and routine monitoring of ECGs, physical examinations, 
vital signs, and ECOG performance status.  
Overall safety profile as characterized by type, frequency, severity of adverse events as 
graded by NCI Common Toxicity Criteria for Adverse Events version 4 (NCI CTCAE 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 15 
v.4.03), timing, seriousness,  and relationship to study therapy, and laboratory abnormalities 
observed.  
Baseline signs and symptoms will be recorded at baseline and then reported as adverse events 
during the trial if they worsen in severity or increase in frequency. 
Adverse events (AEs), hematology, blood chemistry will be assessed as described in the 
Schedule of Activities of the protocol. 
Adverse events will be classified using the MedDRA classification system. The severity of 
the toxicities will be graded according to the NCI CTCAE version 4.03. For labs without 
CTCAE grade definitions, results are summarized as normal, abnormal (per Pfizer Data 
Standards (PDS)) or not done. For other AEs without specific CTCAE definitions, results are 
identified according to CTCAE “other” categories.  
Adverse events leading to death or discontinuation of trial treatment, events classified as NCI 
CTCAE v.4.03 Grade 3 or higher, trial drug related events, and serious adverse events will be 
considered with special attention. 
The hematologic and chemistry laboratory results will be graded according to the NCI 
CTCAE v.4.03 severity grade. For parameters for which an NCI CTCAE v.4.03 scale does 
not exist, the frequency of patients with values below, within, and above the normal range for 
the local lab will be summarized. 
Patients who start treatment are assessed for toxicities up to 28 days after the final dose of 
treatment or start of new treatment (whichever comes first). Toxicities observed beyond 28 
days and recorded in the database per Sponsor's agreement will be included in the 
summaries. 
6.1.2.1.1. Treatment Emergent Adverse Event 
An adverse event is considered treatment emergent if: 
 The event occurs for the first time after the start of study treatment and before 28 days 
after final dose of study treatment and was not seen prior to the start of treatment or 
 The event was seen prior to the start of treatment but increased in NCI CTCAE v.4.0 
grade during study treatment. 
 Disease progression is not considered a treatment emergent adverse event unless the 
patient dies of disease prior to 28 days after discontinuation of treatment. 
6.1.2.1.2. Treatment Related Adverse Event 
Adverse events defined as treatment emergent adverse events with cause possibly, probably 
or definitely related to treatment as judged by the investigator are defined as treatment related 
adverse events. Events that are continuation of baseline abnormalities are not considered 
treatment related unless there is an increase in grade, or if there is an increase following a 
decrease, and the increase is judged by the investigator to be caused by the treatment. 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 16 
6.1.2.2. Laboratory Safety  
Laboratory assessment will be assigned to cycles based on the collection date of the sample 
relative to the start dates of cycles from the study drug administration as described in the 
Schedule of Activities table in Appendix 10.1. 
Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI 
CTCAE version 4.03), and timing; 
Baseline evaluations for laboratory are those collected 
 Within 28 days prior to or on first day of study drug and 
 If there is more than one baseline evaluation, closest to but any time prior to the 1st 
dosing on the first day of study treatment. 
 
Haematology, blood chemistry, coagulation, and urinalysis will be drawn at the time points 
described in the Schedule of Activities and analyzed at local laboratories. 
Additional blood tests should be performed where needed for the purpose of evaluating 
potential DLTs or other adverse events. In particular, if a patient has Grade 3 neutropenia, 
complete blood count (CBC) should be performed every 24-48 hours. 
Urinalysis will be conducted via urine dipstick for urine protein: if the result is positive, a 24-
hour collection and microscopic reflex testing will be conducted. 
Special blood sample for CA19-9 will also be collected. 
Blood tests will include the following: 
Table 6.1 Laboratory Tests 
Hematology 
Chemistry 
Coagulation 
Urinalysis 
Pregnancy Test 
Hemoglobin 
ALT 
PT or INR 
Urine dipstick for 
urine protein: If 
positive, further 
diagnostic testing 
will be performed as 
clinically indicated 
For female patients 
of childbearing 
potential,  serum or 
urine  
Platelets 
AST 
PTT 
WBC 
Alk Phosphatase 
aPTT 
Absolute Neutrophils 
Sodium 
 
Absolute Lymphocytes 
Potassium 
 
Absolute Monocytes 
Magnesium 
 
Urine dipstick for 
urine blood: If 
positive collect a 
microscopic (Reflex 
Testing) 
 
Absolute Eosinophils 
Chloride 
 
 
Absolute Basophils 
Total Calcium 
 
 
 
Total Bilirubin* 
 
 
 
BUN or Urea 
 
 
 
Creatinine 
 
 
 
Uric Acid 
 
 
 
Glucose (non-fasted) 
 
 
 
Albumin 
 
 
 
 
Phosphorous or 
Phosphate 
 
 
 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 17 
 
Amylase (if 
available) 
 
 
 
 
Lipase (if available) 
 
 
 
*For potential Hy’s Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/INR, and alkaline phosphastase.  In addition, acetaminophen levels should be considered. 
 
6.1.2.3. Vital Signs 
Patients will have a physical exam to include, weight, vital signs (pulse rate and blood 
pressure), assessment of Karnofsky (see Appendix 10.8) performance status, and height; 
height will be measured at screening only.  
6.1.2.4. Electrocardiogram (ECG) 
All ECGs will be performed using a 12-lead (with a 10-second rhythm strip) tracing.  ECG 
measurements will include PR interval, QT interval, RR interval, and QRS complex.  It is 
preferable that the machine used has a capacity to calculate the standard intervals 
automatically.  
ECG interval readings by the ECG recorder’s algorithm will be read and interpreted at the 
investigational site for eligibility determination and patient safety monitoring and 
documentation stored in the source documents.  
Triplicate ECGs will be performed for all patients.  
 All ECGs should be obtained after a fast of at least 1 hour.  When scheduled at the 
same nominal time/visit, triplicate ECGs should be collected prior to any blood draws 
for PK, biomarkers, or safety labs and prior to placement of the IV line for nab-
paclitaxel administration. 
 Triplicate ECGs will be obtained for safety monitoring at Screening, and 0 hour 
(pre-dose) on C1D-2, C1D13, C2D1 and C2D15, then on Day 1 of Cycles 4 and 7.  
ECGs will be obtained at the time of End of Treatment or Withdrawal.  ECGs beyond 
Cycle 7 will be performed as clinically indicated. 
 Additional ECGs may be performed as clinically indicated at any time. 
For the purpose of the study, triplicate ECGs are defined as three consecutive ECGs 
performed approximately 2 minutes apart but within 10 minutes for all 3 ECGs at the 
protocol specified timepoints (see Schedule of Activities Section 10.1. for details) to 
determine the mean QTc interval.   
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event.  
When matched with PK sampling, ECG must be carried out before PK sample drawing such 
that the PK samples are collected at the nominal time (i.e. the timing of the PK collections 
overrides the timing of the ECG collections. 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 18 
6.1.2.5. Other Safety Assessments 
A full physical examination including an examination of all major body systems (including 
general appearance, head, ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, 
abdomen, and musculoskeletal), height (at Screening only), weight, blood pressure and pulse 
rate which may be performed by a physician, registered nurse or other qualified health care 
provider, will be required at screening, and Cycle 1 Day -2 and Cycle 2 Day 1.  
Symptom directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits according to the Schedule of Activities. 
6.1.2.6. Efficacy 
Objective Response (OR) is defined as the overall complete response (CR) or partial 
response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 
version 1.1; Appendix 10.4).  Objective Response Rate (ORR) is defined as the proportion 
of patients with a best overall response (BOR based on confirmed responses as described in 
Appendix 10.4) of CR or PR relative to all anti-tumor evaluable patients. Patients who do not 
have on-study radiographic tumor re-evaluation, who receive anti-tumor treatment other than 
the study medication prior to reaching a CR or PR, or who die, progress, or drop out for any 
reason prior to reaching a CR or PR will be counted as non-responders in the assessment of 
ORR. Clinical Benefit Response (CBR) is defined as a patient with a BOR of CR or PR at 
any time, or non-CR/non-PD or SD for at least 16 weeks from start date. 
Tumor response will be determined from tumor assessment data (as described in Appendix 
10.4).   
Duration of Response (DR) is defined as the time from the first documentation of objective 
tumor response (CR or PR) to the first documentation of disease progression or to death due 
to any cause, whichever occurs first.  If tumor progression data include more than 1 date, the 
first date will be used.  DR will be calculated as [the date response ended (i.e. date of PD or 
death) – first CR or PR date + 1)]/30.4.  DR will only be calculated for the subgroup of 
patients with an objective tumor response. 
Patients last known to be 1) alive and 2) progression-free, are censored at the date of the last 
objective disease assessment that verified lack of disease progression. In addition, 
 If a new anti-cancer treatment is started prior to progression and prior to 28 days after 
discontinuation of treatment, then censorship is at the date of the last objective 
disease assessment that verified lack of disease progression prior to the new 
treatment.  
 If patients are removed from the study (withdrew the consent, lost to follow up, etc.) 
prior to progression and death, then censorship is at the date of the last objective 
disease assessment that verified lack of disease progression. 
 Patients with documentation of progression or death after an unacceptably long 
interval (>2 consecutive assessments) since the last tumor assessment will be 
censored at the time of last objective assessment documenting no progression. 
 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 19 
 
