Clinical trial NCT02570711
Conditions: Metastatic Pancreatic Cancer
Keywords: Acalabrutinib
Sponsor: Acerta Pharma BV
Start date: 2015-10-13; Completion date: 2016-04-01
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and efficacy of ACP-196 and nab paclitaxel/gemcitabine in subjects with previously untreated metastatic pancreatic cancer using standard response criteria

Detailed description:
A Phase 2, multicenter, open-label, randomized clinical trial. The study was to evaluate the efficacy and safety of ACP-196 plus nab-paclitaxel/gemcitabine compared with nab-paclitaxel/gemcitabine in subjects who have previously untreated metastatic pancreatic cancer.

Arms: arm 1: ACP-196 and nab-paclitaxel and gemcitabine arm 2: Nab-paclitaxel and gemcitabine
Interventions: intervention 1: ACP-196 intervention 2: Nab-paclitaxel intervention 3: Gemcitabine
Intervention descriptions: intervention 1: ACP-196 capsule intervention 2: Nab-paclitaxel infusion intervention 3: Gemcitabine infusion

Protocol documents:
Prot_SAP_000.pdf: 
Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
Acerta Pharma 
Confidential 
Page 1 of 160 
 
PROTOCOL 
TITLE: 
A Phase 2, Randomized, Proof-of-Concept Study of 
Nab-Paclitaxel/Gemcitabine Alone and in Combination with 
ACP-196 in Subjects with Previously Untreated Metastatic 
Pancreatic Cancer 
PROTOCOL NUMBER: 
ACE-ST-004 
STUDY DRUG: 
ACP-196 (acalabrutinib) 
IND NUMBER: 
124612 
EUDRACT NUMBER: 
2015-003428-30 
SPONSOR MEDICAL MONITOR: 
 
 
SPONSOR: 
Acerta Pharma BV 
Kloosterstraat 9 
5349 AB Oss 
The Netherlands 
STUDY CENTERS 
AND PRINCIPAL 
INVESTIGATORS: 
  
 
 
 
 
PROTOCOL DATE: 
Version 0.0 – 01 March 2015 
AMENDMENT 1 DATE: 
Version 1.0 – 18 May 2015 
AMENDMENT 1.1 DATE: 
Version 1.1 – 30 September 2015 
AMENDMENT 2.0 DATE: 
Version 2.0 – 18 November 2015 
AMENDMENT 3.0 DATE: 
Version 3.0 – 01 February 2016 
 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV that 
must not be disclosed to anyone other than the recipient study staff and members of the 
institutional review board (IRB)/independent ethics committee (IEC).  This information cannot 
be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Acerta Pharma BV. 




Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
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SUMMARY OF AMENDMENT 3.0 
This protocol is being amended to add hepatitis serology testing at screening.  For 
subjects who test positive for latent hepatitis B infection at screening (or who have a 
known history of hepatitis B infection), this protocol will now require monthly 
monitoring for potential hepatitis B reactivation.  The reason for this amendment is 
hepatitis B virus (HBV) reactivation has occurred in patients treated with Btk inhibitors 
(Ngoma 2015), including 1 subject on ACP-196 treatment. 
Clarifying edits and typographical changes have been made throughout the protocol.  
In addition, the following substantive changes were made as part of this amendment: 
Change 
Rationale 
In various parts of the protocol, the nonproprietary name 
for ACP-196 was introduced. 
The nonproprietary name 
of acalabrutinib was 
recently approved for use. 
Title page: 
On 01 January 2016, Sponsor address changed to 
Acerta Pharma BV, Kloosterstraat 9, 5349 AB Oss, The 
Netherlands 
Administrative change. 
Synopsis  
Updated to reflect 
changes made 
throughout the protocol.   
Section 3.3.2 Exclusion Criteria 
Revised exclusion criterion as follows (bold is new text): 
 
15. Known history of HIV or serologic status indicating 
active infection with HCV or HBV infection or any 
uncontrolled active systemic infection requiring 
systemic therapy with 14 days of randomization.  
Subjects with hepatitis B core antibody positive who 
are surface antigen negative or who are hepatitis C 
antibody positive will need to have a negative PCR 
result before enrollment.  Those who are hepatitis B 
surface antigen positive or hepatitis B PCR positive 
and those who are hepatitis C PCR positive will be 
excluded.   
Revised to provide 
greater detail on 
screening for active HBV 
and HCV infections. 
Section 3.10 PRECAUTIONS 
 
New section and corresponding language was added: 
 
Section 3.10.1 Hepatitis B Virus Reactivation 
 
Serious or life-threatening reactivation of viral 
hepatitis may occur in subjects treated with ACP-196.  
Therefore, subjects who are hepatitis B core antibody 
(anti-HBc) positive, or have a known history of HBV 
infection, should be monitored monthly with a 
As HBV reactivation has 
occurred in 1 subject on 
acalabrutinib treatment 
this language is being 
added to ensure 
adequate monitoring of 
patients with a history of 
HBV. 


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
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quantitative PCR test for HBV DNA.  Monthly 
monitoring should continue until 12 months after last 
dose of study drug(s).  Any subject with a rising viral 
load (above lower limit of detection) should 
discontinue study drug(s) and have antiviral therapy 
instituted and a consultation with a physician with 
expertise in managing hepatitis B.  Insufficient data 
exist regarding the safety of resuming ACP-196 in 
subjects who develop HBV reactivation.  
Section 4.1.8 Electrocardiogram 
 
Added the following text: 
In addition, a single ECG will also be performed 1 
hour after ACP-196 administration at Cycle 1 Day -1 
for the first 6 subjects enrolled to Arm 1.   
Revised to clarify a 
discrepancy in the 
protocol. 
 
Section 4.1.9 Urine or Serum Pregnancy Test 
Revised as follows (bold is new text): 
 
Pregnancy tests will be required only for women of 
childbearing potential.  Testing will be done by a central 
or local laboratory as listed on the investigator’s Form 
FDA 1572. 
 
Clarifying edit. 
Section 4.1 DESCRIPTION OF PROCEDURES 
 
New section and corresponding language was added: 
 
Section 4.1.14 Hepatitis B and C Testing 
 
Hepatitis serology testing must include hepatitis B 
surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), anti-HBc, and HCV antibody.  In 
addition, any subjects testing positive for any 
hepatitis serology, must have PCR testing (see 
Appendix 7 and exclusion criterion #15).  Testing will 
be done by local or central laboratory.   
 
Refer to Section 3.10.1 and Appendix 7 regarding 
monitoring of subjects who are anti-HBc positive or 
have a known history of HBV. 
Adds hepatitis serology at 
screening and monitoring 
for potential of HBV 
reaction in subjects with 
latent HBV infections. 
Section 4.3 SAFETY FOLLOW-UP VISIT 
The following text was deleted: 
 
Each subject should be followed for 30 (+ 7) days after 
his or her last dose of study drug (ie, the “safety follow-up 
visit”) to monitor for resolution or progression of AEs (see 
Section 6.2.5) and to document the occurrence of any 
new events; unless, the subject receives a new 
anticancer therapy within this timeframe. 
Updated for consistency 
with other ACP-196 
protocols.  
Section 6.1.1 Adverse Events 
 
The definition of adverse event was revised as follows: 
This change was made 
align the protocol with the 
ICH definition of “adverse 


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
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An AE is any unfavorable and unintended sign, symptom, 
or disease temporally associated with the use of an 
investigational (medicinal) product or other protocol 
imposed intervention, regardless of attribution. 
This includes the following: 
• 
AEs not previously observed in the subject that 
emerge during the protocol specified AE reporting 
period, including signs or symptoms associated 
with pancreatic cancer that were not present 
before the AE reporting period (see Section 
6.2.1). 
• 
Complications that occur as a result of protocol-
mandated interventions (eg, invasive procedures 
such as biopsies). 
• 
Preexisting medical conditions (other than the 
condition being studied) judged by the investigator 
to have worsened in severity or frequency or 
changed in character during the protocol-specified 
AE reporting period. 
events”. 
Section 6.2.1 Adverse Event Reporting Period 
The following sentences were deleted from this section: 
 
The AE reporting period for this study begins when the 
subject receives the first dose of study drug and ends 
with the safety follow-up visit.  If a subject received a new 
anticancer therapy before the safety follow-up visit then 
the AE reporting period ends with initiation of the new 
anticancer therapy.  An exception to this reporting period 
is any AE occurring due to a protocol-defined screening 
procedure. 
Updated for consistency 
with other ACP-196 
protocols. 
Section 6.2.3 Pregnancy 
The following correction was made (bold is new text): 
 
All pregnancies and partner pregnancies that are 
identified during or after this study, wherein the estimated 
date of conception is determined to have occurred from 
the time of consent to 30 90 days after the last dose of 
study medication will be reported, followed to conclusion, 
and the outcome reported. 
Correction. 
Section 6.2.4 Expedited Reporting Requirements for 
Serious Adverse Events 
 
New language was added to this section as follows: 
 
Other Safety Issues Requiring Expedited Reporting 
For studies being conducted in Europe expedited 
reporting is required for safety issues that might 
materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be 
sufficient to consider changes in the investigational 
This language was added 
as this is a global study. 


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
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medicinal products administration or in the overall 
conduct of the trial.  For a detailed description of safety 
issues that may qualify for expedited reporting please 
refer to the European Commission guidance titled, 
“Detailed guidance on the collection, verification and 
presentation of adverse reaction reports arising from 
clinical trials on medicinal products for human use – April 
2006” available at 
http://ec.europa.eu/health/files/eudralex/vol-
10/21_susar_rev2_2006_04_11_en.pdf. 
Section 6.2.5 Type and Duration of Follow-up of Subjects 
after Adverse Events 
 
All AEs and SAEs that are encountered during the 
protocol-specified AE reporting period should be followed 
to resolution, or until the investigator assesses the 
subject as stable, a new anticancer therapy is initiated, or 
the subject is lost to follow-up or withdraws consent. 
Updated for consistency 
with other ACP-196 
protocols. 
Section 7.6 Investigational Study Drug Accountability 
 
The following language was revised as follows (bold is 
new text): 
 
ACP-196 capsules must be kept in a locked limited 
access cabinet or space.  The study drug ACP-196 must 
not be used outside the context of the protocol.   
Study drug accountability records, for ACP-196 and, 
when applicable, for nab-paclitaxel and gemcitabine, 
must be maintained and readily available for inspection 
by representatives of Acerta Pharma and are open to 
inspections by regulatory authorities at any time.   
Clarifying edits. 
Section 8.0 References 
 
Reference list updated. 
Updated to reflect 
changes made 
throughout the protocol.   
Appendix 7 Schedule of Assessments 
 
Added tumor assessment at follow-up phase.  
 
 
 
 
 
Revised footnote “f” as follows (bold is new text): 
f. At Cycle 1 Day 1 and Cycle 1 Day 15, a single ECG will 
be done 1 hour after ACP-196 administration.  In 
addition, a single ECG will also be performed 1 hour 
after ACP 196 administration at Cycle 1 Day -1 for the 
first 6 subjects enrolled to Arm 1.   
 
 
Revised footnote “s” as follows (bold is new text): 
 
 
Added to correct an 
omission in the schedule 
of events. 
 
 
 
Revised to clarify a 
discrepancy in the 
protocol. 
 
 
 
 
 
Revised for clarification. 
 


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
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s. This urine or serum pregnancy test is to be performed 
on Cycle 1 Day 1 (- 3 days).  The pregnancy test can 
be performed any day from -3 days prior to Cycle 1 
Day 1 or on the same day as Cycle 1 Day 1. 
 
 
 
 
Added the following footnote “t”: 
 
t. Per protocol, the first 6 subjects randomized to 
Arm 1 (ACP-196 + nab paclitaxel/gemcitabine) are 
dosed with ACP-196 first at Cycle 1 Day -1.  For these 
6 subjects, hematology, serum chemistry/CA 19-9, 
and coagulation panel must be performed and 
analyzed within 7 days before this first dose of ACP-
196.  Additionally, a urine pregnancy test must be 
performed and analyzed within 1 day of the Cycle 1 
Day -1 first dose of ACP-196.  These 4 labs may be 
performed either locally, or using the central 
laboratory. 
 
 
Added hepatitis serology at screening and HBV PCR 
testing monthly, and added the following associated 
footnotes “u” and “v”: 
u. Hepatitis serology must include hepatitis B surface 
antigen (HBsAg), hepatitis B surface antibody 
(HBsAb), hepatitis B core antibody (anti-HBc), and 
hepatitis C (HCV) antibody.  In addition, any subjects 
testing positive for any hepatitis serology, must have 
PCR testing (see exclusion criterion #15). 
 
v. Subjects who are anti-HBc positive (or have a 
known history of HBV infection) should be monitored 
monthly with a quantitative PCR test for HBV DNA.  
Monthly monitoring should continue until 12 months 
after last dose of study drug(s).  Any subject with a 
rising viral load (above lower limit of detection) 
should discontinue study drug(s) and have antiviral 
therapy instituted and a consultation with a physician 
with expertise in managing hepatitis B. 
 
 
 
 
 
 
 
Revised to add these lab 
assessments at Cycle 1 
Day -1. 
 
 
 
 
 
 
 
 
 
 
 
 
As HBV reactivation has 
occurred in 1 subject on 
acalabrutinib treatment 
hepatitis serology at 
screening and monthly 
HBV PCR testing are 
being added to ensure 
adequate monitoring of 
patients with a history of 
HBV. 
 
 
 
 
 
 
 
 
 
 


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
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TABLE OF CONTENTS 
STUDY SYNOPSIS ............................................................................. 16 
1.0 
BACKGROUND INFORMATION .................................................................. 25 
1.1 
Pancreatic Cancer ............................................................................... 25 
1.2 
The Role of Stroma in Pancreatic Cancer ........................................... 25 
1.3 
Bruton Tyrosine Kinase Inhibition in Cancer ........................................ 26 
1.4 
ACP-196 .............................................................................................. 31 
1.4.1 
Mechanism of Action .............................................................. 32 
1.4.2 
Safety Pharmacology ............................................................. 33 
1.4.3 
Drug-drug Interaction Potential .............................................. 34 
1.5 
In Vivo General Toxicology – ACP-196 ............................................... 34 
1.6 
Clinical Experience – ACP-196 ............................................................ 35 
1.6.1 
Pharmacokinetics and Pharmacodynamics of ACP-196 ........ 35 
1.6.2 
ACP-196 in CLL ..................................................................... 37 
1.7 
Nab-paclitaxel/gemcitabine .................................................................. 39 
1.8 
Benefit/Risk .......................................................................................... 40 
2.0 
STUDY OBJECTIVES ................................................................................... 41 
2.1 
Primary Objective ................................................................................ 41 
2.2 
Secondary Objectives .......................................................................... 41 
2.3 
Exploratory Objectives ......................................................................... 41 
3.0 
STUDY DESIGN ............................................................................................ 41 
3.1 
Study Parameters ................................................................................ 44 
3.1.1 
Safety Parameters .................................................................. 44 
3.1.2 
Pharmacodynamic, Pharmacokinetic, and Biomarker 
Parameters ............................................................................. 44 
3.1.3 
Efficacy Parameters ............................................................... 45 
3.2 
Rationale for Study Design and Dosing Regimen ................................ 45 
3.3 
Selection of Study Population .............................................................. 46 
3.3.1 
Inclusion Criteria..................................................................... 46 
3.3.2 
Exclusion Criteria ................................................................... 47 
3.3.3 
Replacement of Subjects ....................................................... 48 
3.3.4 
Enrollment Procedures ........................................................... 48 
3.4 
Study Drugs ......................................................................................... 49 
3.4.1 
Premedications....................................................................... 49 
3.4.2 
Formulation, Packaging, and Storage .................................... 49 
3.4.3 
Administration of Study Drug .................................................. 49 
3.4.4 
Assuring Subject Compliance ................................................ 50 
3.5 
Study Treatment Schedule .................................................................. 51 


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
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3.5.1 
Arm 1 – ACP-196 + Nab-paclitaxel/Gemcitabine ................... 51 
3.5.2 
Arm 2 – Nab-paclitaxel/Gemcitabine ...................................... 51 
3.6 
Duration of Therapy ............................................................................. 51 
3.7 
Assessment of Dose-Limiting Toxicity (DLT) ....................................... 52 
3.8 
Dosing Delays and Modifications ......................................................... 52 
3.8.1 
Dose Modification and Discontinuation of ACP-196 ............... 53 
3.8.2 
Dose Modification and Discontinuation of 
Nab-paclitaxel/Gemcitabine ................................................... 54 
3.9 
Concomitant Therapy .......................................................................... 55 
3.9.1 
Permitted Concomitant Therapy ............................................. 55 
3.9.2 
Prohibited or Restricted Concomitant Therapy ....................... 56 
3.10 
Precautions .......................................................................................... 56 
3.10.1 Hepatitis B Reactivation ......................................................... 56 
3.10.2 Dietary Restrictions ................................................................ 56 
3.10.3 Drug-drug Interactions ............................................................ 56 
3.10.4 Surgery ................................................................................... 57 
3.10.5 Reproductive Toxicity ............................................................. 58 
3.10.6 Overdose Instructions ............................................................ 58 
3.11 
Withdrawal of Subjects from Study Treatment ..................................... 59 
3.12 
Reasons for Study Exit ........................................................................ 60 
3.13 
Data and Safety Monitoring ................................................................. 60 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ................................................. 60 
4.1 
Description of Procedures.................................................................... 61 
4.1.1 
Informed Consent ................................................................... 61 
4.1.2 
Medical History ....................................................................... 61 
4.1.3 
Adverse Events ...................................................................... 61 
4.1.4 
Concomitant Medications and Therapy .................................. 61 
4.1.5 
Confirmation of Eligibility ........................................................ 61 
4.1.6 
ECOG Performance Status .................................................... 62 
4.1.7 
Physical Examination, Vital Signs, Height & Weight ............... 62 
4.1.8 
Electrocardiogram .................................................................. 62 
4.1.9 
Urine or Serum Pregnancy Test ............................................. 62 
4.1.10 Hematology ............................................................................ 62 
4.1.11 Serum Chemistry .................................................................... 62 
4.1.12 Amylase and Lipase ............................................................... 63 
4.1.13 Coagulation ............................................................................ 63 
4.1.14 Hepatitis B and C Testing ....................................................... 63 
4.1.15 Urinalysis ................................................................................ 63 
4.1.16 T/B/NK/Monocyte Cell Count ................................................. 63 


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
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4.1.17 Disease Markers .................................................................... 63 
4.1.18 Pharmacodynamics/Pharmacokinetics and Biomarker 
Studies ................................................................................... 63 
4.1.19 Tumor Assessments ............................................................... 64 
4.1.20 Treatment Termination Visit ................................................... 65 
4.1.21 Study Drug Accountability ...................................................... 65 
4.2 
Investigator’s Assessment of Response to Treatment ......................... 66 
4.2.1 
Determination of Response at Each Timepoint (RECIST) ...... 67 
4.2.2 
Confirmation of Tumor Status and Determination of Best 
Overall Response (RECIST) .................................................. 67 
4.3 
Safety Follow-up Visit .......................................................................... 68 
4.4 
Survival ................................................................................................ 68 
4.5 
Missed Evaluations .............................................................................. 69 
5.0 
STATISTICAL METHODS OF ANALYSIS .................................................... 69 
5.1 
General Considerations ....................................................................... 69 
5.2 
Definition of Analysis Sets ................................................................... 70 
5.3 
Missing Data Handling ......................................................................... 70 
5.4 
Endpoint Data Analysis ........................................................................ 70 
5.4.1 
Safety Endpoint ...................................................................... 70 
5.4.2 
Demographics and Baseline Characteristics .......................... 71 
5.4.3 
Study Treatment Administration and Compliance .................. 71 
5.4.4 
Analysis of Efficacy Parameters ............................................. 71 
5.4.5 
Pharmacodynamic or Biomarker Analyses ............................. 72 
5.5 
Futility and Toxicity Monitoring ............................................................. 73 
6.0 
ASSESSMENT OF SAFETY ......................................................................... 74 
6.1 
Definitions ............................................................................................ 75 
6.1.1 
Adverse Events ...................................................................... 75 
6.1.2 
Serious Adverse Event ........................................................... 75 
6.1.3 
Severity .................................................................................. 76 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events 76 
6.2.1 
Adverse Event Reporting Period ............................................ 76 
6.2.2 
Assessment of Adverse Events .............................................. 77 
6.2.3 
Pregnancy .............................................................................. 77 
6.2.4 
Expedited Reporting Requirements for Serious Adverse 
Events .................................................................................... 78 
6.2.5 
Type and Duration of Follow-up of Subjects after Adverse 
Events .................................................................................... 79 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ............. 79 
7.1 
Institutional Review Board and Independent Ethics Committee........... 80 


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Date:  01 February 2016 
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7.2 
Informed Consent and Protected Subject Health Information 
Authorization ........................................................................................ 80 
7.3 
Subject Screening Log ......................................................................... 81 
7.4 
Case Report Forms ............................................................................. 81 
7.5 
Study Monitoring Requirements ........................................................... 81 
7.6 
Investigational Study Drug Accountability ............................................ 82 
7.7 
Record Retention ................................................................................. 83 
7.8 
Protocol Amendments ......................................................................... 83 
7.9 
Publication of Study Results ................................................................ 84 
7.10 
Clinical Trial Insurance ........................................................................ 84 
7.11 
General Investigator Responsibilities ................................................... 84 
8.0 
REFERENCES .............................................................................................. 86 
9.0 
APPENDICES ............................................................................................... 89 
 
 
 


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
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IN–TEXT TABLES 
 
Table 1-1. Potency of ACP-196 and Ibrutinib on Group of 3F-Cys Kinases .............33 
Table 1-2. Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001 .........38 
Table 1-3. Preliminary Day 8 PK Results from ACE-CL-001 (December 2014) .......39 
Table 1-4. Best Response by Cohort from ACE-CL-001 (December 2014)..............39 
Table 3-1. Dose Reductions for Arm 1 .....................................................................52 
Table 3-2. Drug Discontinuation Actions for ACP-196 .............................................53 
Table 3-3. Dose Reductions for Arm 2 .....................................................................54 
Table 3-4. Dose Modifications of Nab-paclitaxel/Gemcitabine for Neutropenia and/or 
Thrombocytopenia ..................................................................................55 
Table 3-5. Dose Modifications of Nab-paclitaxel/Gemcitabine for Other Adverse Drug 
Reactions ...............................................................................................55 
Table 4-1. Evaluation of Target Lesions (RECIST) ..................................................66 
Table 4-2. Evaluation of Nontarget Lesions (RECIST) .............................................66 
Table 4-3. Timepoint Response (RECIST)...............................................................67 
Table 4-4. Best Overall Response Assessment and Requirements for Confirmation 
(RECIST) ................................................................................................68 
Table 5-1.  Stopping Boundaries for ACP-196 Toxicity Monitoring (Applies to Arm 1 
Only) .......................................................................................................74 
Table 5-2.  Operating Characteristics of the Design ..................................................74 
 
IN–TEXT FIGURES 
 
Figure 1-1. Efficacy of ACP-196 Monotherapy in a Genetic Model of Pancreatic 
Cancer ....................................................................................................28 
Figure 1-2. Effects of ACP-196 on Tumor-Associated  Immunosuppressive Cells in a 
Genetic Model of Pancreatic Cancer ......................................................28 
Figure 1-3. Effects of ACP-196 on Cytolytic T Cells in a Genetic Model of Pancreatic 
Cancer ....................................................................................................29 
Figure 1-4. ACP-196 Impairs ID8 Ovarian Cancer Growth and Decreased 
Immunosuppressive Cellular Subsets in Syngeneic Murine Model .........29 
Figure 1-5.  Efficacy of ACP-196 Monotherapy in a Genetic Model of Lung Cancer ..30 
Figure 1-6. Efficacy of ACP-196 Monotherapy and Combination Therapy  with 
Gemcitabine in an Orthotopic Model of Pancreatic Cancer .....................31 
Figure 3-1. Study Schema ........................................................................................43 
 
LIST OF APPENDICES 
 
Appendix 1. 
RECIST 1.1 Guidelines .......................................................... 90 
Appendix 2. 
Nab-paclitaxel Prescribing Information ................................. 111 
Appendix 3. 
Gemcitabine Prescribing Information ................................... 135 
Appendix 4. 
Performance Status Scores ................................................. 154 
Appendix 5. 
Known Strong In Vivo Inhibitors or Inducers of CYP3A or 
CYP2C8 ............................................................................................. 155 
Appendix 6. 
Adverse Event Assessment of Causality .............................. 156 
Appendix 7. 
Schedule of Assessments .................................................... 157 


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ABBREVIATIONS  
5-FU 
5-fluorouracil 
AE 
adverse event 
Akt 
protein kinase b 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BCR 
B-cell receptor 
BID 
twice per day (dosing) 
BOR 
best overall response 
Btk 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CA19-9 
cancer antigen 19-9 (carbohydrate antigen 19-9) 
CD 
cluster of differentiation (cell surface marker) 
cGMP 
current Good Manufacturing Practice 
CI 
confidence interval 
CL/F 
oral clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response (remission) 
CSSF 
Clinical Supplies Shipping Receipt Form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria For Adverse Events 
CTLA-4 
cytotoxic t-lymphocyte-associated protein 4 
CYP 
cytochrome p450 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
FDA 
Food And Drug Administration 
FOLFIRINOX 
leucovorin, irinotecan, and oxaliplatin 
GCP 
Good Clinical Practice 


Product: ACP-196 (acalabrutinib) 
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GLP 
Good Laboratory Practice 
HABP 
hyaluronic-acid binding protein 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICF 
Informed Consent Form 
IEC 
independent ethics committee 
IND 
investigational new drug application 
IRB 
institutional review board 
IRR 
Independent Radiology Review 
ITT 
intent-to-treat (analysis set) 
IV 
intravenous or intravenously  
IXRS 
Interactive Voice/Web Response System  
Jak 
Janus kinase 
λz 
terminal elimination rate constant  
LDH 
lactate dehydrogenase 
MDSC 
myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
NE 
nonevaluable 
NK 
natural killer (cells) 
NOAEL 
no-observed-adverse-effect level 
OAT 
organic anion transporter  
OCT 
organic cationic transporter  
ORR 
overall response rate 
OS 
overall survival 
PBMCs 
peripheral blood mononuclear cells  
PCR 
polymerase chain reaction 
PD 
progressive disease or pharmacodynamics 
PD-1 
programmed death-1 (receptor) 
PD-L1 
programmed death ligand-1 
PDX-1 
Pancreatic and duodenal homeobox 1 
PE 
physical exam 


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PFS 
progression-free survival 
P-gp 
p-glycoprotein 1 (transporter) 
PI3K 
phosphatidylinositol-3 kinase 
PK 
pharmacokinetic or pharmacokinetics 
PO 
per os (oral) 
PP 
per-protocol (analysis set) 
PR 
partial response (remission) 
PR+L 
partial response with lymphocytosis 
PT 
prothrombin time  
Q3W 
every three weeks 
Q12W 
every 12 weeks 
QD 
once per day (dosing) 
QM 
every month 
QT 
cardiac QT interval 
QTc 
corrected cardiac QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease or standard deviation 
SLL 
small lymphocytic leukemia 
SMA 
smooth muscle actin 
SUSAR 
suspected unexpected serious adverse reaction 
Syk 
spleen tyrosine kinase 
t½ 
terminal elimination half-life 
TAM 
tumor-associated macrophage 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
Treg 
regulatory T cell (lymphocyte) 
ULN 
upper limit of normal 
Vz 
volume of distribution 
Vz/F 
oral volume of distribution 
WHODRUG 
World Health Organization Drug Dictionary 


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STUDY SYNOPSIS 
Protocol Number: 
ACE-ST-004 
Study Drug: 
ACP-196 (acalabrutinib) 
Comparator Drugs: 
Nab-paclitaxel: paclitaxel protein-bound particles for injectable 
suspension 
Gemcitabine for injection 
Protocol Title: 
A Phase 2, Randomized, Proof-of-Concept Study of  
Nab-Paclitaxel/Gemcitabine Alone and in Combination With 
ACP-196 in Subjects with Previously Untreated Metastatic 
Pancreatic Cancer 
Phase: 
Phase 2 
Study Centers: 
Subjects will be enrolled at up to 30 centers globally. 
Background and 
Rationale for Study 
Pancreatic ductal adenocarcinoma exists in a complex 
desmoplastic microenvironment that provides stromal support 
for tumor growth and conceals the tumor from immune 
surveillance.  Tumor-associated stroma comprises a mix of 
fibroblasts and an abundance of mast cells, 
immunosuppressive regulatory T cells (Tregs), myeloid-derived 
suppressor cells (MDSCs), and tumor-associated 
macrophages (TAMs) that promote tumor growth and restrain 
immunologically mediated tumor cell killing.   
Bruton tyrosine kinase (Btk) is a non-receptor enzyme of the 
Tec kinase family that is expressed in B cells, myeloid cells, 
and mast cells, where it regulates cellular proliferation, 
differentiation, apoptosis, and cell migration.  Btk inhibition 
leads to preferential differentiation of macrophages into M1 
instead of immunosuppressive M2 macrophages; Btk 
inhibition thus decreases the tumor-associated macrophages 
that promote tumor invasion and metastasis.   
Acerta Pharma BV is developing ACP-196, an orally 
bioavailable, small-molecule inhibitor of Btk.  A Phase 1 study 
of ACP-196 in 31 subjects with relapsed/refractory chronic 
lymphocytic leukemia showed an overall response rate of 
94%.  ACP-196 monotherapy has shown robust antitumor 
activity in murine solid tumor models, including models of 
pancreatic cancer.  Treatment with single-agent ACP-196 
substantially slowed tumor growth and increased animal 
survival in a murine pancreatic cancer model.  Further, the 
combination of ACP-196 and gemcitabine resulted in a greater 
reduction in tumor growth when compared to each single 
agent.  The antitumor effect observed with ACP-196 
correlates with biomarkers of response similar to those 
reported for other immunomodulating agents such as 
inhibitors of cytotoxic t-lymphocyte-associated protein 4 


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(CTLA-4), programed cell death receptor (PD-1) and its ligand 
(PD1-L). 
The combination of nab-paclitaxel and gemcitabine has 
demonstrated statistically significant improvement in overall 
survival (OS), progression-free survival (PFS) and overall 
response rate (ORR) as compared with gemcitabine alone in 
first-line treatment of metastatic adenocarcinoma of the 
pancreas.  This proof-of-concept study will assess the clinical 
potential of ACP-196 in combination with nab-paclitaxel and 
gemcitabine by evaluating the safety, pharmacodynamics 
(PD), pharmacokinetics (PK), and efficacy of the ACP-196 
combination in subjects with previously untreated metastatic 
pancreatic cancer.   
Study Design: 
This clinical trial is a Phase 2, multicenter, open-label, 
randomized study evaluating ACP-196 plus 
nab-paclitaxel/gemcitabine compared with 
nab-paclitaxel/gemcitabine in subjects who have previously 
untreated metastatic pancreatic cancer.   
Subjects meeting the eligibility criteria for the study will be 
randomized 1:1 using an Interactive Voice/Web Response 
System (IXRS) to one of the following arms: 
Arm 1:  ACP-196 100 mg administered orally (PO) twice per 
day (BID) on Days 1-28 and nab-paclitaxel 125 mg/m2 + 
gemcitabine 1000 mg/m2 on Days 1, 8, and 15; cycles are 
repeated every 28 days. 
Arm 2:  Nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 
on Days 1, 8, and 15; cycles are repeated every 28 days. 
Although ACP-196 has not demonstrated any dose-limiting 
toxicities (DLTs) to date, the safety of ACP-196 in combination 
with nab-paclitaxel/gemcitabine in this patient population 
needs to be assessed and standard DLT criteria will be 
applied to Arm 1 of the study.  Therefore an interim safety 
analysis will occur once 12 subjects (6 subjects per arm) have 
been successfully randomized and have been treated a 
minimum of 1 cycle (1 cycle = 28 days).  Enrollment will be 
paused while the safety interim analysis occurs.   
If ≤ 1 DLT is observed in Arm 1, then randomization will 
continue to evaluate the safety and efficacy of the ACP-196 
combination (ie, up to 60 subjects per arm).  If ≥ 2 DLTs are 
observed in Arm 1, then enrollment will continue until an 
additional 6 subjects are randomized to Arm 1, but with a 
reduced dose level for ACP-196 (Level -1).  If the DLT review 
is cleared in those additional 6 subjects in Arm 1 then 
continued enrollment will occur at Level -1 for the ACP-196 
combination arm.  If ≥ 2 DLTs are observed in Arm 1 at 
Level -1, then an additional 6 subjects will be randomized at 
Level -2 and assessed for DLTs.  If the DLT review is cleared, 
continued enrollment will occur at Level -2 for the ACP-196 
combination arm.  If the DLT review is not cleared, enrollment 