Progression Free Survival (PFS) is defined as the time from the date of first dose to the 
date of the first documentation of objective tumor progression as per RECIST v.1.1 or death 
due to any cause in the absence of documented PD, whichever occurs first.  If tumor 
progression data include more than 1 date, the first date will be used.  PFS (in months) will 
be calculated as (first event date – first dose date +1)/30.4.  
Tumor assessments will be performed every 8 weeks (± 7 days) (12 weeks (± 7 days) for 
Cycles ≥ 6) from first dose until radiographically and/or clinically (for photographed or 
palpable lesions) documented PD as per RECIST v.1.1, initiation of new anticancer therapy, 
or discontinuation of patient from overall study participation (e.g., death, patient's request, 
lost to follow up). 
Imaging assessments are to be scheduled using the first dose date as the reference date for all 
time-points and are NOT to be scheduled based on the date of the previous imaging time-
point. Patients who discontinue study treatment for reasons other than radiographically 
and/or clinically (for photographed or palpable lesions) documented disease progression as 
per RECIST definitions will continue to have tumor assessment performed during the follow-
up visits every 8 weeks (± 7 days) (12 weeks (± 7 days) for Cycles ≥ 6)  until documented 
disease progression, initiation of new anticancer therapy or discontinuation of patient from 
overall study participation (e.g., death, patient's request, lost to follow-up), whichever occurs 
first. Every effort should be made to perform a last tumor assessment before starting a new 
anticancer therapy. Additional unscheduled tumor assessments may be performed as 
clinically indicated at any time. 
Patients last known to be 1) alive and 2) progression-free, are censored at the date of the last 
objective disease assessment that verified lack of disease progression (see Appendix 10.4 for 
determining the date in details). In addition, 
 Patients with no baseline tumor assessment (including patients with an inadequate 
baseline assessment) within 18 weeks after the randomization date will be censored 
on the randomization date, unless the patient dies within 18 weeks of the 
randomization date, in which case, death will be an event on date of death. 
 Patients with no adequate post-baseline tumor assessments within 18 weeks after the 
randomization date will be censored on the randomization date, unless the patient dies 
within 18 weeks of the randomization date, in which case, death will be an event on 
date of death. 
 If a new anti-cancer treatment is started prior to progression and death, then 
censorship is at the date of the last objective disease assessment that verified lack of 
disease progression prior to the new treatment. 
 If patients are removed from the study (withdrew the consent, lost to follow up, etc.) 
prior to progression and death, then censorship is at the date of the last objective 
disease assessment that verified lack of disease progression. 
 Patients with documentation of progression or death after an unacceptably long 
interval (>2 consecutive assessments) since the last tumor assessment will be 
censored at the time of last objective assessment documenting no progression. 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 20 
 
Six-month progression-free survival (6m-PFS) is defined as the PFS status (progression free 
and alive, or not) at 6-months. The 6-month PFS rate is summarized as a product limit estimator 
based on the Kaplan-Meier method to account for censored events.  
 
Overall Survival (OS) is defined as the time from the date of first dose to the date of death 
due to any cause.  OS (in months) is calculated as (date of death – first dose date +1)/30.4.  
For patients lacking survival data beyond the date of their last follow-up, the OS time will be 
censored on the last date they were known to be alive.  Patients lacking survival data beyond 
first dose will have their OS times be censored at first dose.   
Following the End of Treatment visit, survival status will be collected in all patients every 
month (±7 days) from the last dose of study treatment.  Information on subsequent anticancer 
therapy will also be collected. 
The unacceptably long intervals (>2 consecutive assessments) are defined as following: 1) 
PD occurs during Cycle 4 to 7 or death occurs during Cycle 3 to 6, the unacceptable interval 
is greater than 18 weeks. 2) PD occurs at Cycle 8 or death occurs during Cycle 7, the 
unacceptable interval is greater than 22 weeks. 3) PD occurs at/after Cycle 9 or death occurs 
at/after Cycle 8, the unacceptable interval is greater than 26 weeks.      
 
6.1.2.7. Pharmacokinetics  
Pharmacokinetic parameters of palbociclib and nab-paclitaxel:  
o For palbociclib PK when given with nab-paclitaxel: Multiple Dose (MD) (assuming 
steady-state is achieved) - Css,max, Tss,max, AUCss,, Css,trough, and CL/F, as data permit; 
o For total paclitaxel when nab-paclitaxel is given alone and in combination with 
palbociclib: Cmax, Tmax, AUClast, AUC∞, t1/2, CL, and Vz as data permit.   
 
6.1.2.7.1. Palbociclib Pharmacokinetic Assessments 
Plasma PK samples for palbociclib determination will be collected on Day 13 of Cycle 1 at 0 
(pre-dose), 2, 4, 6, 8 and 24 hours post palbociclib dose, and on Cycle 2 Days 1 and 15 (pre-
dose)  as described in Schedule of Activities. Patients must have received at least 7 
consecutive days of palbociclib before PK assessments on Cycle 1 Day 13 and Cycle 2 Day 
15.   
Additional instructions for serial PK sampling on Cycle 1 Day 13 include the following: 
 The palbociclib dose that is taken on C1D12 should be at least 20 hours from the time 
the pre-dose PK sample is drawn on C1D13. Patients should record the time of their 
C1D12 palbociclib dose in the patient diary. 
 Patients must not take their palbociclib dose on C1D13 until after the pre-dose PK 
sample is drawn.  Patients must be instructed to bring their palbociclib dose with 
them to the clinic. 


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Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 27 
6.2.2. Stratification Factors  
Not applicable. 
7. HANDLING OF MISSING VALUES 
7.1. Missing Dates 
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (e.g., date of onset cannot be prior to day one 
date).  In this case, the date resulting in 1 day duration will be used. If the day of the month 
and the month is missing for any date used in a calculation, January 1 will be used to replace 
the missing date. 
Missing dates for adverse events will be imputed based on the similar principle. 
 For the start date, if the day of the month is missing, the 1st day of the month will be 
used to replace the missing date. If both day and month are missing, January 1 of the 
non-missing year will be used to replace the missing date. If the first dose date is later 
than this imputed date, then impute the start date again to the first dose date. 
 For the stop date, if the day of the month is missing, the last day of the month will be 
used to replace the missing date. If both day and month are missing, December 31 of 
the non-missing year will be used to replace the missing date. 
 
If the start date is missing for an AE, the AE is considered to be treatment emergent unless 
the collection date is prior to the treatment start date. 
 
7.2. Missing Tumor Assessments 
If baseline tumor assessment is inadequate the patient cannot be assessed for response. 
Inadequate baseline assessment may include  
 Not all required baseline assessments were done 
 Assessments were done outside the required window  
 Measurements were not provided for one or more target lesions 
 One or more lesions designated as target were not measurable. 
 
If measurements for one or more target lesions are missing for an evaluation and disease does 
not qualify as progression (or symptomatic deterioration if applicable), the objective status 
for that evaluation is Indeterminate. 
If non-target disease was not assessed, then objective status cannot be a CR even if all target 
disease has disappeared.  Otherwise, missing non-target disease assessments do not 
necessarily affect response determination.  Such cases will be reviewed carefully. 


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Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 29 
values reported as BLQ have been replaced with zero” should be included as a footnote to the 
appropriate tables and figures.  
Deviations, missing concentrations and anomalous values 
In summary tables and plots of median profiles, statistics will be calculated. Concentrations will 
be set to missing if one of the following cases is true:  
 A concentration has been reported as ND (i.e., not done) or NS (i.e., no sample),  
 A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the pharmacokineticist.  
 
Note that summary statistics will not be presented at a particular time point if more than 50% of 
the data are missing. For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data.  
Pharmacokinetic parameters 
Actual PK sampling times will be used in the derivation of PK parameters (and where possible 
the actual dosing information). If a PK parameter cannot be derived from a patient’s 
concentration data, the parameter will be coded as NC (i.e., not calculated). (Note that NC values 
will not be generated beyond the day that a patient discontinues).  
In summary tables, statistics will be calculated by setting NC values to missing; and statistics will 
not be presented for a particular treatment if more than 50% of the data are NC. For statistical 
analyses (i.e., analysis of variance), PK parameters coded as NC will also be set to missing.  
If an individual patient has a known biased estimate of a PK parameter (due for example to an 
unexpected event such as vomiting before all the drug is absorbed in the body), this will be 
footnoted in summary tables and will not be included in the calculation of summary statistics or 
statistical analyses.  
7.7. Missing/Duplicate Biomarker Data 
No values will be imputed for missing data.  If there is duplicate biomarker data for an 
assessment that is not expected (e.g., the same sample was sent twice to the assay laboratory, 
or the laboratory reported two assessments for the same sample), the following will occur.  
Numerical biomarker values will be averaged for reporting purposes and the average will be 
included in the listing of biomarker data along with the original data.  Non-numerical data 
(e.g., mutations present) will be reviewed by the clinical subteam to determine which data 
will be included in the analyses, if any; that record will have a flag added to show it was used 
for analysis purposes. 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 30 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
8.1.1. mTPI Method - Dose Escalation/De-Escalation 
The rules for dose escalation/de-escalation will follow a modified toxicity probability 
interval (mTPI) method. The mTPI method relies upon a statistical probability algorithm 
which is calculated using all patients treated at the same dose level. Upon completion of a 
group (i.e., all patients in that cohort are evaluable for DLT), a decision to escalate, de-
escalate, or stay (i.e., enroll an additional group at the current dose level) will be made.   
Many alternative designs have been proposed to the standard 3+3 design for Phase 1 dose 
escalation studies that improve its accuracy, efficiency and statistical validity.  
The modified toxicity probability interval (mTPI) design uses a Bayesian statistics 
framework and a beta/binomial hierarchical model to compute the posterior probability of 
three dosing intervals that reflect the relative difference between the toxicity rate of each 
dose level to the target rate (pT = 0.28). If the toxicity rate of the currently used dose level is 
far smaller than pT, the mTPI will recommend escalating the dose level; if it is close to target 
probability (pT), the mTPI will recommend continuing at the current dose; if it is far greater 
than pT, the mTPI will recommend de-escalating the dose level. These rules are conceptually 
similar to those used by the 3+3 design, except the decisions of an mTPI design are based on 
posterior probabilities calculated under a coherent probability model.  
Being a model-based design, mTPI automatically and appropriately tailors dose-escalation 
and de-escalation decisions for different studies with different toxicity parameters. More 
importantly, all the dose-escalation decisions for a given study can be pre-calculated under 
the mTPI design and presented in a two-way table below (Table 8.1). Thus, compared to 
other advanced model-based designs published in the literature, the mTPI design is 
logistically less complicated and easier to implement.  
Table 8.1 Number of Patients with DLT for Dose Escalation Decisions at a Dose Level 
 