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will be halted.  In addition, analyses for toxicity will also be 
done as outlined in Section 5.5. 
Treatment can continue until the end of trial, defined as 
52 weeks (13 cycles) after the last subject is randomized to 
the study, for subjects who are tolerating therapy and not 
progressing.  Subjects who have confirmed progressive 
disease will discontinue study treatment. The primary efficacy 
analysis will be based on Investigator assessment.  
Independent radiology review (IRR) of the efficacy data will 
also be performed in accordance with the independent 
radiology review (IRR) charter.  Refer to Appendix 7 for a 
comprehensive list of study assessments and their timing.  A 
study schema is provided in Figure 3-1. 
Definition of Dose-
limiting Toxicity: 
A DLT will be defined as the occurrence of any of the following 
ACP-196-related adverse events (AEs) (note:  AEs clearly 
related to disease progression or the subject’s current medical 
history and associated comorbidities will not be considered 
DLTs): 
1. Grade 4 vomiting or diarrhea 
2. Grade 3 nausea, vomiting, or diarrhea lasting for 
> 72 hours 
3. Other Grade ≥ 3 toxicities (Note:  Transient Grade 3/4 
laboratory abnormalities, including chemotherapy 
induced myelosuppression, that are not clinically 
significant will not be considered DLTs)  
4. Dosing delay due to toxicity for > 21 consecutive days.   
Study Objectives: 
Primary Objective: 
To evaluate the efficacy of ACP-196 and 
nab-paclitaxel/gemcitabine based on ORR in subjects with 
metastatic pancreatic cancer using standard response criteria. 
Secondary Objective: 
To characterize the safety profile of ACP-196 and 
nab-paclitaxel/gemcitabine in subjects with metastatic 
pancreatic cancer. 
Exploratory Objectives: 
• 
 
 
 
 
 
 
 
 
  


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• 
 
Safety Endpoints: 
Type, frequency, severity, timing of onset, duration, and 
relationship to study drug of any treatment-emergent adverse 
events (TEAEs) or abnormalities of laboratory tests, serious 
adverse events (SAEs), DLTs or AEs leading to 
discontinuation of study treatment. 
Pharmacodynamic, 
Pharmacokinetic and 
Biomarker 
Parameters: 
The occupancy of Btk by ACP-196 will be measured in 
peripheral blood mononuclear cells (PBMCs) with the aid of a 
biotin-tagged ACP-196 analogue probe.  The effect of 
ACP-196 and nab-paclitaxel/gemcitabine on B cells, T cells, 
and MDSCs will also be evaluated.  Tumor tissue will be 
evaluated for various tumor markers, including but not limited 
to: 
• 
hyaluronic-acid binding protein (HABP) 
• 
smooth muscle actin (SMA)  
• 
Ki67 proliferation 
• 
cleaved-caspase 3  
• 
PD-1 and its ligand PD1-L 
ACP-196 will be measured in blood plasma. 
Efficacy Endpoints: 
• 
ORR defined as partial response (PR) or complete 
response (CR) based on modified Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 criteria  
• 
Duration of response (DOR) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
Change in serum cancer antigen 19-9 (CA19-9) 
Sample Size: 
 
 
  
 
 
   
Inclusion Criteria: 
1. Men and women ≥ 18 years of age. 
2. Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 
3. Histologically or cytologically confirmed metastatic 
adenocarcinoma of the pancreas.  


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4. Presence of radiographically measurable disease per 
RECIST 1.1. 
5. No previous radiotherapy, chemotherapy or 
investigational therapy for the treatment of metastatic 
disease.  Prior treatment with 5-fluorouracil (5-FU) or 
gemcitabine administered as a radiation sensitizer in 
the adjuvant setting is allowed, provided at least 
6 months have elapsed since completion of the last 
dose and no lingering toxicities are present. 
6. Women who are sexually active and can bear children 
must agree to use highly effective forms of 
contraception during the study and for 90 days after the 
last dose of ACP-196 or 4 months after the last dose of 
nab-paclitaxel/gemcitabine, whichever is longer.  Highly 
effective forms of contraception are defined in Section 
3.10.5. 
7. Men who are sexually active and can beget children 
must agree to use highly effective forms of 
contraception during the study and for 90 days after the 
last dose of ACP-196 or 4 months after the last dose of 
nab-paclitaxel/gemcitabine, whichever is longer.  Highly 
effective forms of contraception are defined in Section 
3.10.5. 
8. Men must agree to refrain from sperm donation during 
the study and for 90 days after the last dose of 
ACP-196 or 4 months after the last dose of 
nab-paclitaxel/gemcitabine, whichever is longer. 
9. Willing and able to participate in all required evaluations 
and procedures in this study protocol including 
swallowing capsules without difficulty. 
10. Ability to understand the purpose and risks of the study 
and provide signed and dated informed consent and 
authorization to use protected health information (in 
accordance with national and local subject privacy 
regulations) 
Exclusion Criteria: 
1. Prior malignancy (other than pancreatic cancer), except 
for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, or other cancer from 
which the subject has been disease free for ≥ 2 years.  
Note:  These cases must be discussed with the medical 
monitor. 
2. Known central nervous system (CNS) metastases 
and/or carcinomatous meningitis.   
3. Significant cardiovascular disease such as uncontrolled 
or symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of screening, or 
any Class 3 or 4 cardiac disease as defined by the New 
York Heart Association Functional Classification, or 
corrected QT interval (QTc) > 480 msec at screening. 


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4. Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or 
small bowel, symptomatic inflammatory bowel disease, 
partial or complete bowel obstruction, or gastric 
restrictions and bariatric surgery, such as gastric 
bypass.  Note:  Subjects with prior 
pancreatoduodenectomy are not excluded. 
5. Biliary obstruction or presence of a percutaneous biliary 
drain.  Note:  Subjects with endobiliary stents may 
participate as long the enrollment criterion relating to 
serum bilirubin concentration is met. 
6. Prior therapy with any inhibitor of Btk, protein kinase B 
(Akt), Janus kinase (Jak), mammalian target of 
rapamycin (mTOR), phosphatidylinositol-3 kinase 
(PI3K), or spleen tyrosine kinase (Syk). 
7. History of interstitial lung disease or active 
non-infectious pneumonitis. 
8. History of bleeding diathesis (eg, hemophilia or von 
Willebrand disease). 
9. Major surgical procedure within 28 days of first dose of 
study drug. 
10. Known hypersensitivity to gemcitabine or 
nab-paclitaxel. 
11. Requires treatment with proton-pump inhibitors (eg, 
omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole). 
12. Requires treatment with a strong cytochrome P450 
(CYP) 3A or CYP2C8 inhibitor/inducer. 
13. Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonists (eg, phenprocoumon) 
within 7 days of first dose of study drug. 
14. Ongoing immunosuppressive therapy, including 
systemic or enteric corticosteroids.  Note:  At screening 
and during study participation, subjects may use topical 
or inhaled corticosteroids or systemic corticosteroids at 
dosages equivalent to prednisone ≤ 10 mg/day as 
therapy for comorbid conditions.  
15. Known history of human immunodeficiency virus (HIV) 
or serologic status indicating active hepatitis C virus 
(HCV) or hepatitis B virus (HBV) infection or any 
uncontrolled active systemic infection.  Subjects with 
hepatitis B core antibody positive who are surface 
antigen negative or who are hepatitis C antibody 
positive will need to have a negative polymerase chain 
reaction (PCR) result before enrollment.  Those who 
are hepatitis B surface antigen positive or hepatitis B 
PCR positive and those who are hepatitis C PCR 
positive will be excluded.   


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16. History of stroke or intracranial hemorrhage within 
6 months before the first dose of study drug. 
17. Absolute neutrophil count (ANC) < 1.5 x 109/L or 
platelet count < 100 x 109/L or hemoglobin < 9.0 g/dL. 
18. Total bilirubin > upper limit of normal (ULN); and 
aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) > 3.0 x ULN. 
19. Prothrombin time (PT) and activated partial 
thromboplastin time (aPTT) > 1.2 x the ULN. 
20. Estimated creatinine clearance of < 30 mL/min, 
calculated using the formula of Cockcroft and Gault 
[(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply 
by 0.85 if female]. 
21. Breastfeeding or pregnant. 
22. Concurrent participation in another therapeutic clinical 
trial. 
23. Presence of a gastrointestinal ulcer diagnosed by 
endoscopy within 3 months before screening. 
Dose Regimen/Route 
of Administration: 
ACP-196 is provided as hard gelatin capsules for oral 
administration.   
Nab-paclitaxel is supplied as lyophilized powder containing 
100 mg of paclitaxel formulated as albumin-bound particles in 
single-use vial for reconstitution.  It is administered as an IV 
infusion over 30 to 40 minutes. 
Gemcitabine is supplied in 200-mg and 1000-mg vials as a 
sterile lyophilized powder for reconstitution.  It is administered 
as an IV infusion over 30 to 40 minutes immediately after 
nab-paclitaxel. 
Arm 1 (ACP-196 plus nab-paclitaxel/gemcitabine): 
ACP-196 
Dose Level 
ACP-196 
Dosing Regimen 
Nab-
paclitaxel/gemcitabine 
Starting Dose 
100 mg BID PO 
See Arm 2 
Level -1 
100 mg QD PO 
See Arm 2 
Level -2 
50 mg BID PO 
See Arm 2 
Abbreviations: BID = twice per day; PO = oral; QD = once per day 
Note: 1 cycle of ACP-196 treatment is 28 days. 
Arm 2 (nab-paclitaxel/gemcitabine):  
Nab-paclitaxel 125 mg/m2 intravenous (IV) infusion on Day 1, 
8 and 15 of every 28-day cycle. 


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Gemcitabine 1000 mg/m2 IV infusion on Day 1, 8 and 15 of 
every 28-day cycle. 
Dose Level 
Nab-paclitaxel 
(mg/m2) 
Gemcitabine 
(mg/m2) 
Starting Dose 
125 
1000 
Level -1 
100 
800 
Level -2 
75 
600 
If additional dose 
reduction required 
Discontinue 
Discontinue 
Concomitant 
Medications: 
The concomitant use of strong inhibitors/inducers of CYP3A 
with ACP-196 should be avoided when possible.  The effect of 
agents that reduce gastric acidity (eg, proton-pump inhibitors, 
H2-receptor antagonists or antacids) on ACP-196 absorption 
was evaluated in a healthy volunteer study (ACE-HV-004).  
Results from this study indicate that subjects should avoid the 
use of calcium carbonate-containing drugs or supplements 
and short-acting H2-receptor antagonists for a period of at 
least 2 hours before and after taking ACP-196.  Use of 
omeprazole, esomeprazole, lansoprazole or any other proton-
pump inhibitors (eg, dexlansoprazole, rabeprazole, or 
pantoprazole) while taking ACP-196 is not recommended due 
to a potential decrease in study drug exposure.  Caution 
should be exercised when administering nab-paclitaxel 
concomitantly with medicines known to inhibit or induce either 
CYP2C8 or CYP3A. 
Statistical Methods: 
Analysis Methods 
Descriptive statistics (including means, standard deviations, 
and medians for continuous variables and proportions and 
confidence intervals [CIs] for discrete variables) will be used to 
summarize data as appropriate. 
Statistical Basis for the Sample Size 
For the safety interim analysis (DLT review), enrollment of 
6 subjects in the combination arm for DLT review is consistent 
with sample sizes used in oncology studies for determination 
of maximum tolerated dose (MTD).  The trial employs the 
standard National Cancer Institute definition of MTD (dose 
associated with DLT in ≤ 17% of subjects).  Provided the 
study is not stopped early due to toxicity in the ACP-196 
combination arm, then a total of 60 subjects will be 
randomized per arm.   
The sample size for this 2-arm trial was determined by a 
Z-test for normal approximation of binomial distribution, based 
on one-sided α = 0.10, 80% power, with projected response 
rates of 42% in the ACP-196 combination arm and 23% in 


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nab-paclitaxel/gemcitabine arm.  Accounting for 10% drop-out 
rate (6 in each arm), final sample size is 60 in each arm. 


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1.0 
BACKGROUND INFORMATION 
1.1 
PANCREATIC CANCER 
In 2014, ~46,420 people in the United States will be diagnosed with pancreatic cancer 
(Siegel 2014).  Because of the aggressive nature of this cancer, the annual mortality 
rates almost matches the incidence rate, and it is expected that ~39,590 will die from 
this disease in the same year.  For the 20% of patients with disease involving only the 
pancreas, surgical resection is the primary therapy.  In the ~80% of patients with 
regional disease extension or metastases at presentation, chemotherapy is the 
primary treatment (Tempero 2014).  Among the therapeutic options, 
polychemotherapy with infusional 5-fluorouracil (5-FU), leucovorin, irinotecan, and 
oxaliplatin (FOLFIRINOX) or gemcitabine plus albumin-bound paclitaxel 
(nab-paclitaxel) are commonly employed (Tempero 2014).  Erlotinib in combination 
with gemcitabine has also been approved for front-line treatment of pancreatic cancer 
(TARCEVA prescribing information).   
In the Phase 3 study, nab-paclitaxel + gemcitabine was tolerable and demonstrated 
superiority to gemcitabine alone for all efficacy endpoints in patients with metastatic 
pancreatic cancer.  This trial met the study’s primary endpoint by demonstrating a 
significant improvement in OS (median 8.5 vs 6.7 months; hazard ratio [HR] 0.72; 
95% CI, 0.617 to 0.835; P < 0.001) and the secondary endpoints of PFS (median 
5.5 vs 3.7 months; HR 0.69; 95% CI, 0.581 to 0.821; P < 0.001) and ORR (23% vs 
7%; P < 0.001) (Von Hoff 2013).   
However, because of the inherent chemoresistance of pancreatic cancer, median 
PFS with currently available regimens is ≤ 6 months (Conroy 2011, Von Hoff 2013).  
Moreover, while antitumor benefit has been observed with such regimens, toxicity is 
substantial.  Novel, less toxic approaches are desperately needed for this lethal 
cancer. 
1.2 
THE ROLE OF STROMA IN PANCREATIC CANCER  
The importance of pancreatic cancer stroma in the biology of pancreatic cancer has 
been increasingly recognized (Feig 2012, Rucki 2014, Wilson 2014).  Pancreatic 
ductal adenocarcinoma exists in a complex desmoplastic microenvironment that 
provides stromal support for tumor growth and conceals the tumor from immune 
surveillance.  Tumor-associated stroma comprises a mix of fibroblasts (pancreatic 
stellate cells) and an abundance of mast cells, immunosuppressive Tregs, MDSCs, and 


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TAMs that promote tumor growth and restrain immunologically mediated tumor cell 
killing (Shibuya 2014).  Pancreatic cancers secrete chemokines that recruit immune 
cells to the tumor site.  These immune cells are then activated either by direct contact 
or by cancer cell–derived triggers to selectively release “procancer” mediators (Feig 
2012, Ma 2014).  These mediators induce angiogenesis, promote tumor proliferation, 
inhibit antitumor responses, and alter the surrounding stroma to permit metastases.  
Treatment of tumor-bearing mice with agents that block immunocyte migration and 
function has been shown to decrease the growth of pancreatic cancer (Ma 2014, 
Shibuya 2014).   
1.3 
BRUTON TYROSINE KINASE INHIBITION IN CANCER 
Btk is a non-receptor enzyme in the Tec kinase family that is expressed among cells 
of hematopoietic origin, including B cells, myeloid cells, mast cells and platelets, 
where it regulates multiple cellular processes including proliferation, differentiation, 
apoptosis, and cell migration (Khan 2001, Mohamed 2009, Bradshaw 2010).  In 
addition, Btk-dependent activation of mast cells, myeloid cells and other immunocytes 
in peritumoral inflammatory stroma has been shown to sustain the complex 
microenvironment needed for lymphoid and solid tumor maintenance (Soucek 2011, 
Ponader 2012, de Rooij 2012).  Taken together, these findings suggest inhibition of 
Btk may offer an attractive strategy for treating B-cell neoplasms, other hematologic 
malignancies, and solid tumors.   
In model systems, ex vivo analyses demonstrated Btk inhibition results in 
macrophages that polarize into M1 macrophages, instead of showing enhanced 
induction of immunosuppressive M2 macrophages (Ni Gabhann 2014).  These data 
suggest inhibition of Btk may impair the capacity of tumor-associated macrophages 
critical for promotion of tumor invasion and metastasis (Mouchemore 2013).  Several 
lines of evidence demonstrate Btk inhibition interferes with cross-talk between 
malignant cells and their microenvironment, suggesting disruption of intrinsic and 
extrinsic survival signals may be a critical mechanism for the clinical activity of Btk 
inhibitors (Ponader 2012, Herman 2013).  Furthermore, epithelial derived tumors 
contain large numbers of TAMs, which are the dominant innate immune cell in 
mammary cancers of humans (Pollard 2009).  Therefore, the clinical usefulness of Btk 
inhibitors may extend to the treatment of invasive solid tumors. 