 
Total Number of DLT Evaluable Patients 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Escalate 
0 
0 
0 
0 
0-1 
0-1 
0-1 
0-2 
0-2 
Stay 
1 
1 
1 
1-2 
2 
2 
2 
 
3 
De-Escalate & revisit 
allowed 
 
2 
2 
 
 
3 
3-4 
3-4 
4-5 
De-Escalate & revisit not 
allowed  
2 
3 
3-4 
3-4 
3-5 
4-5 
5 
5 
6 
 
Decision rules are based on calculating unit probability mass (UPM) of three dosing intervals 
corresponding to under, proper, and overdosing in terms of toxicity. Specifically, the 
underdosing interval is defined as (0; pT-e1), the overdosing interval (pT+e2), and the proper-
dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions. Based on the safety 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 31 
profile of palbociclib as a single-agent in Study A5481001, e1 is selected as 0.03, and e2 is 
selected as 0.045. Therefore, the target interval for the DLT rate is (0.25, 0.325). 
The three dosing intervals are associated with three different dose-escalation decisions. The 
underdosing interval corresponds to a dose escalation (E), overdosing corresponds to a dose 
de-escalation (D), and proper-dosing corresponds to remaining at the current dose (R). Given 
a dosing interval and a probability distribution, the unit probability mass (UPM) of that 
dosing interval is defined as the probability of a patient belonging to that dosing interval 
divided by the length of the dosing interval. The mTPI design calculates the UPMs for the 
three dosing intervals, and the one with the largest UPM informs the corresponding dose-
finding decision, which is the dose level to be used for future patients. For example, if the 
underdosing interval has the largest UPM, the decision will be to escalate, and the next 
cohort of patients will be treated at the next higher dose level. Ji et al. (2010) have 
demonstrated that the decision based on UPM is optimal in that it minimizes a posterior 
expected loss (i.e. minimizes the chance of making a wrong dosing decision).  
The dose-finding portion of the study is terminated when either approximately 30 DLT 
evaluable patients have been enrolled or when at least 9 evaluable patients have been treated 
at the highest dose with DLT rate <33%, whichever comes first. 
8.1.2. Estimating the Maximum Tolerated Dose  
As previously described, the estimated MTD is the highest tested dose level with DLT rate 
<0.33 in at least 9 DLT evaluable patients. It is assumed that higher doses of either 
palbociclib or nab-paclitaxel result in higher toxicity rates.  But, due to the relatively low 
number of patients that may be potentially allocated to any dose combination, this 
assumption may be violated. 
For example, at the end of the study, the dose combination palbociclib 100 mg and nab-
paclitaxel 125 mg/m2 may have a higher proportion of observed toxicities than, say, 
palbociclib 125 mg, nab-paclitaxel 125 mg/m2, and this variability may be simply related to 
small cohort size alone.  To overcome this potential problem, a bivariate isotonic regression 
is used to smooth the resulting toxicity surface to a monotonically increasing one.  The 
determination of the MTD contour is accomplished using the Dykstra-Roberston algorithm. 
Once a monotonically increasing toxicity surface is obtained (either observed or smoothed 
according to the bivariate isotonic regression algorithm), the MTD combinations closest to 
the targeted DLT rate of 0.28 but still <0.33 are calculated.  Clinical judgment will be 
exercised in taking forward combinations to the MTD expansion cohort(s) in case no clear 
choice exists between more than 1 competing MTD combinations. While the limited sample 
size may result in up to 2 dose combinations of equal potential anti-tumor activity, under the 
circumstances of this study, it is possible that 2 MTD expansion cohorts will be explored. 
This decision will be based upon the combination of data related to safety, PK, PD, anti-
tumor activity, and clinical judgment of the investigators and the sponsor. 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 32 
8.1.3. Analyses for Time-to-Event Data 
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate.  Median event times and 2-sided 95% confidence interval (CI) 
for the median based on Brookmeyer-Crowley method will be provided.   
 
The X-year survival probability will be estimated using the Kaplan-Meier method and a 2-
sided 95% CI for the log [-log(X-year survival probability)] will be calculated using a normal 
approximation and then back transformed to give a confidence interval for the X-year 
survival probability itself. 
 
8.1.4. Analyses of Binary Data 
Binary endpoints will be summarized by percentage rates along with the corresponding exact 2-
sided 95% CIs using the exact method based on Clopper-Pearson method.  
 
8.1.5. Analyses of Continuous Data 
Continuous endpoints will be summarized by descriptive statistics, including the mean, standard 
deviation, median, minimum, and maximum values. Descriptive statistics for PK parameters 
and biomarkers will include %CV. 
 
8.1.6. Analyses for Categorical Data  
The number and percentage of patients in each category will be provided for categorical 
variables.   
8.1.7. Analyses for QTc Data  
 
8.1.7.1. Derived Analysis Variables 
All ECGs will be recorded in triplicate i.e. three ECGs taken 2 minutes apart. ECG 
assessments reported by the site will include the following parameters: 
 
ECG Parameter 
Units 
Abbreviation 
QTc, Fridericia’s correction 
msec 
QTcF 
QTc, Bazett’s correction 
msec 
QTcB 
QT Interval 
msec 
QT 
Heart Rate 
bpm 
HR 
PR Interval 
msec 
PR 
RR Interval 
msec 
RR 
QRS Complex 
msec 
QRS 
 
 
Averaging of triplicate measurements:  
After the above variables have been derived within each patient and scheduled time-point, 
each ECG parameter (including QTcF, QTcB, QT, HR, PR, RR, QRS) should each be 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 33 
averaged as follows:  (1st measurement + 2nd measurement + 3rd measurement) / 3.  All 
summary statistics, analyses and figures will be based on the triplicate averaged data. 
 
8.1.7.2. Assessment of QT Correction Methods   
This assessment will utilize only Screening and Day 0 triplicate averaged data (“Study drug-
free” ECG data). 
The relationship between QT/QTc and RR and the adequacy of each of the 3 QT correction 
methods will be assessed by the following scatterplots (see Figure 1): 
 QT, QTcF, and QTcB vs. RR  
Interpretation of the scatterplots should give the following information: 
 Variability of the QT/QTc relative to changing RR 
 Slope or lack of slope and pattern to assess adequacy of QT correction method 
 Apparent patterns in the data 
Figure 8.1. A Sample scatterplot of relationship between QT/QTc and RR 
 
 
 
8.1.7.3. Change from Baseline Definition 
The change from baseline calculations for ECG measurements (abbreviated as “change”) is 
derived from the triplicate averaged measurements.  The baseline ECG assessment is defined 
as the triplicate ECG assessment taken pre-dose on Cycle 1 Day 1, or the most recent 
triplicate ECG assessment reported prior to the first administration of study drug.  Change 
from baseline is defined as a patient’s parameter value at a particular time-point minus the 
appropriately matched baseline value (value - baseline value). Change from baseline 
calculations should only use post-dose ECG measurements. 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 34 
8.1.7.4. Outlier Analysis 
QT/QTc outlier values will be summarized and tabulated by the following CTCAE grade 
v.4.03.  
 
Grade 
1 
2 
3 
4 
5 
Prolonged 
QTc 
interval 
QTc  450 – 
480 msec 
QTc 481 – 
500 msec 
QTc 501 
msec on at 
least two 
separate 
ECGs 
QTc 501 or >60 msec 
change from baseline 
and Torsade de pointes 
or polymorphic 
ventricular tachycardia 
or signs/symptoms of 
serious arrhythmia 
Death 
 
The change from baseline will summarize occurrences of shift by  1 grade by CTC. 
Individual QT and QTc values 501 msec from each ECG within a triplicate will be flagged 
in data listings. 
In addition, the maximum QTc value for each patient can be categorized and summarized in 
the following cut-offs.  All post dose QTc interval data should be used in determining the 
maximum for a patient, including all scheduled and unscheduled ECG’s.  
 Absolute QTc interval 
prolongation 
QTc < 450 msec 
450 msec ≤ QTc ≤ 480 msec 
481 msec ≤ QTc ≤ 500 msec 
QTc 501 msec 
 
The maximum increase from baseline QTc value for each patient by treatment will be 
categorized and summarized as well.  For reporting the maximum increase QTc value the 
following categories: <30 msec, 30-59 msec and ≥60 msec will be used. 
8.2. Statistical Analyses  
All safety and efficacy analyses will be conducted on safety analysis set. Efficacy analyses 
will also be conducted on Per Protocol Analysis Set Evaluable for Anti-tumor Activities. All 
analyses will be performed by using SAS® Version 9.4 or higher.  
The analyses of endpoints dependent on disease assessments (PFS, OR, and DR) will be 
based on investigator assessments of disease response and progression.  


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 35 
8.2.1. Analysis of Primary Endpoint (DLT) 
Dose Limiting Toxicity (DLT) is the primary endpoint of the dose escalation component of 
the study.  The occurrence of DLTs observed in the dosing cohorts is used to estimate the 
MTD(s) as described in the protocol.  Adverse Events constituting DLTs will be listed per 
dose level with the following information. 
 
Patient ID.  
 
Dose and Date at which DLT occurred.  
 
Time from treatment start to onset of DLT.  
 
Time to resolution of DLT to Grade 1 or baseline.  
 
Dose interruption (yes, no).  
 
Time to resumption of treatment.  
 
DLT term.  
 
Action(s) taken due to DLT (stopped temporarily, permanently discontinued, no action 
taken, etc).  
 
8.2.2. Analysis of Secondary Safety Endpoints 
8.2.2.1. Adverse Events 
All patients treated with at least one dose of study treatment (i.e. palbociclib or nab-
paclitaxel) will be included in all the safety analyses.  
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v.4.03 whenever possible (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for selected events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation.  
Adverse events will be summarized by treatment and by the frequency of patients 
experiencing treatment emergent adverse events corresponding to body systems and 
MedDRA preferred term.  Adverse events will be graded by worst NCI CTCAE v.4.03 grade. 
Adverse events will be summarized by cycle and by relatedness to trial treatment. Detailed 
information collected for each AE will include a description of the event, duration, whether 
the AE was serious, intensity, relationship to study drug, action taken, and clinical outcome. 
Emphasis in the analysis will be placed on AEs classified as treatment emergent, those with 
initial onset or increasing in severity after the first dose of investigational product.  The 
number and percentage of patients who experienced any AE, serious AE (SAE), treatment 
related AE, and treatment related SAE will be summarized according to worst toxicity 
grades.  The summaries will present AEs both on the entire study period and by cycle (Cycle 
1 and cycles beyond 1).  


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 36 
Adverse events leading to death or discontinuation of trial treatment, events classified as NCI 
CTCAE v.4.03 Grade 3 or higher, trial drug related events, and serious adverse events will be 
considered with special attention. 
The percentage of patients with an event will be calculated using the number of patients in 
the safety analysis set as the denominator. The denominator for summary tables for each 
laboratory parameter will be all patients in the safety analysis set with at least one evaluable 
cycle for that parameter. 
The following summaries of treatment emergent adverse events will also be provided: 
 Discontinuations Due to Adverse Events including causality: all cause, treatment 
related, including relationship to specific study treatment of palbociclib and/or nab-
paclitaxel. 
 Temporary Discontinuations or Dose Reductions Due to Adverse Events including 
causality and relationship to specific study treatment of palbociclib and/or nab-
paclitaxel. 
 Treatment-Emergent Adverse Events (All Causality, and Treatment Related) 
including the number of patients evaluable for adverse events, total number of 
adverse events (counting each unique preferred term across all patients), number of 
patients with serious adverse events, number of patients with Grades 3 and 4 adverse 
events, number of patients with Grade 5 adverse events, and number with dose 
reductions or temporary discontinuations due to adverse events 
 Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred 
Term and Maximum NCI CTCAE v.4.03 Grade (All Causality, and Treatment 
related) 
 Treatment-Emergent Adverse Events by MedDRA Preferred Term sorted by 
Descending Order of AE Frequency (All Causality, and Treatment related) 
 Treatment-Emergent Adverse Events by Preferred Term – Grade 3/4/5 events with 
number of patients experienced Grade 3-5 AEs and total number of Grade 3-5 AEs, 
sorted by Descending Order of AE Frequency (All Causality, and Treatment 
Related).). 
A summary of Serious Adverse Events and listing of deaths reported as serious adverse 
events will be provided. 
8.2.2.2. Laboratory abnormalities 
Hematologic, chemistry and urinalysis laboratory data will be summarized by cycle. The 
hematologic and chemistry laboratory results will be graded according to the NCI CTCAE 
v.4.03 severity grade. The number and percentage of patients who experienced laboratory 
test abnormalities will be summarized according to worst toxicity grade observed for each 
lab assay.  The analyses will summarize laboratory tests both on the entire study period and 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 37 
by cycle (Cycle 1 and cycles beyond 1).  Shift tables will be provided to examine the 
distribution of laboratory toxicities. 
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal or not done. 
For CA19-9, results will be summarized in patients count (n) and percentage under the un-
mutually exclusive categories as Maximum %Reduction from baseline ≥20%, ≥50%, ≥70%,  
and ≥90%. Reduction from baseline at Week 8 ≥20%, >50%, and ≥70%‘ , respectively.    
8.2.3. ECG Analyses 
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data.  Baseline is defined as Cycle 1 Day -2.   
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points. 
QT intervals will be corrected for heart rate (QTc) using standard correction factors [i.e. 
Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, response rate (RR), PR, QRS, 
QTc (QTcF, QTcB), and dose.  Individual QT (all evaluated corrections) intervals will be 
listed by time and dose.  The most appropriate correction factor will be selected and used for 
the following analyses of central tendency and outliers and used for the study conclusions.  
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment by dose and time point.  For each patient, the maximum change from 
baseline will be calculated as well as the maximum post-baseline interval across time points.  
Categorical analysis will be conducted for the maximum change from baseline in corrected 
QT and the maximum post-baseline QT interval.  
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction method will be used) using maximum CTCAE Grade.  Shift tables will also be 
provided for ECG abnormality at baseline vs. on treatment (yes, no, not done: (n, %)). 
Patients experiencing clinically-relevant morphological ECG changes will be summarized 
(including frequency and percentage). 
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically. Additional concentration-corrected QT analyses may be performed. Data may be 
pooled with other study results and/or explored further with PK/PD models. 
For all patients in the safety analysis set, categorical analysis of the QTcF/QTcB data will be 
conducted and summarized as follows:  


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 38 
 QT/QTc outlier values will be summarized and tabulated by the following CTCAE grade 
v.4.03 according to Section 8.1.7.5. 
 The change from baseline will summarize occurrences of shift by  1 grade by CTC. 
  Individual QT and QTc values 501 msec from each ECG within a triplicate will be 
flagged in data listings. 
 The number of and percentage patients with maximum post-dose QTcF/QTcB  
(<450, 450-480, 481-500, and ≥501 ms), including all scheduled and unscheduled ECG’s.   
 The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB (<30, 30- 60, and > 60 ms), including all scheduled and unscheduled ECG’s.   
 PR changes from baseline ≥ 50% if absolute baseline value was < 200 ms, and ≥ 25% if 
absolute baseline value was > 200 ms.  
 QRS changes from baseline ≥ 50% if absolute baseline value was < 100 ms, and ≥ 25% if 
absolute baseline value was > 100 ms. 
 The number and percentage of individuals with abnormal ECG findings. 
 
8.2.4. Analyses of Efficacy Endpoints 
The number and proportion of patients achieving objective response (CR or PR) will be 
summarized in the Per Protocol Analysis Set Evaluable for Anti-tumor Activities along with 
the corresponding exact 2-sided 95% CI.   
PFS based on the assessment of investigator will be summarized in the safety analysis set 
using the Kaplan-Meier method and displayed graphically where appropriate. The median 
event time and corresponding 2-sided 95% CI for the median will be provided for PFS.   
DR will be summarized using the Kaplan-Meier methods and displayed graphically where 
appropriate.  DR will be calculated for the subgroup of patients with objective tumor 
response. The median event time and 2-sided 95% CI for the median will be provided.  
Six-month progression-free survival (6m-PFS) rate will be summarized as a product limit 
estimator based on the Kaplan-Meier method to account for censored events, together with the 
corresponding 2-sided 95% CI. The 2-sided 95% CI for the log[-log(6-month PFS probability)] 
will be calculated using normal approximation and then back transformed to give the CI for the 
6-month PFS rate itself. Analysis result will be included in the table for the PFS analysis.  
Patients will be followed and have tumor assessments performed every 8/12 weeks until disease 
progression or death, patient refusal, start of another anti-cancer treatment, or until 1-year from 
C1D1 of last enrolled patient, whichever occurs first.  
Tumor Response will be presented in the form of patient data listings that include, but are not 
limited to, received (maximum) dose, overall tumor response at each visit, and best overall 
response. In addition, progression date, death date, date of first response and last tumor 
assessment date, dates of first dose and last dose will be listed, together with DR and PFS.  
OS will be summarized in the safety analysis set using the Kaplan-Meier methods and 
displayed graphically where appropriate.  The median event time and 2-sided 95% CI for the 
median will be provided.  


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 39 
The 6-months, 1-year and 2-year survival probabilities will be provided with their 95% CIs. 
 