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Btk is also a signaling hub in immature myeloid cells known as MDSCs (Schmidt 
2004).  Recent evidence suggests MDSCs play an important part in suppression of 
host immune responses through several mechanisms such as production of 
arginase 1, release of reactive oxygen species, nitric oxide and secretion of 
immune-suppressive cytokines.  This leads to an immunosuppressive environment 
necessary for the growth of malignant cells (Wesolowski 2013).   
Immune evasion is one of the multiple characteristics of cancer.  Monoclonal 
antibodies that block negative regulators of T cells, such as PD-1, amplify immune 
responses.  Antibodies against PD-1 are showing impressive results in advanced 
hematologic and solid malignancies (Hamid 2013, Westin 2014, Berger 2008, 
Topalian 2014).  Interestingly, studies examining circulating MDSCs in anti-CTL4 and 
anti-PD-1/PD-L1-treated patients have shown alterations in the myeloid cell 
compartment correlate with clinical outcome.  Specifically, solid tumor progressors 
had proportionally higher circulating MDSC levels and a high myeloid gene signature 
(Powles 2014, Heery 2014, Weide 2014, Meyer 2014).  Recent preclinical results 
show elevated MDSC levels are responsible for this lack of response and elimination 
of MDSCs may lead to increased efficacy with immune checkpoint blockade (Highfill 
2014, Kim 2014).   
Given the potential for Btk inhibition to affect TAMs and MDSCs, single-agent 
ACP-196 was evaluated in mice with advanced pancreatic cancer arising as the result 
of genetic modifications of oncogenes KRAS and p53, and the pancreatic and 
duodenal homeobox 1 differentiation promoter PDX-1 (KPC mice).  The KPC mouse 
model recapitulates many of the molecular, histopathologic, and clinical features of 
human disease (Westphalen 2012).  Mice were enrolled after identification of 
spontaneously appearing tumors in the pancreas that were ≥ 100 mm3 (as assessed 
by high-resolution ultrasonography).  Mice were treated with vehicle (N=6) or 
ACP-196 administered orally at a dosage of 15 mg/kg/dose BID (N=6).  As shown in 
Figure 1-1, treatment with single-agent ACP-196 substantially slowed pancreatic 
cancer growth and increased animal survival.   


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Figure 1-1. 
Efficacy of ACP-196 Monotherapy in a Genetic Model of 
Pancreatic Cancer 
 
Analysis of tumor tissues showed that immunosuppressive TAMs 
(CD11b+Ly6ClowF4/80+Csf1r+), MDSCs (Gr1+Ly6CHi), and Treg (CD4+CD25+FoxP3+) 
were significantly reduced with ACP-196 treatment by 47%, 30%, and 20%, 
respectively (Figure 1-2).  As expected the decrease in these immunosuppressive cell 
subsets correlated with a significant increase in CD8+ cells (Figure 1-3).   
Figure 1-2. 
Effects of ACP-196 on Tumor-Associated  
Immunosuppressive Cells in a Genetic Model of Pancreatic Cancer 
 
Abbreviations: MDSC = myeloid-derived suppressor cell; TAM = tumor-associated macrophage, Treg = 
regulatory T cell. 


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Figure 1-3. 
Effects of ACP-196 on Cytolytic T Cells in a Genetic Model of 
Pancreatic Cancer 
 
 
Similar single-agent activity was also observed with ACP-196 (15 mg/kg BID) in the 
ID8 syngeneic orthotopic ovarian model.  Figure 1-4 shows a substantial decrease of 
tumor growth in this model with ACP-196 monotherapy compared with vehicle.  This 
antitumor effect correlated with a significant decrease in immunosuppressor cells and 
an increase in cytolytic T cells similar to the KPC pancreatic model. 
Figure 1-4. 
ACP-196 Impairs ID8 Ovarian Cancer Growth and Decreased 
Immunosuppressive Cellular Subsets in Syngeneic Murine Model 
 
Abbreviation:  MDSC = myeloid-derived suppressor cell. 
Single-agent ACP-196 also was evaluated in mice with non-small cell lung carcinoma 
arising as the result of G12D mutant Kras triggered by spontaneous 


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intrachromosomal recombination (KrasLA2 mice).  This model has several 
advantages over traditional transgenic strategies, including that it more closely 
recapitulates spontaneous oncogene activation as seen in human cancers (Johnson 
2001).  Mice were enrolled after identification of spontaneously appearing tumors in 
the lung by micro-computed tomography (CT) scanning (~ 10 to 12 weeks of age).  
Mice were treated with vehicle (N=8) or ACP-196 administered orally at a dosage of 
15 mg/kg/dose BID (N=8) for 3 weeks.  As shown in Figure 1-5, treatment with single-
agent ACP-196 produced tumor regressions, as measured by micro-CT scanning, of 
≥ 25% in 5 of 8 mice (63%) compared with a single mouse in the vehicle group that 
had a reduction of 12%. 
Figure 1-5.  Efficacy of ACP-196 Monotherapy in a Genetic Model of Lung 
Cancer 
 
 
Lastly, the activity of ACP-196 was confirmed in an orthotopic mouse model 
evaluating both single-agent and combination efficacy.  In this study, 10,000 KPC 
mouse pancreatic cancer cells were injected into the pancreases of 24 female mice.  
After one week of expansion, drug treatment was started in mice developing 
pancreatic tumors.  Animals were treated with vehicle (N=6); ACP-196, 15 mg/kg/BID 
given orally (N=6); gemcitabine 50 mg/kg IV administered every 4 days for 3 
injections (N=6); or ACP-196, 15 mg/kg/BID given orally together with gemcitabine, 
50 mg/kg IV administered every 4 days for 3 injections (N=6).  At 2 weeks after 
initiation of treatment, mice in the vehicle group showed signs of deteriorating health 
and all groups were euthanized.  Tumors were collected and measured (Figure 1-6); 


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relative to the vehicle treatment, ACP-196 monotherapy resulted in a 2-fold reduction 
in tumor growth, results which compared favorably with gemcitabine alone.  The 
combination of ACP-196 and gemcitabine resulted in a further reduction in tumor 
growth when compared to each single agent. 
Figure 1-6. 
Efficacy of ACP-196 Monotherapy and Combination Therapy  
with Gemcitabine in an Orthotopic Model of Pancreatic Cancer 
 
Abbreviation: Gem = gemcitabine. 
In summary, ACP-196 alone and in combination with gemcitabine produces robust 
antitumor effects in established solid tumor models.  The antitumor effect observed 
with ACP-196 correlates with biomarkers of response similar to those reported for 
other immunomodulating agents such as inhibitors of CTLA-4, PD-1 and PD-L1.   
This proof-of-concept study will assess the clinical potential of combined Btk inhibition 
and chemotherapy by evaluating the safety, PD, PK and efficacy of ACP-196 and 
nab-paclitaxel/gemcitabine in subjects with previously untreated metastatic pancreatic 
cancer. 
Summaries of preclinical and clinical studies for ACP-196 are provided below.  For 
more detailed information please refer to the Investigator Brochure for ACP-196.  For 
detailed information on nab-paclitaxel/gemcitabine refer to the nab-paclitaxel 
prescribing information provided in Appendix 2. 
1.4 
ACP-196 
ACP-196 (also known as acalabrutinib) is an imidazopyrazine analogue with a 
molecular weight of 465.5 g/mol.  The compound has 1 stereogenic center and 


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ACP-196 is the S-enantiomer.  ACP-196 is orally bioavailable and is suitable for 
formulating in capsules.  For clinical testing, ACP-196 has been manufactured and 
formulated according to current Good Manufacturing Practice (cGMP). 
ACP-196 is an investigational product and has not been approved for marketing in 
any country.   
1.4.1 
Mechanism of Action 
ACP-196 is a potent covalent inhibitor of Btk with a half maximal inhibitory 
concentration (IC50) of 3.1 nM in a biochemical kinase assay for Btk.  ACP-196 was 
specifically designed to be a more potent and selective inhibitor of Btk to avoid 
off-target side effects as seen with ibrutinib, a first generation covalent Btk inhibitor.  
When profiled against 282 human kinases, ACP-196 was more selective than 
ibrutinib.   
ACP-196 is a covalent inhibitor of Btk, forming a covalent interaction with Cys481 in 
the front position of the ATP-binding pocket of Btk.  In addition to Btk there are 
9 kinases with a cysteine in the same position as Btk: Tec, Bmx, Itk, Txk, epidermal 
growth factor receptor (EGFR), ErbB2, ErbB4, Blk and Janus kinase (Jak) 3.  Due to 
the position of the cysteine in the ATP pocket, these kinases are referred as the group 
of 3F-Cys kinases (Barf 2012). 
In Table 1-1 the group of 3F-Cys kinases are listed with the IC50 for ACP-196 and 
ibrutinib.  For ACP-196, the strongest inhibition was observed for Btk with less activity 
against Tec, Bmx and ErbB4.  However, ibrutinib showed inhibition of all 10 kinases.  
One kinases potently inhibited by ibrutinib is EGFR, which may explain the 
ibrutinib-related incidence of diarrhea, rash and hemorrhaging events reported for 
ibrutinib in clinical trials of hematologic malignancies (IMBRUVICA prescribing 
information).   


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Table 1-1. 
Potency of ACP-196 and Ibrutinib on Group of 3F-Cys Kinases 
 
IC50 (nM) 
ACP-1961 
Ibrutinib2 
Btk 
3.1 
0.5 
Tec 
29 
78 
Bmx 
39 
0.80 
Itk 
>1000 
10.7 
Txk 
291 
2.01 
EGFR 
>1000 
5.6 
ErbB2 
912 
9.4 
ErbB4 
13.2 
2.71 
Blk 
>1000 
0.5 
Jak3 
>1000 
16.1 
Abbreviation:  IC50 = inhibitory concentration causing 
half-maximal inhibition. 
1. Profiling at Life Technology 
2. Honigberg 2010; ibrutinib data for Txk and ErbB4 
profiled at Life Technology 
 
1.4.2 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with ACP-196 have demonstrated a 
favorable nonclinical safety profile.   
When screened at 10 μM in binding assays evaluating interactions with 80 known 
pharmacologic targets such as G-protein-coupled receptors, nuclear receptors, 
proteases, and ion channels, ACP-196 showed significant activity only against the 
A3 adenosine receptor; follow-up dose-response experiments indicated an IC50 of 
2.7 µM, suggesting a low clinical risk of off-target effects.   
The in vitro effect of ACP-196 on human ether-à-go-go-related gene (hERG) channel 
activity was investigated in vitro in human embryonic kidney cells stably transfected 
with hERG.  ACP-196 inhibited hERG channel activity by 25% at 10 μM, suggesting a 
low clinical risk that ACP-196 would induce clinical cardiac QT interval (QT) 
prolongation as predicted by this assay. 
ACP-196 was well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacologic safety.  A functional observation battery in rats at doses 
through 300 mg/kg (the highest dose level) revealed no adverse effects on 


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neurobehavioral effects or body temperature.  A study of respiratory function in rats 
also indicated no treatment-related adverse effects at doses through 300 mg/kg (the 
highest dose level).  In a cardiovascular function study in awake telemeterized male 
beagle dogs, single doses of ACP-196 at dose levels through 30 mg/kg (the highest 
dose level) induced no meaningful changes in body temperature, cardiovascular, or 
electrocardiographic (including QT interval) parameters.  The results suggest that 
ACP-196 is unlikely to cause serious off-target effects or adverse effects on critical 
organ systems. 
1.4.3 
Drug-drug Interaction Potential 
The in vitro studies suggest CYP-mediated metabolism of ACP-196 appears to be 
catalyzed predominantly by CYP3A.  However, in elimination studies in preclinical 
species, the metabolic fate of ACP-196 is dominated by direct conjugation of 
ACP-196 with glutathione, providing evidence for a significant non-CYP mechanism of 
elimination.  In a healthy volunteer study (ACE-HV-001), the effect of coadministration 
of a potent CYP3A and p-glycoprotein 1 (P-gp) inhibitor, itraconazole, on the plasma 
levels of ACP-196 was evaluated.  The mean plasma ACP-196 maximum 
concentration (Cmax) and area under the curve (AUC0-last) values increased 3.7- and 
5.1-fold, respectively, in the presence of itraconazole relative to no pretreatment.  In 
vitro studies also show that ACP-196 is a substrate for P-gp.   
ACP-196 is unlikely to be a perpetrator of a drug-drug interaction at the level of 
inhibition or induction of CYP isoforms. 
Results from drug transporter studies suggest that ACP-196 is not anticipated to alter 
the PK of other therapeutic agents that are substrates for MDR1, OATP1B1, 
OATP1B3, OAT1, OAT3 and OCT2.   
Please refer to Section 3.10.3 for guidance on drugs that may cause drug-drug 
interactions. 
1.5 
IN VIVO GENERAL TOXICOLOGY – ACP-196 
The systemic toxicity of ACP-196 has been investigated in six repeat-dose general 
toxicology studies, three with recovery periods, in the rat and the dog.  The pivotal 
GLP studies were two 28-day repeat dose studies in Sprague Dawley rats with 
32- and 28-day recovery periods, and a 28-day study in Beagle dogs with a 28-day 
recovery period. 