The Clinical Benefit Response (CBR) rate is defined as the percentage of patients with CBR. 
The CBR rate will be summarized in the Per Protocol Analysis Set Evaluable for Anti-tumor 
Activities along with the corresponding exact 2-sided 95% CI.  
 
8.2.5. Standard Analyses  
Descriptive statistics will be used to summarize study conduct and patient disposition, 
baseline characteristics, and treatment administration/compliance.   
 
 Study Conduct and Patient Disposition - an accounting of the study patients will be 
tabulated including treated, accrual by study center, assessed for AEs, laboratory data, 
biomarkers, PK, and QTc, etc.  Patients not meeting the eligibility criteria will be 
identified.  Patients not completing the study will be listed along with the reason for their 
premature discontinuation.  Reasons for premature discontinuation will be summarized.   
 Baseline Characteristics - patient characteristics such as patient age, height, weight, 
gender, race, ethnicity, Karnofsky performance status,  Ca19Ca19-9, primary diagnosis, 
prior therapy (radiotherapy, surgery, systemic therapy), baseline disease site, prior 
medication, medical history, and signs and symptoms at study entry will be summarized 
in frequency tables, and descriptive statistics will be provided for quantitative variables.  
 Treatment Administration and Compliance  
 Extent of Treatment 
The extent of treatment will be summarized as follows: 
 
 The number and % of patients on treatment and off for each reason 
 Treatment assigned vs. actual received  
 The number and percent of patients beginning 1, 2, 3, 4, 5+ cycles of either study 
drug  
 The number of cycles started (median, minimum, maximum) will be reported 
(overall and by study treatment).    
 Duration of treatment (weeks) (overall and by study treatment) 
 Cumulative dose and relative dose intensity (see Appendix 10.7 for details) 
(overall and by cycle; by study treatment).).  
 
 Treatment Delays and Dose Modifications 
Treatment delays and dose modifications of study treatments will be summarized as 
follows including number and percent (see Appendix 10.7 for details): 
 
 The number of patients with at least one palbociclib or nab-paclitaxel dose reduction and 
the number of patients with at least one palbociclib or nab-paclitaxel dose omission at 
any time during drug administration will be reported. 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 40 
 The number of patients with at least one palbociclib or nab-paclitaxel dose 
reduction due to an adverse event will be reported. 
 The number of patients with at least one palbociclib or nab-paclitaxel dose delay 
(i.e. start of following cycle is delayed) and percentage due to each reason for the 
delay will be reported  
 
 Concomitant medications and Non-drug treatments 
 
Concomitant and non-drug treatments refer to all drug and non-drug treatments taken 
while on active treatment (during the effective duration of study treatment), whether 
or not they are recorded at baseline (i.e. have stop day greater than or equal to day 1 
relative to first dose of study drug). Concomitant medication will be summarized in 
frequency tables by treatment. 
 
 Follow-Up Therapy  
Follow-up cancer therapy will be summarized by treatment as patients with number 
of regimens (0, 1, 2, 3), and patients with particular agents. 
 
8.2.6. Analyses of Pharmacokinetic and Pharmacodynamic  
8.2.6.1. Palbociclib 
PK samples for palbociclib determination will be collected on Day 13 of Cycle 1 when 
palbociclib is given in combination with nab-paclitaxel for all patients at all dose levels 
studied.  Plasma pharmacokinetic parameters including maximum plasma concentration at 
steady state (Css,max), time for Css,max (Tss,max), trough plasma concentration at steady state 
(Css,trough), area under the plasma concentration-time curve for dosing interval AUCss,τ), and 
apparent clearance (CL/F) for palbociclib will be estimated using non-compartmental 
analysis. The effect of nab-paclitaxel on steady-state palbociclib exposure will be evaluated 
by comparing palbociclib PK parameters, including Cmax and AUCτ obtained on Day 13 of 
Cycle 1 with historical data. 
 
8.2.6.2. Nab-Paclitaxel 
PK samples for total paclitaxel determination will be collected on Days -2 to 1 when nab-
paclitaxelis given alone and on Days 13-15 when nab-paclitaxel is given in combination with 
multiple doses of palbociclib.  Plasma PK parameters including maximum plasma 
concentration (Cmax), time for Cmax (Tmax), area under the plasma concentration-time curve 
from time 0 to last quantifiable concentration (AUClast), area under the plasma concentration-
time curve from time 0 extrapolated to infinite time (AUCinf), terminal plasma elimination 
half-life (t1/2), clearance (CL), and volume of distribution (Vz) will be estimated using non-
compartmental analysis if data permit.  The effect of palbociclib on total paclitaxel PK will 
be evaluated by determining the ratios of adjusted geometric means (nab-paclitaxel in 
combination with palbociclib/nab-paclitaxel alone) and 90% CIs for the ratios (AUCinf and 
Cmax). 


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Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 44 
8.3. Summary of Key Clinical Efficacy Analyses  
Type of Analysis 
Endpoint 
Analysis Set 
Statistical Method  
Secondary  
 
ORR, CBR  Evaluable (All,  
MTD expansion, 
MTD arm + MTD 
expansion),   
Investigator 
assessments  
(See 8.2.4.) 
Exact CI based on Clopper-Pearson method (95% 
CI)  
Secondary 
 
DR 
Evaluable (All,  
MTD expansion, 
MTD arm + MTD 
expansion),   
patients with a 
CR or PR  
Investigator 
assessments  
(See 8.2.4.) 
K-M method (median and 95% CI) 
Secondary 
PFS 
Safety analysis 
set (All, MTD 
expansion, MTD 
arm + MTD 
expansion), 
Investigator 
assessment 
(See 8.2.4.) 
K-M method (median and 95% CI) 
 
Secondary 
OS 
Safety analysis 
set (All, MTD 
expansion, MTD 
arm + MTD 
expansion) 
(See 8.2.4.) 
K-M method (median and 95% CI) 
 
Abbreviations: 
Evaluable: Per Protocol Analysis Set Evaluable for Anti-tumor Activities; MTD expansion cohort is a subset of 
Evaluable. 
DR: duration of response; OR: objective response; OS: overall survival; PFS: progression-free survival.


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 45 
9. REFERENCES  
1. Brookmeyer R, Crowley JJ.  A confidence interval for the median survival time.  Biometrics 
1982; 38:29-41. 
2. Cox DR. Regression models and life-tables (with discussion). Journal of the Royal Statistical 
Society, Series B 1972; 34:187-220.  
3. Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumors: Revised RECIST guideline version 1.1. Eur J 
Can 45: 228-47, 2009. 
4. Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc 
1958; 53:457-481. 
5. ICH Harmonised Tripartite Guideline. The Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. E 14. May 12, 2005. 
6. National Cancer Institute (NCI). Common Terminology Criteria For Adverse Events (CTCAE). 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
7. Sprangers MAG, Groenvold M, Arraras JL, et. Al. The European Organization for Research and 
Treatment of Cancer Breast Cancer-Specific Quality-of-Life Questionnaire Module: First Results 
From a Three-Country Field Study. J Clin Oncol 1996; 14(10): 2756-2768. 
8. Ji Y, Liu P, Li Y, and Bekele BN. A modified toxicity probability interval method for 
dose-finding trials. Clinical Trials 2010; 7:653 663. 
9. Dykstra R, Robertson T. An algorithm for isotonic regression for two or more 
independent variables. Ann Stat. 1982; 10:708-716.  


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 46 
10. APPENDICES  
10.1. Criteria for Dose Escalation 
Dose escalation will start from DL 1.  The sequential dose escalation scheme and the rules 
for determining dose escalation, de-escalation, or ‘stay’ (i.e. enroll an additional group of 
patients to the current DL) at any given dose level are described in the following paragraph 
and are illustrated in Figure 3.  
Starting from DL1:  
 Once DL 1 has been found to be tolerable, DL 2A and DL 2B will be evaluated in 
parallel.    
 If dose de-escalation is required at DL 1, then DL -1 will be evaluated next.   
The following rules apply if escalation to DL 2A and DL 2B will be explored: 
 If both DL 2A and DL 2B are tolerated and further dose escalation is considered, then 
DL 3A and DL 3B will be evaluated in parallel.      
 If DL 2A is tolerated and further dose escalation is recommended, but no dose 
escalation is determined from DL 2B, then only DL 3A will be evaluated as the 
subsequent dose escalation step.     
 If DL 2B is tolerated, but no dose escalation is determined at DL 2A, then no further 
dose escalation will be performed and DL 2B will be expanded to 9 patients, unless 
already done, in order to determine the MTD.     
 If no dose escalation is determined at DL 2A and DL 2B, then no further dose 
escalation will be performed and DL 1 will be re-evaluated (expanded up to 9 
patients, unless already done, in order to enable a dose escalation or de-escalation 
decision).    
 If dose de-escalation is recommended after DL 2A, then DL 1 will be re-evaluated  ( 
expanded up to 9 patients, unless already done, in order to enable a dose escalation or 
de-escalation decision).   
 If dose de-escalation is recommended after DL 2B, then DL 1.5 will be evaluated. 
If dose escalation to DL 3A and DL 3B will be explored:  
 If further dose escalations are recommended at both DL 3A and DL 3B, then DL 4 
will be evaluated.      
 If dose escalation is recommended only at DL 3A or DL 3B, then no further dose 
escalation will be performed and DL 3A or DL 3B will be expanded to 9 patients, 
unless already done, in order to determine the MTD.    
 If dose de-escalation is recommended after both DL 3A and DL 3B, or after DL 3B 
only, then DL 2A and DL 2B will be re-evaluated (expanded up to 9 patients, unless 
already done, in order to enable a dose escalation or de-escalation decision; the order 
of the evaluation will be determined based on the toxicities observed from DL 2A and 
DL 2B).   


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 47 
 If dose de-escalation is only recommended after DL 3A (but not at DL 3B), then DL 
2A will be re-evaluated (expanded up to 9 patients, unless already done, in order to 
enable a dose escalation or de-escalation decision). 
If dose escalation to DL 3A will only be explored:  
 DL 4 will not be evaluated regardless of the outcome at DL3A.      
 If dose de-escalation is recommended at DL 3A, then DL 2A will be re-evaluated 
(expanded up to 9 patients, unless already done, in order to enable a dose escalation 
or de-escalation decision).   
If dose escalation to DL 4:  
 Dose escalation will be stopped at this DL. 
 If dose de-escalation is recommended after DL 4, then DL 3A and DL 3B will be re-
evaluated (expanded up to 9 patients, unless already done, in order to enable a dose 
escalation or de-escalation decision; the order of the evaluation will be determined 
based on the toxicities observed at DL 3A and DL 3B). 
If de-escalation to DL -1:  
 If dose escalation is determined from DL-1, then DL 1 will be re-evaluated (expanded 
up to 9 patients, unless already done, in order to enable a dose escalation or de-
escalation decision). 
 If dose de-escalation is determined from DL -1, the study will be terminated. 
Three (3) patients per group will be initially treated at any given combination DL. Up to 3 
groups for a total of 9 patients can be treated at the same DL. Figure 10.1 illustrates the 
general dose escalation and de-escalation schema with a group size of 3 patients for a given 
DL based on this method. Detailed dose re-escalation and de-escalation schemas for a 
previous DL are provided in Figures 10.2 -10.5. 
 
 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
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Figure 10.1 The General Dose Escalation and De-Escalation Schema with a Group Size 
of 3 Patients at a Given Dose Level 
≥2 DLTs
3 Patients 
(1 group)
1 DLT
2 DLTs
0 DLT
6 patients
(2 groups)
≥3 DLTs
1 DLT
9 patients
(3 groups)
≥3 DLTs
2 DLTs
De-escalate to 
the previous 
dose level
Escalate to 
the next dose 
level
 
Note: In the figure, the term “DLT” means “patients with DLT”, not the actual number of DLT 
events. 
 
Initially a group of 3 patients will be enrolled at the starting DL.  When all 3 patients are 
available for DLT assessment, the number of patients with DLT(s) will inform the decision 
for the next step: 
 If 0 patient with a DLT out of 3 evaluable patients, escalate. 
 If 1 patient with a DLT out of 3 evaluable patients, stay. 
 If 2 patients with a DLT out of 3 evaluable patients, de-escalate. 
 If 3 patients with a DLT out of 3 evaluable patients, stop the dose escalation. 
Based on the decision above, a second group of 3 patients will be enrolled at the 
corresponding DL.  Upon completion of the second group, a decision will be made again to 
either escalate, de-escalate, or stay. Table 8.1 is derived from a generalized approach that 
extends the current mTPI method and preserves its decision-theoretical properties.  
There are two scenarios under the decision of de-escalation: de-escalate and revisit allowed 
or de-escalate and revisit not allowed.  The latter means that the current DL is determined to 
be unacceptably toxic; this DL and the subsequent higher DLs will be excluded from the 
study.  
The decision-making needs to consider all patients treated at the current DL under 
evaluation.  For example, if the decision is to stay at the starting DL after the first group of 3 
patients (i.e. there is 1 patient with a DLT), and another group of 3 additional patients is 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 49 
enrolled at the same DL, the next decision will be made based on all 6 patients treated at that 
DL: 
 If 1 patient experiences a DLT out of 6 evaluable patients, escalate. 
 If 2 patients experience a DLT out of 6 evaluable patients, stay. 
 If ≥3 patients experience a DLT out of 6 evaluable patients, stop the dose escalation. 
Dose escalation will continue until at least 9 patients have been treated at any given DL.  
Doses will not be escalated if the starting DL is deemed overly toxic, or if reaching the 
maximum sample size of approximately 30 patients is reached (i.e. the number of DLT-
evaluable patients).     
The MTD determination will be based on the observed toxicity rates among all evaluable 
patients at any given DL.  When dose escalation is stopped, the highest DL with an observed 
DLT rate <33% (in at least 9 DLT-evaluable patients) will be considered the MTD.  It is 
possible that more than one MTD will be determined, in which case a decision will be made 
to expand one or both MTDs in order to determine the RP2D.     
The general approach to dose-finding, using the mTPI method, involves the following: 
 The target group size is 3. However, patients can be enrolled in group sizes of 2-4 
patients if necessary, depending on the number of potential patients identified at 
participating sites (see Table 8.1);   
 The next group of patients can be enrolled when all patients at a given  DL have been 
evaluated for 28 days in the first treatment cycle, or any of the patients experience a 
DLT, whichever comes first; 
 If a patient withdraws from the study before having received >80% of the planned 
first-cycle dose for palbociclib and nab-P for reasons other than investigational 
product-related toxicity, another patient will be enrolled to replace that patient at the 
current DL; 
The dose escalation portion of the study is completed when at least 9 evaluable patients have 
been treated at the highest DL associated with a DLT rate <33%. It is estimated that 
approximately 30 ‘DLT-evaluable’ patients will be enrolled to reach n = 9 ‘DLT-evaluable’ 
patients at the estimated MTD. 
Dose escalation may be completed without determining the MTD based on emerging safety 
data, and upon agreement between the investigators and the sponsor. 
 
The RP2D will be determined in the MTD dose expansion cohort(s), taking into account the 
MTD(s) from the dose-escalation component, and other factors related to safety, efficacy, 
and PK/PD involving all available data from all tested DLs.  


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 50 
Figure 10.2 Dose de-escalation scheme to a previous dose level where 3 patients have 
been treated with 0 DLT 
 
 
 
 
Figure 10.3 Dose de-escalation scheme to a previous dose level where 6 patients have 
been treated with ≤1 DLT 
De-escalate to 
6 patients 
with ≤1 DLT
9 patients
(3 groups)
≥3 DLTs
≤2 DLTs
Re-Escalate 
to the next 
dose level
De-escalate to 
the previous 
dose level
 
 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 51 
Figure 10.4 Dose re-escalation scheme from a previous dose level where 3 patients have 
been treated with 2 DLTs 
 
 
Figure 10.5 Dose re-escalation scheme from a previous dose level where 6 patients have 
been treated with 3 DLTs 
Escalate from 
6 patients 
with 3 DLTs
Stop
 
 
 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 52 
10.2. RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 Guidelines 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247  
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions   
Lesions that can be accurately measured in at least one dimension. 
 Lesions with longest diameter twice the slice thickness and at least 10 mm or greater  
when assessed by CT or MRI  (slice thickness 5-8 mm) 
 Lesions with longest diameter at  least 20 mm when assessed by Chest X-ray   
 Superficial lesions with longest diameter 10 mm or greater when assessed by caliper   
 Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE:  The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions.  
Non-measurable disease  
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical examination that are not measurable 
by reproducible imaging techniques. 
 Bone disease:  Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability 
at baseline.   
 Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
Normal sites 
 Cystic lesions: Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease.  Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above. If 
non-cystic lesions are also present, these are preferred as target lesions. 
 Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
RECORDING TUMOR ASSESSMENTS  
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start. For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 53 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.   
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. Target 
lesions should be selected on the basis of size (longest lesions) and suitability for accurate 
repeated measurements.  Record the longest diameter for each lesion, except in the case of 
pathological lymph nodes for which the short axis should be recorded.  The sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at 
baseline will be the basis for comparison to assessments performed on study.  
  If two target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used. 
 Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded.. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 
Non-target disease  
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION. 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.   
Target disease 
 Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis < 
10 mm).  All target lesions must be assessed. 
 Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions.  All 
target lesions must be assessed.   
 Stable: Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  
Stable can follow PR only in the rare case that the sum increases by less than 20% from 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
Page 54 
the nadir, but enough that a previously documented 30% decrease no longer holds.   
 Objective Progression (PD):  20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm.   
 Indeterminate. Progression has not been documented, and  
 one or more target measurable lesions have not been assessed  
 or assessment methods used were inconsistent with those used at baseline 
 or one or more target lesions cannot be measured accurately (e.g., poorly visible 
unless due to being too small to measure) 
 or one or more target lesions were excised or irradiated and have not reappeared or 
increased.   
Non-target disease 
 CR: Disappearance of all non-target lesions and normalization of tumor marker levels. 
All lymph nodes must be ‘normal’ in size (<10 mm short axis). 
 Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the normal limits.  
 PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of SD or 
PR in target disease, progression due to unequivocal increase in non-target disease should 
be rare.   
 Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at baseline. 
New Lesions  
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion. 
Supplemental Investigations 
 If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR. 
 If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status.  
Subjective progression 
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 


Protocol A5481059 
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Page 55 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.   
Table 10.4. Objective Response Status at each Evaluation 
 
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used: 
 
Table 10.5. Objective Response Status at each Evaluation for Patients with Non-Target 
Disease Only 
 