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The no observable adverse effect level (NOAEL) in the dog was 30 mg/kg/day, which 
was the highest dose evaluated.  In rats, 30 mg/kg/day resulted in minimal 
inflammation of the pancreas in some animals, with reversal, indicating the rat to be 
the more sensitive preclinical species.  The pancreatic effects were minimally 
increased at 100 mg/kg/day in the rat though there was no clinical evidence of 
toxicity.  Hence, 100 mg/kg/day was selected to conservatively represent the highest 
non-severely toxic dose.  The pancreatic findings were investigated in subsequent rat 
toxicology studies and found to be treatment related, non-adverse at lower doses, and 
not associated with systemic toxicity or changes in biomarkers of pancreatic function.  
The islet cell changes resemble a spontaneous pancreatic lesion that is described as 
an age-related finding in male rats of this strain.  In dogs at 30 mg/kg/day, there were 
no microscopic findings in the pancreas, and all clinical biomarkers of pancreatic 
function were normal.   
In rats and dogs, no adverse ECG or histopathologic cardiovascular effects were 
noted at the planned conclusion of the 28-day toxicology studies.  However, in 5 of 
6 rats from the 300-mg/kg dose group that died early in the study, slight to moderate 
necrosis of the myocardium and/or white blood cell infiltration/inflammation of the 
myocardium were noted on microscopic examination of the hearts.  These findings 
were most likely incidental postmortem changes. 
1.6 
CLINICAL EXPERIENCE – ACP-196 
For more detailed information on the clinical experience for ACP-196 please refer to 
the Investigator Brochure.   
1.6.1 
Pharmacokinetics and Pharmacodynamics of ACP-196 
ACE-HV-001 was a PK/pharmacodynamic, dose-ranging, food-effect, and drug-drug 
interaction study evaluating BID and QD dosing for 1 or 2 days in healthy volunteers.  
This study evaluated the PK and pharmacodynamics of ACP-196 at various dose 
levels and regimens.  The starting dose for ACP-196 was 2.5 mg BID.  This study has 
been completed and no adverse laboratory, vital signs, or ECG findings were 
observed (2.5 to 50 mg BID; 50 to 100 mg QD).  Three AEs related to study drug 
were reported.  Each AE was Grade 1 and resolved without treatment.  The AEs were 
constipation (2.5 mg BID), feeling cold (75 mg QD), and somnolence (75 mg QD). 
In Part 1, PK properties of ACP-196 were evaluated after oral administration of 2 daily 
divided doses of 2.5 to 50 mg and a single dose of 100 mg.  Of the 30 subjects 


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evaluated, all observed systemic concentrations of ACP-196.  ACP-196 plasma time 
to maximum concentration (Tmax) values were between 0.5 and 1.0 hour for all dose 
cohorts and were independent of dose level.  The increase in mean Cmax values was 
greater than dose proportional based on the increases of Cmax from the first dose 
administered.  When evaluating AUC0-12, AUC0-12 or AUC0-inf, the mean values 
increased in a dose proportional manner based on the increases of the total dose 
administered.  Mean half-life (t1/2) values ranged from 0.97 to 2.1 hours, and appeared 
to decrease as the dose increased.  The mean calculated oral clearance 
(CL/F: 165 to 219 L/h) and volume of distribution values (Vz/F: 233 to 612 L) 
appeared to be independent of the dose administered. 
ACP-196 was not detected in the urine of subjects receiving the 2.5- or 5.0-mg BID 
doses of ACP-196.  ACP-196 was detected in urine of other subjects (0.4% to 0.6% of 
dose) and amounts increased in a dose-dependent manner. 
In Part 2, the effect of food on the PK of ACP-196 (75 mg) after a single oral 
administration was evaluated in 6 men and 6 women.  Median ACP-196 plasma Tmax 
values were increased in the fed state (2.5 hours) relative to the fasted state 
(0.5 hour).  The mean plasma ACP-196 Cmax fed values decreased to 27.3% of the 
Cmax values observed in the fasted state.  In contrast, the relative AUC exposure of 
ACP-196 remained mostly unchanged in both states.   
In Part 3, the effect of itraconazole on the PK of ACP-196 (50 mg) after a single oral 
administration was evaluated in 17 subjects.  No difference in ACP-196 Tmax values 
was observed in the presence or absence of itraconazole. 
Mean ACP-196 exposures (as assessed by Cmax, AUC0-last, AUC0-12, and AUC0-inf) 
increased in the presence of itraconazole.  The mean plasma ACP-196 Cmax values 
increased 3.7-fold in the presence of itraconazole.  The mean plasma AUC0-last, 
AUC0-12, and AUC0-inf values also increased between 4.9- to 5.1-fold in the presence 
of itraconazole.  Mean CL/F and Vz/F values decreased in the presence of 
itraconazole (CL/F: 217 vs 44 L/h; Vz/F: 1190 vs 184 L).  No differences in half-life 
values were observed (3.3 vs 2.5 hours). 
The pharmacodynamics of ACP-196 was evaluated using a Btk occupancy assay and 
correlated with a functional assay that determines the level of Btk inhibition by 
measuring expression of CD69 and CD86 on B cells.  A dose-dependent increase in 
Btk occupancy and corresponding decrease in CD69/86 expression was observed in 


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this study.  Full Btk occupancy (≥ 90%) and complete CD86 and CD69 inhibition 
(≥ 90%) occurred at the 75- and 100-mg single dosed cohorts 1 to 3 hours after 
administration.  However, only the 100-mg cohort maintained high Btk occupancy 
(91.5%) and high B-cell receptor (BCR) functional inhibition (CD86: 86 ± 3% and 
CD69: 78 ± 8%) at 24 hours.  For subjects receiving a second dose of ACP-196 
12 hours after the first administration, full Btk target occupancy was observed 3 hours 
after the second dose for the 50-mg dosed cohort (Btk occupancy 97 ± 4%). 
1.6.2 
ACP-196 in CLL 
ACE-CL-001 (NCT02029443), an ongoing Phase 1/2 study in subjects with 
relapsed/refractory or previously untreated CLL or Richter’s syndrome, has a 
sequential, dose-escalation design.  As of 22 January 2015, 125 subjects have 
received ACP-196 at dosages from 100 to 400 mg QD or 100 to 200 mg BID for up to 
11 cycles (1 cycle = 28 days). 
To date, ACP-196 has been well tolerated at all dose levels evaluated.  No DLTs 
have occurred at any dose level.  The MTD was not reached in this study; however, 
per the protocol, dose escalation was stopped once a plateau in PK was observed (ie, 
between 250 and 400 mg).   
Preliminary pharmacodynamics data show that Btk occupancy with ACP-196 QD 
dosing, in peripheral blood cells, is > 95% at 4 hours after dosing but decreases to 
< 95% at 24 hours, while with BID dosing complete Btk occupancy (97% to 100%) is 
maintained over 24 hours at steady state (Table 1-2).  These data suggest that 
synthesis of de novo Btk may occur within 24 hours. 


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Table 1-2. 
Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001 
  
  
Sample 
Cohort 
Metric 
Day 1 
4hr 
post 
Day 2 
pre 
Day 8 
pre 
Day 8 
4hr post 
Day 28 
pre 
Day 28 
4hr post 
100 mg QD 
% Btk 
Occupancy 
96.1 
84.4 
87.6 
98.0 
 
 
Std.  dev. 
3.2 
9.8 
5.1 
1.8 
 
 
N 
8 
8 
8 
8 
 
 
175 mg QD 
% Btk 
Occupancy 
97.1 
79.2 
84.0 
96.9 
 
 
Std.  dev. 
2.3 
11.2 
12.9 
4.8 
 
 
N 
8 
8 
8 
8 
 
 
200 mg QD 
(Naive) 
% Btk 
Occupancy 
97.4 
86.2 
91.3 
99.8 
92.3 
99.0 
Std.  dev. 
4.4 
7.5 
7.8 
1.1 
0.9 
0.9 
N 
9 
9 
9 
9 
3 
3 
200 mg QD 
(Ibrutinib 
intolerant) 
% Btk 
Occupancy 
96.7 
94.4 
99.7 
96.2 
93.3 
99.9 
Std.  dev. 
 
 
 
 
 
 
N 
1 
1 
1 
1 
1 
1 
100 mg BID 
% Btk 
Occupancy 
97.0 
94.8 
97.8 
99.3 
97.3 
99.6 
Std.  dev. 
2.7 
2.7 
2.0 
0.6 
1.3 
0.3 
N 
10.00 
10.00 
10.00 
10.00 
6.00 
6.00 
250 mg QD 
% Btk 
Occupancy 
94.4 
82.4 
93.1 
100.1 
 
 
Std.  dev. 
12.4 
10.6 
2.7 
0.4 
 
 
N 
6 
6 
6 
6 
  
  
400 mg QD 
% Btk 
Occupancy 
98.8 
89.9 
94.7 
99.4 
93.6 
99.8 
Std.  dev. 
1.1 
10.5 
2.5 
0.6 
4.5 
0.2 
N 
6 
6 
6 
6 
6 
6 
200 mg BID 
(Richter's) 
% Btk 
Occupancy 
99.7 
92.7 
98.6 
99.8 
99.0 
100.0 
Std.  dev. 
 
 
 
 
 
 
N 
1 
1 
1 
1 
1 
1 
BID = twice per day; Btk = Bruton tyrosine kinase; QD = once per day 
Preliminary PK data from Day 8 show dose linearity from 100 to 250 mg and no 
accumulation with repeat dosing (Table 1-3). 


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Table 1-3. 
Preliminary Day 8 PK Results from ACE-CL-001 (December 2014) 
Cohort 
Mean Cmax ± SD 
(ng/mL) 
Mean AUC0-6 ± SD 
(ng•h/mL) 
100 mg QD (N=8) 
529 ± 286 
634 ± 197 
175 mg QD (N=7) 
800 ± 692 
1240 ± 788 
250 mg QD (N=7) 
1350 ± 933 
2170 ± 1180 
400 mg QD (N=6) 
932 ± 576 
1870 ± 1040 
100 mg BID (N=22) 
716 ± 658 
837 ± 485* 
Timepoints: Predose, 0.25, 0.50, 0.75, 1.0, 2.0, 4.0, and 6.0 postdose. 
BID regimens were not sampled during the second daily dose interval; 0-24 hour exposures 
are expected to be approximately 2-fold the AUC0-6 values shown. 
AUC = area under the curve; BID = twice per day; Cmax = maximum concentration; QD = once 
per day; SD = standard deviation 
To date, 31 subject have been evaluated for tumor response based on International 
Working Group response criteria (Hallek 2008) as recently updated (Cheson 2012) to 
include partial response with treatment-induced lymphocytosis.  Based on preliminary, 
unaudited data an ORR of 94% (29 of 31 subjects) has been observed (Table 1-4). 
Table 1-4. 
Best Response by Cohort from ACE-CL-001 (December 2014) 
n (%) 
All 
Cohorts 
(N = 31) 
100 mg  
QD 
(N = 8) 
175 mg  
QD 
(N = 8) 
250 mg  
QD 
(N = 7) 
100 mg 
BID 
(N = 3) 
400 mg QD 
(N = 5) 
PR 
22 (71) 
7 (88) 
5 (63) 
5 (71) 
3 (100) 
2 (40) 
PR+L 
7 (23) 
0 (0) 
3 (37) 
2 (29) 
0 (0) 
2 (40) 
SD 
2 (6) 
1 (12) 
0 (0) 
0 (0) 
0 (0) 
1 (20) 
PD 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
Median (range)  
 
7.3 
(3.0-10.8) 
10.0 
(9.0-10.8) 
8.6 
(3.0-8.8) 
7.0 
(7.0-7.3) 
5.2 
(4.7-5.5) 
5.0  
(4.8-5.5) 
 
BID = twice per day; PR = partial response; PR+L = partial response with lymphocytosis; SD = 
stable disease; PD = progressive disease; QD = once per day 
1.7 
NAB-PACLITAXEL/GEMCITABINE 
Nab-paclitaxel/gemcitabine is approved for first-line treatment of patients with 
metastatic pancreatic cancer.  For complete information on 
nab-paclitaxel/gemcitabine, including contraindications and warnings and precautions 
refer to the nab-paclitaxel prescribing information (Appendix 2).  
Nab-paclitaxel/gemcitabine treatment is associated with: 
• 
myelosuppression 
• 
sensory neuropathy 


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• 
sepsis (with or without neutropenia) 
• 
pneumonitis 
• 
severe hypersensitivity reactions with fatal outcome 
Management of these specific adverse reactions is described in the prescribing 
information (Appendix 2). 
Additional AEs reported in ≥ 20% of patients with metastatic pancreatic cancer treated 
with nab-paclitaxel/gemcitabine included neutropenia, fatigue, peripheral neuropathy, 
nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, 
rash, and dehydration. 
1.8 
BENEFIT/RISK 
ACP-196 is a potent, orally available small-molecule inhibitor of Btk.  In the Phase 1/2 
study of ACP-196 in subjects with CLL or Richter’s syndrome, no DLTs have been 
identified at dosages of ≤ 400 mg QD or 100 to 200 mg BID.  The ORR in the 
evaluable subjects for this study is currently 94% with some subjects obtaining PRs 
after only 2 cycles of therapy.  In summary, the preliminary data suggest that 
ACP-196 is well tolerated and has robust activity as a single agent in the treatment of 
subjects with CLL/small lymphocytic leukemia (SLL).   
Based on the currently known toxicity profiles of ACP-196 and 
nab-paclitaxel/gemcitabine, overlapping toxicities are expected to be limited.  At the 
dosage of ACP-196 administered in this study, no drug-drug interactions are 
anticipated between ACP-196 and nab-paclitaxel/gemcitabine.   
In nonclinical studies, ACP-196 monotherapy has shown robust antitumor activity in 
murine solid tumor models of pancreatic, lung and ovarian cancer.  Preliminary results 
from a murine pancreatic cancer model suggest a synergistic anti-tumor effect of 
ACP-196 in combination with gemcitabine.  These results support evaluating 
ACP-196 in combination with nab-paclitaxel/gemcitabine in this protocol. 


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2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To evaluate the efficacy of ACP-196 and nab-paclitaxel/gemcitabine based on ORR in 
subjects with metastatic pancreatic cancer using standard response criteria 
2.2 
SECONDARY OBJECTIVES 
To characterize the safety profile of ACP-196 and nab-paclitaxel/gemcitabine in 
subjects with metastatic pancreatic cancer 
2.3 
EXPLORATORY OBJECTIVES 
• 
 
 
 
 
 
 
 
 
 
 
3.0 
STUDY DESIGN 
This clinical trial is a Phase 2, multicenter, open-label, randomized study evaluating 
ACP-196 plus nab-paclitaxel/gemcitabine compared with nab-paclitaxel/gemcitabine 
in subjects who have previously untreated metastatic pancreatic cancer.   
Subjects meeting the eligibility criteria for the study will be randomized 1:1 using an 
IXRS to one of the following arms: 
Arm 1:  ACP-196 100 mg administered orally BID on Days 1-28 with nab-paclitaxel 
125 mg/m2 and gemcitabine 1000 mg/m2 administered IV on Days 1, 8, and 15; 
cycles are repeated every 28 days. 
Arm 2:  Nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 are administered IV 
on Days 1, 8, and 15; cycles are repeated every 28 days. 
Although ACP-196 has not demonstrated any DLTs to date, the safety of ACP-196 in 
combination with nab-paclitaxel/gemcitabine in this patient population needs to be 
assessed and standard DLT criteria will be applied to Arm 1 of the study.  Therefore 
an interim safety analysis will occur once 12 subjects (6 subjects per arm) have been 
successfully randomized and have been treated a minimum of 1 cycle (1 cycle = 
28 days).  Enrollment will be paused while the safety interim analysis occurs.   


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If ≤ 1 DLT is observed in Arm 1, then randomization will continue to evaluate the 
safety and efficacy of the ACP-196 combination (ie, up to 60 subjects per arm).  If 
≥ 2 DLTs are observed in Arm 1, then enrollment will continue until an additional 
6 subjects are randomized to Arm 1, but with a reduced dose level for ACP-196 
(Level -1).  If the DLT review is cleared in those additional 6 subjects in Arm 1 then 
continued enrollment will occur at Level -1 for the ACP-196 combination arm.  If 
≥ 2 DLTs are observed in Arm 1 at Level -1, then an additional 6 subjects will be 
randomized at Level -2 and assessed for DLTs.  If the DLT review is cleared, 
continued enrollment will occur at Level -2 for the ACP-196 combination arm.  If the 
DLT review is not cleared, enrollment will be halted.  In addition, analyses for toxicity 
will also be done as outlined in Section 5.5. 
Treatment can continue until the end of trial, defined as 52 weeks (13 cycles) after the 
last subject is randomized to the study, for subjects who are tolerating therapy and 
not progressing.  Subjects who have confirmed progressive disease will discontinue 
study treatment.  Subjects who discontinue study drug for any reason other than 
disease progression, death, lost to follow-up, or withdrawal of consent will be followed 
for tumor assessment until disease progression or initiation of any other anticancer 
therapies, whichever comes first. 
All subjects will have hematology, chemistry, and urinalysis safety panels performed 
at screening.  Once dosing commences (Day 1), all subjects will be evaluated for 
safety, including serum chemistry, serum amylase and lipase, and hematology.  PD 
(subjects in both arms) and PK testing (only the first 20 subjects enrolled in Arm 1) 
will be performed during the first few months of treatment.  Radiologic tumor 
assessments will be completed at baseline and at approximately 8-week intervals 
during the trial.  The primary efficacy analysis will be based on investigator 
assessment.  Independent radiology review (IRR) of the efficacy data will also be 
performed in accordance with an IRR charter.   
Refer to Appendix 7 for a comprehensive list of study assessments and their timing.  
A study schema is provided in Figure 3-1. 