BOR Based on Confirmed Responses 
CR:  Two objective statuses of CR a minimum of four weeks apart documented before 
progression and start of new anti-cancer therapy. 
PR:  Two objective statuses of PR or better (PR followed by PR or PR followed by CR) a 
minimum of four weeks apart documented before progression and start of new anti-cancer 
therapy, but not qualifying as CR.  Sequences of PR- Stable- PR are considered PRs as long 
as the two PR responses are observed at a minimum of 4 weeks apart. 
 Target Lesions 
Non-target Disease 
New 
Lesions 
Objective 
status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Indeterminate or Missing  
No 
PR 
PR 
Non-CR/Non-PD, 
Indeterminate, or Missing 
No 
PR 
SD 
Non-CR/Non-PD, 
Indeterminate, or Missing 
No 
Stable 
Indeterminate or Missing 
Non-PD 
No 
Indeterminate 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Non-target Disease 
New Lesions 
Objective status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Indeterminate 
No 
Indeterminate 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 


Protocol A5481059 
Statistical Analysis Plan V4 
 
 
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SD:  At least one objective status of stable or better documented at least 6 weeks after start 
date and before progression and the start of new anti-cancer therapy but not qualifying as CR 
or PR.   
PD:  Progression documented within 18 weeks after start date and not qualifying as CR, PR 
or SD.   
Not Evaluable (NE):  All other cases.  Note that reasons for NE should be summarized and 
the following reasons could be used:  
 Early death (Note: death < 6 weeks after start date) 
 No post-baseline assessments  
 All post-baseline assessments have overall response NE 
 New anti-cancer therapy started before first post-baseline assessment 
 SD too early (<6 weeks after start date) 
 PD too late (>18 weeks after start date) 
Special and rare cases where BOR is NE due to both early SD and late PD will be 
classified as ‘SD too early’. 
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs the sequence PR-
SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met. 
The overall response rate (ORR) is defined as the percentage of patients with a best overall 
response of CR or PR relative to the appropriate analysis set.  


Protocol A5481059 
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10.3. Rules for Determining PFS Status and Date 
Situation 
Date of Progression/Censoring1 
Outcome 
Inadequate baseline 
assessment  
First dose date (Day 1)2 
Censored 
No on-study assessments 
First dose date (Day 1) 2 
Censored 
Alive and no Progression  
Date of last objective tumor assessment 
documenting no progression 
Censored 
Progression Documented on 
or between scheduled tumor 
assessments 
Date of first objective tumor assessment 
documenting objective progression 
 
Progressed 
(Event) 
Patients are removed from 
the study (withdrew the 
consent, lost to follow up, etc.)  
prior to progression or death 
Date of last objective tumor assessment 
documenting no progression 
Censored 
New anticancer treatment 
prior to progression or death 
Date of last objective tumor assessment 
documenting no progression prior to 
new anticancer treatment 
Censored 
Death prior to first planned 
tumor assessment  
Date of death 
Death (Event)         
Death without objective 
progression prior to 
treatment discontinuation2 
Date of death 
Death (Event) 
                   
Death or progression after 2 
or more missed tumor 
assessments 
Date of last objective tumor assessment 
documenting no progression prior to the 
event 
Censored 
1 For date of censorship, if a tumor assessment takes place over a number of days (e.g., superficial lesions one 
day, scans another), the first date is used as PD date and the last date is used as the other assessment date. 
1 First dose date is defined as the first Palbociclib dose date 
 


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10.4. Data Derivation Details 
Enrollment  
Date of assignment of the randomization number 
Study Day 1 
First dose day  
 
Treatment-Palbociclib start 
Day 1 of Cycle 1  
Treatment-nab-P start 
Day -2 of Cycle 1  
Day 1 (cycle start date) of Cycle x 
Day 1 of a cycle is every 28 days unless there is a 
dosing delay. 
Cycle length (all but final cycle) 
Cycle length is 28 days (previous cycle length may 
exceed planned length if there is a delay in study 
treatment administration). 
Final cycle 
For patients off treatment, from Day 1 of final cycle to 
28 days after final dose or until start of new anticancer 
treatment (whichever comes first).   
For patients on treatment, from Day 1 of most recent 
cycle start to protocol specified cycle length. 
Follow-up Period for AEs 
From 28 days after final dose until start of new 
anticancer treatment (whichever comes first).   
Baseline lab values 
From date closest to, but prior to, start of study 
treatment.  
Baseline triplicate ECGs 
Cycle 1 Day -2 dose date or from date closest to, but 
prior to, start of any of study treatments if C1D-2 is 
not available.  
Tumor assessment baseline values 
From date closest but prior to first dose.   
Adequate baseline tumor 
assessment 
Within 35 (28 + 7) days prior to first dose. 
Maximum diameter reported for each target lesion 
listed.  All required pre-treatment scans done. 
Cycle k treatment delayed. 
If study treatment administration is delayed for cycle k 
then cycle k-1 is extended.  
 


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10.5. Study Treatment Modification and Compliance  
10.5.1. Dose Modification 
In the event of significant treatment-related toxicity, palbociclib and/or nab-paclitaxel dosing 
may be interrupted or delayed and/or reduced as described below.  In the event of multiple 
toxicities, dose modification should be based on the worst toxicity observed.  Patients are to 
be instructed to notify Investigators at the first occurrence of any adverse sign or symptom. 
Dose modifications may occur in three ways: 
 Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 
 Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start; 
 In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
10.5.2. Summarizing Relative Dose (RD) and Relative Dose Intensity (RDI)  
The following types of summaries are proposed for administration of palbociclib and nab-
paclitaxel. 
 
When palbociclib is administered orally once a day for 21 days of every 28-day cycle 
followed by 7 days off treatment (cyclical dosing) in combination with nab-paclitaxel (IV, 
D1, D8, D15), the following summaries can be presented: 
 
 RDI for palbociclib: by Cycle and Overall  
 RDI for nab-paclitaxel: by Cycle and Overall 
 
When palbociclib is administered orally daily in combination with nab-paclitaxel (IV, D1, 
D15) and uses 28 days as a cycle definition, the following summaries can be presented: 
 
 RDI for palbociclib: by Cycle and Overall 
 RDI for nab-paclitaxel: by Cycle and Overall 
 
Note: the denominator for tables summarizing “nab-paclitaxel” will be all patients who 
received at least one dose of nab-paclitaxel and for tables summarizing “palbociclib” will be 
all patients who took at least one dose of palbociclib. 
 
Examples for the summaries described in above are included in the tables below. 
 
Conventions: 
 
The Intended Daily Dose is the same for all cycles: the daily dose is fixed at the start of 
treatment rather than start of a cycle and the intended treatment duration is the same for 


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the entire dosing period (e.g. for a 3/1 dosing schedule, all non-last cycles have an 
intended duration of 4 weeks. The intended treatment duration for the last cycle is from 
the 1st dose date of the last cycle to the EOT date or duration of 4 weeks which is 
shorter);  
 
Actual Dose Intensity is calculated based on actual cycle length  


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Table 10.6 Cyclical Palbociclib By Cycle 
Treatment / 
Summary 
Type  
Calculation of RDI 
Cyclical 
palbociclib 
(3/1) or 
continued/ 
By Cycle  
 
 
 
                                       
 
100
*
ilyDose
IntendedDa
sity
yDoseInten
ActualDail
RDI 
% 
% 
Where: 
Intended Daily Dose (mg/day in 21/7 schedule or continued schedule) = 
75, 100, 125  
 
Actual Daily Dose Intensity (mg/day in 21/7 schedule) =  
      Actual Average Daily Dose (mg/day in x/y schedule) * 
     (Actual Dose Days / Intended Dose Days ) * 
     (Intended Cycle Duration / Actual Cycle Duration) 
   
 
Actual Average Daily Dose (mg/day in x/y schedule) =  
             Actual Total Dose / Actual Dose Days   
 
Intended Dose Days = 
 For 3/1 schedule: 
                    For  non-last cycle: 21  
       For last cycle: minimum (21, (Decision date of stopping trt from 
EOT page -1st dose date in last cycle +1)) 
 For continued schedule: 
                    For  non-last cycle: 28  
       For last cycle: minimum (28, (Decision date of stopping trt from 
EOT page -1st dose date in last cycle+1)) 
 
 
Intended Cycle Duration =  
For non-last cycle: 28  
      For last cycle: minimum (28, (Decision date of stopping trt from EOT 
page -1st dose date in last cycle+1)) 
 
 
Actual Cycle Duration for last cycle = 
o For non-last cycle: Next cycle’s Day 1 date – Current cycle’s 
Day 1 date   
o For last cycle: (Min [Decision date of stopping trt from EOT 
page, EOS date]   - 1st dose date in last cycle +1                    ) 
 


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Table 10.7 Cyclical Palbociclib Overall 
Treatment / 
Summary 
Type  
Calculation of RD/RDI 
Cyclical 
palbociclib / 
Overall  
 
 
 
100
*
ilyDose
IntendedDa
sity
yDoseInten
ActualDail
RDI 
% 
% 
Where: 
Intended Daily Dose (mg/day in 21/7 schedule or continued schedule) = 
75, 100, 125  
 
 
Actual Daily Dose Intensity (mg/day in 21/7 schedule  or continued 
schedule) =  
      Actual Average Daily Dose (mg/day in x/y schedule) * 
     (Actual Dose Days / Intended Dose Days ) * 
     (Intended Cycle Duration / Actual Cycle Duration) 
   