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Figure 3-1. 
Study Schema 
 
Abbreviations:  BID = twice per day; IV = intravenous. 
*ACP-196 and nab-paclitaxel/gemcitabine administration begins on the same day except for the first 
6 subjects enrolled due to pharmacokinetic sampling.  In the first 6 subjects, ACP-196 will be 
administered on Cycle 1 Day -1.  On Cycle 1 Day 1, the first nab-paclitaxel/gemcitabine infusion will 
occur.  When ACP-196 and nab-paclitaxel/gemcitabine are administered on the same day, ACP-196 is 
administered first followed by the nab-paclitaxel and then gemcitabine infusions. 


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3.1 
STUDY PARAMETERS 
3.1.1 
Safety Parameters 
The safety of ACP-196 and nab-paclitaxel/gemcitabine will be characterized by the 
type, frequency, severity, timing of onset, duration, and relationship to study drug(s) of 
any treatment emergent AEs or abnormalities of laboratory tests; SAEs; or AEs 
leading to discontinuation of study treatment.   
For consistency of interpretation, AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), and the severity of AEs and laboratory abnormalities 
will be graded using the Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.03.  Standard definitions for seriousness will be applied (see Section 6.1). 
3.1.2 
Pharmacodynamic, Pharmacokinetic, and Biomarker 
Parameters 
The occupancy of Btk by ACP-196 will be measured in PBMCs with the aid of a 
biotin-tagged ACP-196 analogue probe.  The effect of ACP-196 and 
nab-paclitaxel/gemcitabine on B cells, T cells and MDSCs and cytokines may also be 
evaluated.  Tissue sections from either an archived or newly obtained tumor sample 
(most recent biopsy) are to be provided at screening.   Tumor tissue from archival 
tumor biopsies and/or any newly obtained biopsies performed during the study will be 
evaluated for various tumor markers, including but not limited to: 
• 
HABP 
• 
SMA  
• 
Ki67 proliferation 
• 
cleaved-caspase 3  
• 
PD-1 and its ligand, PD1-L 
Additional exploratory correlative studies of tumor tissue, when available, may include 
characterization of tumor subtypes by immunohistochemistry.   
The following PK parameters will be calculated, whenever possible, from plasma 
concentrations of ACP-196: 
• 
AUC0-last:  Area under the plasma concentration-time curve calculated using 
linear trapezoidal summation from time 0 to time last, where “last” is the time 
of the last measurable concentration. 
• 
AUC0-12:  Area under the plasma concentration-time curve from 0 to 12 hours, 
calculated using linear trapezoidal summation. 


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• 
AUC0-inf:  Area under the plasma concentration-time curve from 0 to infinity, 
calculated using the formula: AUC0-inf = AUC0-last + Clast / λz, where λz is the 
apparent terminal elimination rate constant. 
• 
AUC0-24calc:  Area under the plasma concentration-time curve from 0 to 
24 hours, calculated by doubling the value for AUC0-12. 
• 
Cmax:  Maximum observed plasma concentration 
• 
Tmax:  Time of the maximum plasma concentration (obtained without 
interpolation) 
• 
t½:  Terminal elimination half-life (whenever possible) 
• 
λz: Terminal elimination rate constant (whenever possible) 
• 
CL/F:  Oral clearance 
• 
Vz/F:  Oral volume of distribution 
Leftover plasma may be analyzed for ACP-196 metabolites. 
3.1.3 
Efficacy Parameters 
Efficacy will be evaluated based on assessments of tumor response and progression 
using the standardized Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 (Eisenhauer 2009, Appendix 1).   
Efficacy endpoints will include: 
• 
ORR, defined as PR or CR based on modified RECIST 1.1 criteria  
• 
DOR 
• 
OS 
• 
PFS 
• 
Change in CA19-9 
 
3.2 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
As described in Section 1.6.2, ACP-196 is currently being evaluated in a Phase 1/2 
study in subjects with CLL or Richter’s syndrome (ACE-CL-001).  In this study, 
subjects have received oral dosages of 100 to 400 mg QD and 100 to 200 mg BID of 
ACP-196.  All tested dose levels have been well tolerated and, to date, no 
drug-related toxicities have been observed in ACE-CL-001.   


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Robust clinical responses have been observed with dosages as low as 100 mg QD.  
Preliminary PK data from ACE-CL-001 suggests a plateauing of exposure after 250 
mg QD (Table 1-3).  Pharmacodynamic results from this study also show 100 and 200 
mg BID have the highest Btk occupancy at 24 hours of all the regimens evaluated 
(Table 1-2).   
The nab-paclitaxel/gemcitabine dose regimen being evaluated in this study is 
consistent with the prescribing information of these drugs for the treatment of 
metastatic pancreatic cancer (nab-paclitaxel prescribing information).   
As described in Section 1.4 and Section 1.5, Acerta Pharma has conducted 
nonclinical solid tumor studies of ACP-196 monotherapy and ACP-196 in combination 
with chemotherapy (ie, gemcitabine).  The robust results observed for ACP-196 
monotherapy and in combination with chemotherapy warrant testing these regimens 
on this protocol.   
3.3 
SELECTION OF STUDY POPULATION 
3.3.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria:  
1. Men and women ≥ 18 years of age. 
2. ECOG performance status of 0 or 1. 
3. Histologically or cytologically confirmed metastatic adenocarcinoma of the 
pancreas.   
4. Presence of radiographically measurable disease per RECIST 1.1. 
5. No previous radiotherapy, chemotherapy or investigational therapy for the 
treatment of metastatic disease.  Prior treatment with 5-FU or gemcitabine 
administered as a radiation sensitizer in the adjuvant setting is allowed, provided 
at least 6 months have elapsed since completion of the last dose and no lingering 
toxicities are present. 
6. Women who are sexually active and can bear children must agree to use highly 
effective forms of contraception during the study and for 90 days after the last 
dose of ACP-196 or 4 months after the last dose of nab-paclitaxel/gemcitabine, 
whichever is longer.  Highly effective forms of contraception are defined in Section 
3.10.5. 
7. Men who are sexually active and can beget children must agree to use highly 
effective forms of contraception during the study and for 90 days after the last 
dose of ACP-196 or 4 months after the last dose of nab-paclitaxel/gemcitabine, 
whichever is longer.  Highly effective forms of contraception are defined in Section 
3.10.5. 


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8. Men must agree to refrain from sperm donation during the study and for 90 days 
after the last dose of ACP-196 or 4 months after the last dose of 
nab-paclitaxel/gemcitabine, whichever is longer. 
9. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing capsules without difficulty 
10. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information (in 
accordance with national and local subject privacy regulations) 
3.3.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Prior malignancy (other than pancreatic cancer), except for adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer 
from which the subject has been disease free for ≥ 2 years.  Note:  These cases 
must be discussed with the medical monitor. 
2. Known CNS metastases and/or carcinomatous meningitis. 
3. Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or QTc > 480 msec at screening. 
4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
or resection of the stomach or small bowel, symptomatic inflammatory bowel 
disease, partial or complete bowel obstruction, or gastric restrictions and bariatric 
surgery, such as gastric bypass.  Note:  Subjects with prior 
pancreatoduodenectomy are not excluded. 
5. Biliary obstruction or presence of a percutaneous biliary drain.  Note: Subjects 
with endobiliary stents may participate as long the enrollment criterion relating to 
serum bilirubin concentration is met. 
6. Prior therapy with any inhibitor of Btk, Akt, Jak, mTOR, PI3K, or Syk. 
7. History of interstitial lung disease or active non-infectious pneumonitis. 
8. History of bleeding diathesis (eg, hemophilia or von Willebrand disease). 
9. Major surgical procedure within 28 days of first dose of study drug. 
10. Known hypersensitivity to gemcitabine or nab-paclitaxel. 
11. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
12. Requires treatment with a strong CYP3A or CYP2C8 inhibitor/inducer. 
13. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. 
14. Ongoing immunosuppressive therapy, including systemic or enteric 
corticosteroids. Note:  At screening and during study participation, subjects may 
use topical or inhaled corticosteroids or systemic corticosteroids at dosages 
equivalent to prednisone ≤ 10 mg/day as therapy for comorbid conditions.  
15. Known history of HIV or serologic status indicating active HCV or HBV infection or 
any uncontrolled active systemic infection.  Subjects with hepatitis B core antibody 
positive who are surface antigen negative or who are hepatitis C antibody positive 
will need to have a negative PCR result before enrollment.  Those who are 


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hepatitis B surface antigen positive or hepatitis B PCR positive and those who are 
hepatitis C PCR positive will be excluded.   
16. History of stroke or intracranial hemorrhage within 6 months before the first dose 
of study drug.  
17. ANC < 1.5 x 109/L or platelet count < 100 x 109/L or hemoglobin < 9.0 g/dL. 
18. Total bilirubin > ULN; and AST or ALT > 3.0 x ULN. 
19. PT and aPTT > 1.2 x the ULN. 
20. Estimated creatinine clearance of < 30 mL/min, calculated using the formula of 
Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 
0.85 if female]. 
21. Breastfeeding or pregnant. 
22. Concurrent participation in another therapeutic clinical trial. 
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months 
before screening. 
3.3.3 
Replacement of Subjects 
Any subject who does not complete study therapy through Cycle 1 for reasons other 
than the occurrence of a DLT may be replaced at the discretion of the study 
investigators and sponsor.   
3.3.4 
Enrollment Procedures 
Enrollment of a subject into the study will be performed according to the following 
procedure:  
• 
The study center will notify the sponsor when a clinically eligible subject is 
identified and is ready to screen, to ensure enrollment availability on the study. 
• 
After the subject has signed and dated the Informed Consent Form (ICF), all 
screening procedures have been completed, and eligibility has been confirmed, 
the subject can be officially enrolled into the study.   
• 
To enroll a subject, the study center will fax/email a completed Enrollment 
Confirmation Form to the sponsor.  The enrollment date will be the date that 
the sponsor confirms enrollment. 
• 
The sponsor will aim to fax/email a completed Enrollment Confirmation Form to 
the study center within 24 hours.  
• 
Screening and treatment assignment will occur through the use of an IXRS.  As 
subjects qualify for enrollment, designated study center personnel will contact 
the IXRS, which will assign a treatment arm to each eligible subject.   
Treatment must begin within the screening window (see Appendix 7) and after the site 
has received the treatment-arm allocation per IXRS.   


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3.4 
STUDY DRUGS  
3.4.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
ACP-196 or nab-paclitaxel/gemcitabine administration.   
3.4.2 
Formulation, Packaging, and Storage 
ACP-196 
ACP-196 is manufactured according to cGMP regulations and will be provided to the 
investigational site by Acerta Pharma or designee.  ACP-196 should be stored 
according to the instructions on the label that is affixed to the package of the drug 
product.  ACP-196 will be provided in white, high-density polyethylene bottles.   
If a drug shipment arrives damaged, or if there are any other drug complaints, a 
SAE/Product Complaint Form should be completed and emailed or faxed to the 
sponsor or the sponsor’s representative.  Refer to the ACP-196 Investigator Brochure 
for additional information regarding the drug product to be used in this trial. 
Nab-paclitaxel/gemcitabine 
Commercially available nab-paclitaxel and gemcitabine will be used in this study.  The 
provisioning of these drugs for use in this study will be detailed in the clinical trial 
agreement with each site. 
Nab-paclitaxel (100 mg/vial) is provided as lyophilized powder in single-use vials for 
reconstitution. 
Gemcitabine (200 mg or 1 g/vial) is provided as lyophilized powder in single-use vials 
for reconstitution. 
Information on the formulation, packaging and storage of nab-paclitaxel is provided in 
the prescribing information (Appendix 2).  Information on the formulation, packaging 
and storage of gemcitabine is provided in the prescribing information (Appendix 3).   
3.4.3 
Administration of Study Drug  
Investigators are prohibited from supplying ACP-196 to any subjects not properly 
enrolled in this study or to any physicians or scientists except those designated as 
subinvestigators on Food and Drug Administration (FDA) Form 1572.  The 
investigator must ensure that subjects receive ACP-196 or nab-paclitaxel/gemcitabine 


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only from personnel who fully understand the procedures for administering the 
drugs. 
ACP-196 100 mg is intended to be administered orally twice daily with 8 ounces 
(approximately 240 mL) of water (avoid grapefruit juice or Seville orange juice due to 
potential CYP3A inhibition).  Doses should be administered 12 hours apart (a window 
of ± 1 hour is allowed).  The capsules should be swallowed intact and subjects should 
not attempt to open capsules or dissolve them in water.   
If a dose is missed, it can be taken up to 3 hours after the scheduled time with a 
return to the normal schedule the same or following day.  If it has been > 3 hours, the 
dose should not be taken and the subject should take the next dose at the scheduled 
time the next day.  The missed dose will not be made up and must be returned to the 
site at the next scheduled visit. 
Guidance on co-administration of ACP-196 with agents that affect gastric pH is 
provided in Section 3.10.3. 
Nab-paclitaxel (125 mg/m2) will be administered as an IV infusion over 30 to 
40 minutes on Day 1, 8 and 15 of every 28-day cycle.  Detailed information on 
preparation of nab-paclitaxel for infusion is provided in Appendix 2.   
Gemcitabine (1000 mg/m2) will be administered immediately after nab-paclitaxel as an 
IV over 30 to 40 minutes on Days 1, 8 and 15 of each 28-day cycle.  Do not increase 
infusion time > 60 minutes as increased toxicity may occur.  Detailed information on 
preparation of gemcitabine for infusion is provided in Appendix 3. 
When ACP-196 and nab-paclitaxel/gemcitabine are administered on the same day, 
ACP-196 should be administered first, followed by nab-paclitaxel and then 
immediately by gemcitabine.  When PK sampling is done, the 
nab-paclitaxel/gemcitabine infusion should begin within 10 minutes of ingesting 
ACP-196.  However, for the first 6 subject enrolled on the ACP-196 combination arm 
(Arm 1), ACP-196 will be administered alone on Day -1 and then concomitantly with 
nab-paclitaxel/gemcitabine on Day 1 as described above. 
3.4.4 
Assuring Subject Compliance 
For treatments that are taken in the clinic, subjects should take the dose from the 
drug dispensed for them for that particular time period.  All other ACP-196 treatments 


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will be taken at home.  Subjects will receive a drug diary to record the specific time 
each dose was taken and to record reasons for any missed doses.   
Nab-paclitaxel/gemcitabine infusions will be administered only at the clinics per the 
study schedule and must be administered by study personnel experienced with 
this regimen.   
Subject compliance with ACP-196 dosing will be assessed on Day 1 of every cycle.  
The subject will be instructed to bring the diary and any remaining capsules to the 
clinic at their next visit.  The study staff will review the diary and ask the subject if all 
of the capsules were administered.  Any remaining or returned capsules will be 
counted and recorded as described in Section 7.6.  Returned capsules must not be 
redispensed to another subject.   
3.5 
STUDY TREATMENT SCHEDULE 
3.5.1 
Arm 1 – ACP-196 + Nab-paclitaxel/Gemcitabine 
The ACP-196 100 mg BID will be administered orally every day of the 28-day cycle.  
Nab-paclitaxel/gemcitabine will be administered as described in Section 3.4.3.  
ACP-196 and nab-paclitaxel/gemcitabine dosing will begin on the same day (Cycle 1 
Day 1) except for the first 6 subjects enrolled due to PK sampling.  The first 6 subjects 
enrolled will receive ACP-196 on Cycle 1 Day -1.  Then on Cycle 1 Day 1, the first 
nab-paclitaxel/gemcitabine infusion will be administered.   
3.5.2 
Arm 2 – Nab-paclitaxel/Gemcitabine 
For complete information on dosing and dose modifications refer to the respective 
prescribing information for each drug (Appendix 2 and Appendix 3); a summary of this 
information is shown in Table 3-3 in Section 3.8.2. 
3.6 
DURATION OF THERAPY 
Treatment can continue until the end of trial, defined as 52 weeks (13 cycles) after the 
last subject is randomized to the study, for subjects who are tolerating therapy and 
not progressing.  Subjects who have confirmed progressive disease will discontinue 
study treatment. 


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3.7 
ASSESSMENT OF DOSE-LIMITING TOXICITY (DLT)  
An interim safety analysis will occur once 12 subjects (6 subjects per arm) have been 
successfully randomized and have been treated a minimum of 1 cycle.  Enrollment 
will be paused while the safety interim analysis occurs.   
A DLT will be defined as the occurrence of any of the following ACP-196-related AEs 
(note: AEs clearly related to disease progression or the subject’s current medical 
history and associated comorbidities will not be considered DLTs): 
1. Grade 4 vomiting or diarrhea 
2. Grade 3 nausea, vomiting, or diarrhea lasting for > 72 hours 
3. Other Grade ≥ 3 toxicities (Note: transient Grade 3/4 laboratory abnormalities, 
including chemotherapy induced myelosuppression, that are not clinically 
significant will not be considered DLTs) 
4. Dosing delay due to toxicity for > 21 consecutive days. 
For any DLT related to ACP-196, the dose of ACP-196 will be withheld until the 
toxicity is Grade 1 or lower.  Thereafter, ACP-196 will be resumed at one lower dose 
level (Table 3-1).  The minimum dose of ACP-196 is 50 mg PO BID.  
Table 3-1. 
Dose Reductions for Arm 1 
ACP-196 
Dose Level 
ACP-196 
Dosing Regimen 
Nab-paclitaxel/Gemcitabine 
Starting Dose 
100 mg BID PO 
See Arm 2 
Level -1 
100 mg QD PO 
See Arm 2 
Level -2 
50 mg BID PO 
See Arm 2 
Abbreviations: BID = twice per day; IV = intravenous, PO = oral. 
 
3.8 
DOSING DELAYS AND MODIFICATIONS 
Subjects should be followed closely for AEs or laboratory abnormalities that might 
indicate ACP-196- or nab-paclitaxel/gemcitabine-related toxicity.  If a subject 
experiences a treatment-related AE or other intolerable AE during the course of 
therapy, then ACP-196, nab-paclitaxel/gemcitabine, or both drugs should be held, as 
necessary, until the AE resolves or stabilizes to an acceptable degree.  For Arm 1, 
ACP-196 treatment should continue when nab-paclitaxel/gemcitabine treatment is 
held or dose reduced for expected AEs associated with chemotherapy.  Similarly, 
gemcitabine and nab-paclitaxel may be continued if ACP-196 is held.  


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3.8.1 
Dose Modification and Discontinuation of ACP-196 
After the DLT review is cleared, the actions in Table 3-2 should be followed for the 
following toxicities: 
• 
Grade 4 ANC (< 500/μL) for > 7 days (neutrophil growth factors are permitted 
per American Society of Clinical Oncology (ASCO) guidelines [Smith 2006] 
and use must be recorded on the case report form [CRF]). 
• 
Grade 3 platelets in presence of significant bleeding. 
• 
Grade 4 platelets.  
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal 
antiemetic and/or anti-diarrheal therapy. 
• 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
Table 3-2. 
Drug Discontinuation Actions for ACP-196 
Occurrence 
Action 
1st – 2nd 
Hold ACP-196 until recovery to Grade ≤ 1 or baseline; may restart at 
original dose level 
3rd 
Hold ACP-196 until recovery to Grade ≤ 1 or baseline; restart at one 
dose level lower (100 mg QD) 
4th 
Discontinue ACP-196 
 
As appropriate, certain laboratory abnormalities may warrant more frequent 
monitoring (eg, once per week) until abnormalities have recovered to Grade ≤ 1.  If 
ACP-196 is reduced for apparent treatment-related toxicity, the dose need not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  However, 
if the subject tolerates a reduced dose of ACP-196 for ≥ 4 weeks then the dose may 
be increased to the next higher dose level, at the discretion of the investigator.  Such 
re-escalation may be particularly warranted if further evaluation reveals that the AE 
that led to the dose reduction was not treatment-related.  However, the maximum 
dose of ACP-196 is 100 mg BID for this protocol. 
Treatment with ACP-196 should be held for any unmanageable, potentially study 
drug-related toxicity that is Grade ≥ 3 in severity.  Any other clinically important events 
where dose delays may be considered appropriate by the Investigator must be 
discussed with the medical monitor.  Study drug may be held for a maximum of 
28 consecutive days from expected dose due to toxicity.  Study treatment should be 


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discontinued in the event of a toxicity lasting > 28 days, unless reviewed and 
approved by the medical monitor. 
Note:  Temporary withholding of ACP-196 for as little as 7 days can cause a transient 
worsening of disease and/or of constitutional symptoms.  Refer to Section 3.11 for 
more information on assessing disease progression under these circumstances. 
3.8.2 
Dose Modification and Discontinuation of 
Nab-paclitaxel/Gemcitabine  
The dose levels for nab-paclitaxel and gemcitabine are summarized below in Table 
3-3. 
Table 3-3. 
Dose Reductions for Arm 2 
Dose Level 
Nab-paclitaxel (mg/m2) 
Gemcitabine (mg/m2) 
Starting Dose 
125 
1000 
Level -1 
100 
800 
Level -2 
75 
600 
If additional dose 
reduction required 
Discontinue 
Discontinue 
 
Dose reductions/modifications for nab-paclitaxel/gemcitabine in response to 
neutropenia, thrombocytopenia, febrile neutropenia, peripheral neuropathy, 
cutaneous toxicity, and gastrointestinal toxicity are summarized below (Table 3-4 and 
Table 3-5).  For any toxicities not listed in these tables, the nab-paclitaxel prescribing 
information (Appendix 2) will be referred to after discussion with study monitor.  As 
mentioned previously, for subjects in Arm 1, ACP-196 treatment should be continued 
when nab-paclitaxel/gemcitabine are held or dose reduced for AEs expected with this 
chemotherapy regimen.  Study drug may be held for a maximum of 28 consecutive 
days from expected dose due to toxicity.  Study treatment should be discontinued in 
the event of a toxicity lasting > 28 days, unless reviewed and approved by the 
medical monitor. 
Severe and sometimes fatal hypersensitivity reactions, including anaphylactic 
reactions, have been reported.  Subjects who experience a severe hypersensitivity 
reaction to nab-paclitaxel/gemcitabine should not be re-challenged and will be 
discontinued from the study. 


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Table 3-4. 
Dose Modifications of Nab-paclitaxel/Gemcitabine for Neutropenia 
and/or Thrombocytopenia 
Cycle Day 
ANC 
(cells/mm3) 
 
Platelet count 
(cells/mm3) 
Nab-paclitaxel/Gemcitabine 
Day 1 
< 1500 
OR 
< 100,000 
Delay doses until recovery 
Day 8 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 1 dose level 
 
< 500 
OR 
< 50,000 
Withhold doses 
Day 15: If Day 8 doses were reduced or given without modification: 
 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 1 dose level from Day 8 
 
< 500 
OR 
< 50,000 
Withhold doses 
Day 15:  If Day 8 doses were withheld: 
 
≥ 1000 
OR 
≥ 75,000 
Reduce 1 dose level from Day 1 
 
500 to < 1000 
OR 
50,000 to < 75,000 
Reduce 2 dose levels from Day 1 
 
< 500 
OR 
< 50,000 
Withhold doses 
Abbreviation: ANC = absolute neutrophil count. 
 
Table 3-5. 
Dose Modifications of Nab-paclitaxel/Gemcitabine for Other 
Adverse Drug Reactions 
Adverse Drug Reaction 
Nab-paclitaxel 
Gemcitabine 
Febrile Neutropenia 
Grade 3 or 4 
Withhold until fever resolves and ANC ≥ 1500; resume 
at next lower dose level 
Peripheral Neuropathy 
Grade 3 or 4 
Withhold until improves to 
≤ Grade 1; resume at next 
lower dose level 
No dose reduction 
Cutaneous Toxicity 
Grade 2 or 3 
Reduce to next lower dose level; discontinue treatment 
if toxicity persists 
Gastrointestinal Toxicity 
Grade 3 or higher 
mucositis or diarrhea 
Withhold until resolved to Grade 1 and lower by 1 dose 
level  
Abbreviation: ANC = absolute neutrophil count. 
 
3.9 
CONCOMITANT THERAPY 
3.9.1 
Permitted Concomitant Therapy 
Standard supportive care medications, including growth factor support, antiemetic and 
antidiarrheal medications, are permitted as per institutional standards.   


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3.9.2 
Prohibited or Restricted Concomitant Therapy 
Any chemotherapy, anticancer immunotherapy, corticosteroids (at dosages equivalent 
to prednisone > 10 mg/day), warfarin or equivalent vitamin K antagonists (eg, 
phenprocoumon), experimental therapy, and radiotherapy (other than palliative 
radiation for symptom management) are prohibited.   
The concomitant use of strong inhibitors/inducers of CYP3A (see Appendix 5) should 
be avoided when possible (see Section 3.10.3).  If a subject requires a strong CYP3A 
inhibitor while on study, monitor the subject closely for potential toxicities.  
Conversely, concomitant administration of a strong inducer of CYP3A has the 
potential to decrease exposure of ACP-196 and could reduce efficacy.  For additional 
information on drugs with potential drug-drug interactions, refer to Section 3.10.3. 
3.10 PRECAUTIONS 
3.10.1 
Hepatitis B Reactivation 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated 
with ACP-196.  Therefore, subjects who are hepatitis B core antibody (anti-HBc) 
positive, or have a known history of HBV infection, should be monitored monthly with 
a quantitative PCR test for HBV DNA.  Monthly monitoring should continue until 
12 months after last dose of study drug(s).  Any subject with a rising viral load (above 
lower limit of detection) should discontinue study drug(s) and have antiviral therapy 
instituted and a consultation with a physician with expertise in managing hepatitis B.  
Insufficient data exist regarding the safety of resuming ACP-196 in subjects who 
develop HBV reactivation. 
3.10.2 
Dietary Restrictions 
ACP-196 can be taken with or without food.  Because ACP-196 may be metabolized 
by CYP3A, subjects should be strongly cautioned against excessive consumption of 
grapefruit, grapefruit juice, or Seville orange juice (which contain potent CYP3A 
inhibitors) or using herbal remedies or dietary supplements (in particular, St John’s 
wort, which is a potent CYP3A inducer). 
3.10.3 
Drug-drug Interactions 
At the systemic exposure levels expected in this study, ACP-196 inhibition of CYP 
metabolism is not anticipated.  However, as discussed in Section 1.4.3, concomitant 
administration of ACP-196 with a strong CYP3A inhibitor increased exposure by 


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approximately 5-fold.  Consequently, the concomitant use of strong inhibitors/inducers 
of CYP3A (see Appendix 5) should be avoided when possible.   
Based on these considerations, subjects who require therapy with drugs listed in 
Appendix 5 should not be enrolled into the study.  If medically justified, subjects may 
be enrolled if such inhibitors or inducers can be discontinued or alternative drugs that 
do not affect these enzymes can be substituted within 7 days before first dose of 
study drug.  If a subject requires a strong CYP3A inhibitor while on study, the 
ACP-196 dose should be reduced by one level (refer to Table 3-1 for dose 
reductions).  Conversely, concomitant administration of a strong inducer of CYP3A 
has the potential to decrease exposure of ACP-196 and could reduce efficacy. 
The effect of agents that reduce gastric acidity (eg, proton-pump inhibitors, 
H2-receptor antagonists or antacids) on ACP-196 absorption was evaluated in a 
healthy volunteer study (ACE-HV-004).  Results from this study indicate that subjects 
should avoid the use of calcium carbonate containing-drugs or supplements (eg, 
antacids and calcium supplements) and short-acting H2-receptor antagonists for a 
period of at least 2 hours before and after taking ACP-196.  Use of omeprazole, 
esomeprazole, lansoprazole or any other proton-pump inhibitors (eg, 
dexlansoprazole, rabeprazole, or pantoprazole) while taking ACP-196 is not 
recommended due to a potential decrease in study drug exposure.   
The metabolism of nab-paclitaxel is catalyzed by CYP2C8 and CYP3A4.  Caution 
should be exercised when administering nab-paclitaxel concomitantly with medicines 
known to inhibit (eg, ketoconazole and other imidazole antifungals, erythromycin, 
fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or 
induce (eg, rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either 
CYP2C8 or CYP3A (nab-paclitaxel prescribing information).  No formal drug 
interaction studies have been reported for gemcitabine (gemcitabine prescribing 
information).   
3.10.4 
Surgery 
Susceptibility to bleeding has been observed with the first generation Btk inhibitor, 
ibrutinib (IMBRUVICA prescribing information).  As a precaution, it is suggested that 
ACP-196 be held for 3 days before and after any major surgical procedure. 


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3.10.5 
Reproductive Toxicity 
Pilot reproductive toxicity studies have been performed that evaluate the effects of 
ACP-196 on embyrofetal development.  Definitive studies of ACP-196 on embryofetal 
development are pending. 
Nab-paclitaxel/gemcitabine is Pregnancy Category D.  Women who are sexually 
active and can bear children must use highly effective forms of contraception during 
the study and for 90 days after the last dose of ACP-196 or 4 months after the last 
dose of nab-paclitaxel/gemcitabine, whichever is longer.  Men who are sexually active 
and can beget children must use highly effective forms of contraception during the 
study and for 90 days after the last dose of ACP-196 or 4 months after the last dose 
of nab-paclitaxel/gemcitabine, whichever is longer.  Examples of highly effective 
methods of contraception include combined or progesterone-only hormonal 
contraceptives associated with inhibition of ovulation (implants, injectables or oral), 
intrauterine devices, intrauterine hormone releasing system, true sexual abstinence, 
bilateral tubal occlusion or vasectomized partner.  .  Note that barrier methods with 
and without spermaticide, progesterone-only hormonal contraceptives where 
inhibition of ovulation is not the primary mode of action, periodic abstinence (eg, 
calendar, ovulation, symptothermal, or postovulation methods) or withdrawal are not 
acceptable methods of contraception.  Men must refrain from sperm donation during 
the study and for 90 days after the last dose of ACP-196 or 4 months after the last 
dose of nab-paclitaxel/gemcitabine, whichever is longer. 
Subjects should promptly notify the investigator if they, or their partner, become 
pregnant during this period.  If a woman becomes pregnant during the treatment 
period, she must discontinue ACP-196 and nab-paclitaxel/gemcitabine immediately.  
Pregnancy in a female subject or a male subject’s partner must be reported as 
outlined in Section 6.2.3. 
3.10.6 
Overdose Instructions 
For any subject experiencing an ACP-196 overdose (administration of a dose 
≥ 1000 mg of ACP-196 at once), observation for any symptomatic side effects should 
be instituted, and vital signs, biochemical and hematologic parameters should be 
followed closely (consistent with the protocol or more frequently, as needed).  
Appropriate supportive management to mitigate adverse effects should be initiated.  If 