 
Actual Average Daily Dose (mg/day in x/y schedule) =  
Sum over all cycles of “Actual Total Dose” /  
Sum over all cycles of “Actual Dose Days” 
  
 
Actual Dose Days = Sum over all cycles of “Actual Dose Days”   
 
Intended Dose Days = Sum over all cycles of “Intended Dose Days” 
 
Actual Cycle Duration = Sum over all cycles of “Actual Cycle 
Duration” 
 
Intended Cycle Duration = Sum over all cycles of  “Intended Cycle 
Duration” 
 
 
 
 
 


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Statistical Analysis Plan V4 
 
 
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Table 10.8 Nab-paclitaxel by Cycle and Overall 
Treatment (Schedule) / Summary Type 
Calculation of Relative Dose Intensity (RDI) 
Nab-P (3/1 or Biweekly)  
/ By Cycle 
 
 
100
*
erageDose
IntendedAv
Intensity
ActualDose
RDI 
% 
% 
Where: 
Intended Average Dose (mg/Q7d) = {
100                                                                                         for DL1, DL2A, DL3A, MDR2
125                                                                                         for DL2B, DL3B, DL4, MDR1
 𝑠𝑎𝑚𝑒 𝑎𝑠 𝑡ℎ𝑒𝑖𝑟 𝑜𝑟𝑖𝑔𝑖𝑛𝑎𝑙 𝑑𝑜𝑠𝑒 𝑐𝑜ℎ𝑜𝑟𝑡               𝑜𝑛 𝑡ℎ𝑒 𝑀𝑇𝐷 𝑜𝑟 𝑀𝐷𝑅 𝐸𝑥𝑝𝑎𝑛𝑠𝑖𝑜𝑛 
 
Actual Dose Intensity (mg/Q7d in planned schedule) =  
      Actual Average Dose each time (mg/Qxd) in the Cycle 
      * (Actual Freq in the Cycle/ Intended Freq in the Cycle)    
      * (Intended Cycle Duration/ Actual Cycle Duration) 
 
Factor in dose reductions or potential overdose:  
Actual Average Dose each time (mg/Qxd) in the Cycle =  
             Actual Total Dose in the Cycle / Actual Freq in the Cycle   
 
Factor in dose interruptions: 
Actual freq on Drug / Intended Freq on Drug 
 
Factor in cycle delays: 
      Intended Cycle Duration / Actual Cycle Duration 
 
Intended Freq on Drug in each Cycle 
 
{
  
 
  
 
 
2                                                                                             for non-last Cycle in MDR1, MDR2, MDR Expansion
3                                                  for non-last cycle in DL1, DL2A, DL2B, DL3A, DL3B, DL4, MTD, MTD Expansion
1                                               for last Cycle and its actual cycle duration ≤ 14 in MDR1, MDR2, MDR Expansion
2                                                for last Cycle and its actual cycle duration > 14 in MDR1, MDR2, MDR Expansion
1    for last cycle and actual cycle duration ≤ 5 in DL1, DL2A, DL2B, DL3A, DL3B, DL4, MTD, MTD Expansion
2    for last cycle and actual cycle duration ≤10 in DL1, DL2A, DL2B, DL3A, DL3B, DL4, MTD, MTD Expansion
3    for last cycle and actual cycle duration ≤ 17 in DL1, DL2A, DL2B, DL3A, DL3B, DL4, MTD, MTD Expansion
 
 
Intended Cycle Duration = {
28                                                   for non-last cycle
min(28, Actual last Cycle Duration)     for last cycle 
 Actual Cycle Duration = 


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{(Day 1 of next cycle - Day 1 of of current cycle)                                                                                 for non-last cycle
max(nabP EOT date, NabP last dose date from dose page)–  1st day of the last cycle + 1        for last cycle  
 


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Nab-P (3/1 or Biweekly)  
/ Overall 
 
 
 
100
*
erageDose
IntendedAv
Intensity
ActualDose
RDI 
% 
% 
Where: 
Intended Average Dose (mg/Q7d) = {
100                                                                                         for DL1, DL2A, DL3A, MDR2
125                                                                                         for DL2B, DL3B, DL4, MDR1
 𝑠𝑎𝑚𝑒 𝑎𝑠 𝑡ℎ𝑒𝑖𝑟 𝑜𝑟𝑖𝑔𝑖𝑛𝑎𝑙 𝑑𝑜𝑠𝑒 𝑐𝑜ℎ𝑜𝑟𝑡               𝑜𝑛 𝑡ℎ𝑒 𝑀𝑇𝐷 𝑜𝑟 𝑀𝐷𝑅 𝐸𝑥𝑝𝑎𝑛𝑠𝑖𝑜𝑛 
 
Actual Dose Intensity (mg/Q7d in planned schedule) =  
      Actual Average Dose each time (mg/Qxd)  
      * (Actual Freq in the Cycle/ Overall Intended Freq)    
      * (Intended Total Cycle Duration/ Overall Actual Cycle Duration) 
 
 
Factor in dose reductions or potential overdose:  
Actual Average Dose each time (mg/Qxd) =  
             Actual Total Dose / Actual Total Freq on Drug  
 
Factor in dose interruptions: 
Actual Total Freq on Drug / Intended Total Freq on Drug 
 
Factor in cycle delays: 
      Intended Total Cycle Duration / Actual Total Cycle Duration 
 Intended Total Freq on Drug: 
  
{
 
 
 
 
 
 
 
 
 
For MDR1, MDR2, MDR Expansion Expansion:                                                                                
= 2*(total of non-last cycle) + (1 or 2 for last cycle based on following situation)              
1                                   for last Cycle and its actual cycle duration ≤ 14
2                                   for last Cycle and its actual cycle duration > 14
For DL1, DL2A, DL2B, DL3A, DL3B, DL4, MTD, MTD Expansion:                                              
= 3*(total of non-last cycle) + (1 or 2 or 3 for last cycle based on following situation) 
1    for last cycle and actual cycle duration ≤ 5 
2    for last cycle and actual cycle duration ≤10
3    for last cycle and actual cycle duration ≤ 17
 
 
Intended Total Cycle Duration = {28*(total of non-last cycle) + min(28, Actual last Cycle Duration) 
 
Actual Total Cycle Duration: max(decision date on stopping NabP from EOT page, NabP last dose date+6) – Day 1 of Cycle 1 +1 


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10.6. Karnofsky Performance Status 
 


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10.9. List of Abbreviation 
Abbreviat
ion 
Term 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome  
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
twice daily 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
Cycle 
C 
degrees Celsius 
CHF 
congestive heart failure 
CI 
confidence interval 
CL 
Clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CSA 
clinical study agreement 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
CT 
computed tomography 
CTA 
clinical trial application 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
D 
day 
DAI 
dosage and administration instructions 
DCT 
data collection tool 
DDI 
drug-drug interaction 
DEHP 
di-ethylhexylphthalate 
DL 
dose level 
DLT 
dose limiting toxicity 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DR 
Duration of Response 
EC 
ethics committee 
ECG 
electrocardiogram 
EDP 
exposure during pregnancy 
EDTA 
edetic acid (ethylenediaminetetraacetic acid) 


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eg 
for example 
ESoE 
Early Signs of Efficacy 
etc 
‘and other things’ or ‘and so forth’ 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration (United States) 
FDAAA 
Food and Drug Administration Amendments Act (United States) 
FFPE 
formalin-fixed  paraffin-embedded  
FSH 
follicle-stimulating hormone 
g 
gravity 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulation factor 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
IB 
investigator’s brochure 
IC50 
concentration of an inhibitor where the response (or binding) is reduced by half 
ICH 
International Conference on Harmonisation 
ID 
identification 
ie 
that is 
IHC 
immunohistochemistry 
IND 
investigational new drug application 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
IP 
investigational product 
IV 
intravenous 
K2EDTA 
dipotassium ethylene diamine tetraacetic acid 
KPS 
Karnofsky performance status 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LFT 
liver function test 
mTPI 
modified toxicity probability interval 
MAPK 
Mitogen-activated protein kinase 
MD 
multiple dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
maximum feasible dose 
MID 
minimally important difference 
mPDAC 
Metastatic Pancreatic Ductal Adenocarcinoma 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
N/A 
not applicable 
Nab-P 
nanoparticle albumin-bound Paclitaxel 
NCI  
National Cancer Institute  


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NGS 
Next Generation Sequencing 
NS 
not significant 
ORR 
overall response rate 
OS 
overall survival 
pT 
target probability 
PCD 
primary completion date 
PD 
pharmacodynamics 
PD 
progressive disease 
PDAC 
Pancreatic ductal adenocarcinoma 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PPI 
Proton-pump inhibitor 
PR 
partial response 
p-Rb1 
Phosphorylated retinoblastoma protein 
PS 
performance status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PVC 
plasticized polyvinyl chloride 
QD 
every day 
QT 
time between the start of the Q wave and the end of the T wave 
R 
ratio 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
Relapse-Free Survival 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SIB 
suicidal ideation and behavior 
SOA 
Schedule of Activities 
SPC 
Summary of Product Characteristics 
SRSD 
single reference safety document 
T 
Time 
T1/2 
terminal elimination half-life 
TBR 
tumor background ratio 
TTD 
time to deterioration 
ULN 
upper limit of normal 
UPM 
unit probability mass 
US 
United States 
USPI 
United States Package Insert 
V 
volume of distribution 
WBC 
white blood cell