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the overdose ingestion is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered. 
There is no known antidote for nab-paclitaxel or gemcitabine overdosage.  The 
primary anticipated complications of overdosage for nab-paclitaxel would consist of 
bone marrow suppression, sensory neurotoxicity, and mucositis (nab-paclitaxel 
prescribing information).  Myelosuppression, paresthesias, and severe rash were the 
principal toxicities seen when a single dose of gemcitabine as high as 5700 mg/m2 
was administered by IV infusion over 30 minutes every 2 weeks to several patients in 
a dose-escalation study (gemcitabine prescribing information). 
The medical monitor must be contacted if a study drug overdose occurs.   
3.11 WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
Any subject has the right to withdraw from the study at any time. 
• 
Any subject who has confirmed objective evidence of cancer progression while 
receiving ACP-196 and/or nab-paclitaxel/gemcitabine should be withdrawn 
from the study treatment.  If there is uncertainty regarding whether there is true 
cancer progression, the subject may continue study treatment and remain 
under close observation (eg, evaluated at 3- to 6-week intervals) pending 
confirmation of progression.  In particular, transient worsening of disease early 
in therapy or during temporary interruption of study therapy (eg, for drug-
related toxicity, surgery, or intercurrent illness) may not indicate cancer 
progression.  In such circumstances, and if medically appropriate, subjects may 
resume therapy and relevant clinical, laboratory, and/or radiographic 
assessment can be attempted to document whether tumor control can be 
maintained or whether cancer progression has occurred. 
• 
Any subject whose medical condition substantially changes after entering the 
study should be carefully evaluated by the investigator in consultation with the 
medical monitor.  Such subjects should be withdrawn from study treatment if 
continuing would place them at risk.   
• 
Any subject who becomes pregnant or begins breastfeeding should be 
removed from study treatment. 
• 
Any subject who becomes significantly noncompliant with study drug 
administration, study procedures, or study requirements should be withdrawn 


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from study treatment in circumstances that increase risk or substantially 
compromise the interpretation of study results. 
• 
The investigator, in consultation with the medical monitor, may withdraw any 
subject from study treatment, if, in the investigator’s opinion, it is not in the 
subject’s best interest to continue.   
Subjects who discontinue study therapy will continue to be followed on study for 
follow-up of safety (Section 4.3) and survival unless they withdraw consent for further 
follow-up.  Thus, all subjects receiving ≥ 1 dose of study drug will be followed during 
the immediate post-therapy and long-term follow-up assessments unless the subject 
withdraws consent for such follow-up to be conducted.  The date the subject is 
withdrawn from study treatment or from the study (including long-term follow-up) and 
the reason for discontinuation will be recorded and also should be described on the 
appropriate CRF.   
3.12 REASONS FOR STUDY EXIT 
Reasons for study exit are: 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 
• 
Subject lost to follow-up 
• 
Death 
3.13 DATA AND SAFETY MONITORING 
This trial will be conducted in accordance with the sponsor’s Pharmacovigilance 
Committee procedures.  AEs and SAEs will be reviewed by the sponsor on an 
ongoing basis to identify safety concerns.  Conference calls among the sponsor and 
the investigators will be conducted periodically to discuss study progress, obtain 
investigator feedback and exchange of study information, review safety events (in 
particular: DLTs; SAEs; AEs leading to dose interruption, dose reduction, or therapy 
discontinuation), determine transitions between dose regimens, or discuss potential 
amendments to the protocol. 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 7.  Descriptions of the scheduled 
evaluations are outlined below and complete information on study drug and dosing is 
provided in Section 3.4. 


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Before study entry, throughout the study, and at the follow-up evaluation, various 
clinical and diagnostic laboratory evaluations are outlined.  The purpose of obtaining 
these detailed measurements is to ensure adequate safety and tolerability 
assessments.  Clinical evaluations and laboratory studies may be repeated more 
frequently if clinically indicated.   
4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the IRB/IEC-approved ICF confirming his 
or her willingness to participate in this study before initiating any screening activity 
that is not standard of care.  Subjects must also grant permission to use protected 
health information. 
4.1.2 
Medical History 
Collect and record the subject’s complete history through review of medical records 
and by interview.  Concurrent medical signs and symptoms must be documented to 
establish baseline severities.  A disease history, including the date of initial diagnosis 
and list of all prior anticancer treatments, and responses and duration of response to 
these treatments, also will be recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.  All medical 
occurrences from the time of first dose that meet this definition must be recorded.  
Important additional requirements for reporting SAEs are explained in Section 6.2. 
4.1.4 
Concomitant Medications and Therapy 
Document all concomitant medications and procedures from within 21 days before the 
start of study drug administration through 30 days after the last dose of study drug. 
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.3.  All screening 
procedures, unless otherwise indicated, should be completed within 21 days of the 
first dose of study drug.  Eligibility must be confirmed by the medical monitor before 
randomization. 


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4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 4. 
4.1.7 
Physical Examination, Vital Signs, Height & Weight 
The screening physical examination will include, at a minimum, the general 
appearance of the subject, height (screening only) and weight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal 
system, nervous system, and lymphatic system. 
Symptom-directed physical exams will be done during the treatment period and at the 
safety follow-up visits. 
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be 
assessed after the subject has rested in the sitting position.   
4.1.8 
Electrocardiogram  
Subjects should be in supine position and resting for at least 10 minutes before any 
study-related ECGs.  ECGs will be done at screening (3 ECGs taken at least 1 minute 
apart), on Cycle 1 Day 1 (1 ECG taken 1 hour [± 10 minutes] after taking ACP-196 on 
Day 1), Cycle 1 Day 15 (1 ECG taken 1 hour [± 10 minutes] after taking ACP-196), 
and at the treatment termination and/or safety follow-up visit (1 ECG at any time 
during the visit).  In addition, a single ECG will also be performed 1 hour after 
ACP-196 administration at Cycle 1 Day -1 for the first 6 subjects enrolled to Arm 1.   
4.1.9 
Urine or Serum Pregnancy Test 
Pregnancy tests will be required only for women of childbearing potential.  Testing will 
be done by a central or local laboratory as listed on the investigator’s Form FDA 
1572. 
4.1.10 
Hematology 
Hematology studies must include complete blood count with differential and platelet 
counts.  Testing will be done by a central laboratory as listed on the investigator’s 
Form FDA 1572. 
4.1.11 
Serum Chemistry 
Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood 
urea nitrogen (BUN), bone-specific alkaline phosphatase, C-reactive protein, calcium, 
chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, 


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phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and uric acid.  
If an unscheduled ECG is done at any time, then an electrolyte panel (ie, calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing.  Testing 
will be done by a central laboratory as listed on the investigator’s Form FDA 1572. 
4.1.12 
Amylase and Lipase 
Serum amylase and serum lipase testing will be done by a central laboratory as listed 
on the investigator’s form FDA 1572. 
4.1.13 
Coagulation 
Coagulation studies must include PT and aPTT.  Testing will be done by a central 
laboratory as listed on the investigator’s Form FDA 1572. 
4.1.14 
Hepatitis B and C Testing 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis 
B surface antibody (HBsAb), anti-HBc, and HCV antibody.  In addition, any subjects 
testing positive for any hepatitis serology, must have PCR testing (see Appendix 7 
and exclusion criterion #15).  Testing will be done by local or central laboratory.   
Refer to Section 3.10.1 and Appendix 7 regarding monitoring of subjects who are 
anti-HBc positive or have a known history of HBV. 
4.1.15 
Urinalysis 
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
Testing will be done by a central laboratory as listed on the investigator’s Form FDA 
1572.   
4.1.16 
T/B/NK/Monocyte Cell Count 
Flow cytometry testing for CD3+, CD4+, CD8+, CD14+, CD19+, and CD16/56+ cells.  
Testing will be done by a central laboratory as listed on the investigator’s Form FDA 
1572. 
4.1.17 
Disease Markers  
Serum samples will be used for the determination of CA19-9.   
4.1.18 
Pharmacodynamics/Pharmacokinetics and Biomarker 
Studies 
Blood samples will be used for pharmacodynamic testing (Section 3.1.2).   


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Tissue sections from archival tumor biopsies and/or any newly obtained biopsies 
performed during the study will be used for exploratory biomarker studies 
(Section 3.1.2).  Tissue sections from either an archived or newly obtained tumor 
sample (most recent biopsy) are to be provided at screening, if allowed by regional 
authorities.  If available, de-identified pathology reports from the most recent 
diagnostic work-up, including immunohistochemistry and cytogenetic analyses of 
tumor tissue, may be requested by the sponsor. 
Refer to the laboratory manual for instructions on collection and shipment of the 
pharmacodynamic and biomarker samples.  All testing will be done by the sponsor or 
designee.   
For Arm 1 (for the first 20 subjects enrolled only), the following PK sampling will be 
done for the measurement of ACP-196 levels:  0 (predose), 0.5, 1, 2, and 4 hours 
after ACP-196 administration on Cycle 1 Day -1 (for the first 6 subjects enrolled only), 
Cycle 1 Day 1,  and Cycle 2 Day 15.  The predose sample can be taken up to 30 
minutes before dosing.  The window for other timepoints is ± 5 minutes.  Leftover 
plasma samples may be used for ACP-196 metabolite analyses.  Testing will be done 
by a central laboratory.  Refer to the laboratory manual for instructions on collection 
and shipment of PK samples. 
4.1.19 
Tumor Assessments 
A pretreatment CT scan with contrast (unless contraindicated) is required of the 
chest, abdomen, and pelvis and any other disease sites (eg, neck) within 30 days 
before the first dose of study drug.  Magnetic resonance imaging (MRI) may be used 
for subjects allergic to CT contrast media. 
On treatment CT scans with contrast (unless contraindicated) of the chest, abdomen, 
and pelvis and any other disease sites (eg, neck) will be done for tumor assessments 
on Cycle 3 Day 1 then on Day 1 every other cycle (± 7 days) thereafter or more 
frequently at investigator discretion.  At all other visits, tumor assessments will be 
done by physical exam and laboratory results.   
RECIST 1.1 guidelines (Eisenhauer 2009) will be followed for selection of measurable 
and nonmeasurable lesions and also with regard to the number of lesions to be 
assessed (refer to Appendix 1 for more details on RECIST 1.1).   
De-identified copies of all radiology results may be requested by the sponsor.   


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4.1.20 
Treatment Termination Visit 
A treatment termination visit is required for safety assessments as outlined in the 
Schedule of Assessments (Appendix 7).  The treatment termination visit will occur 
within 7 days of the last dose of study drug and is not required for subjects who 
discontinue from the study within 10 days of a scheduled study visit.  If the treatment 
termination visit and the safety follow-up visit coincide, then these can be combined 
into 1 visit. 
4.1.21 
Study Drug Accountability 
See Section 7.6. 


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4.2 
INVESTIGATOR’S ASSESSMENT OF RESPONSE TO TREATMENT 
Responses will be categorized as CR, PR, SD, or PD.  The definitions of response in 
target lesions are provided in Table 4-1.  The definitions of response in nontarget 
lesions are provided in Table 4-2. 
Table 4-1. 
Evaluation of Target Lesions (RECIST) 
Response 
Category 
Definition 
CR 
Disappearance of all target and nontarget lesions including normalization of 
an elevated tumor marker level.  Any pathological lymph nodes (whether 
target or nontarget) must have reduction in short axis to <10 mm.   
PR 
A ≥ 30% decrease in the sum of the diameters of target lesions taking as a 
reference the baseline sum of the diameters.   
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as reference the smallest sum diameters while on study. 
PDa 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  (Note: the 
appearance of one or more new lesions is also considered progression).   
a. Transient apparent worsening of disease early in therapy or during temporary 
interruption of study therapy (eg, for drug-related toxicity or intercurrent illness) may not 
indicate true cancer progression.  If there is uncertainty regarding whether there is true 
cancer progression, the subject may continue or resume study treatment and remain 
under close observation (eg, evaluated at 3- to 6-week intervals) pending confirmation of 
progression. 
Abbreviations:  CR = complete response; PD = progressive disease; PR = partial response, 
SD = stable disease. 
Evaluation of nontarget lesions:  while some nontarget lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the Schedule of Assessments. 
Table 4-2. 
Evaluation of Nontarget Lesions (RECIST) 
Response 
Category 
Definition 
CR 
Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/ 
Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PDa 
Unequivocal progressionb of existing non-target lesions.  (Note: the 
appearance of one or more new lesions is also considered progression).   
a. 
Transient apparent worsening of disease early in therapy or during temporary interruption of study 
therapy (eg, for drug-related toxicity or intercurrent illness) may not indicate true cancer progression.  
If there is uncertainty regarding whether there is true cancer progression, the subject may continue 
or resume study treatment and remain under close observation (eg, evaluated at 3- to 6-week 
intervals) pending confirmation of progression 
b. 
Refer to RECIST 1.1 criteria for detailed explanation of “unequivocal progression”. 
Abbreviations:  CR = complete response; PD = progressive disease. 


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4.2.1 
Determination of Response at Each Timepoint (RECIST) 
The tumor response at each timepoint will be determined.  Table 4-3 provides a 
summary of the overall response status calculation at each timepoint.   
Table 4-3. 
Timepoint Response (RECIST) 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated No 
PR 
SD 
Non-PD or not all evaluated No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations:  CR = complete response; PD = progressive disease; PR = partial 
response; SD = stable disease; NE = nonevaluable.. 
 
4.2.2 
Confirmation of Tumor Status and Determination of Best 
Overall Response (RECIST) 
The best overall response (BOR) recorded from the start of treatment until tumor 
progression will be determined.  Adjudication of BOR is based on evaluation of each 
successive set of 2 scans as indicated in Table 4-4.   


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Table 4-4. 
Best Overall Response Assessment and Requirements for 
Confirmation (RECIST) 
Response Category 
at First Timepoint 
Response Category at 
Subsequent Timepoint 
Best Overall Response 
CR  
CR  
CR  
CR  
PR  
SD, PD, or PRa 
CR  
SD  
SD provided minimum criteria for SD 
duration met otherwise PD 
CR  
PD  
SD provided minimum criteria for SD 
duration met otherwise PD  
CR  
NE  
SD provided minimum criteria for SD 
duration met otherwise NE  
PR  
CR  
PR  
PR  
PR  
PR  
PR  
SD  
SD  
PR  
PD  
SD provided minimum criteria for SD 
duration met otherwise PD  
PR  
NE  
SD provided minimum criteria for SD 
duration met otherwise NE  
NE  
NE  
NE  
Abbreviations:  BOR = best overall response; CR = complete response; PD = progressive 
disease; PR = partial response; SD = stable disease; NE = nonevaluable 
a. If a CR is truly met at first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(since disease must have reappeared after CR).  Best response would depend on whether 
minimum duration for SD was met.  However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the subject 
had PR, not CR at the first time point.  Under these circumstances, the original CR should 
be changed to PR and the best response is PR. 
4.3 
SAFETY FOLLOW-UP VISIT 
Each subject should be followed for 30 (+ 7) days after his or her last dose of study 
drug (ie, the “safety follow-up visit”) to monitor for resolution or progression of AEs 
(see Section 6.2.5) and to document the occurrence of any new events.  Subjects 
who withdraw consent for study treatment should still be encouraged to complete the 
safety follow-up assessments, but these assessments cannot be mandated if subject 
consent for further study participation is withdrawn.  The Schedule of Assessments 
(Appendix 7) describes the procedures required for safety follow-up.   
4.4 
SURVIVAL 
After discontinuing study therapy, subjects will be contacted approximately every 
12 weeks until death, withdrawal by subject, lost to follow up, or study terminated by 
the sponsor, whichever comes first.   


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4.5 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the original 
scheduled date as possible.  An exception is made when rescheduling becomes, in 
the investigator’s opinion, medically unnecessary or unsafe because it is too close in 
time to the next scheduled evaluation.  In that case, the missed evaluation should be 
abandoned. 
5.0 
STATISTICAL METHODS OF ANALYSIS 
The statistical and analytical plans presented below summarize the more complete 
plans to be detailed in the Statistical Analysis Plan (SAP).  A change to the data 
analysis methods described in the protocol will require a protocol amendment only if it 
alters a principal feature of the protocol.  Should the SAP and this protocol differ, the 
methods in the SAP prevail.  The SAP will be finalized before database lock.  Any 
changes to the methods described in the final SAP will be described and justified in 
the clinical study report. 
5.1 
GENERAL CONSIDERATIONS 
Descriptive statistics (including means, standard deviations, and medians for 
continuous variables and proportions and CIs for discrete variables) will be used to 
summarize data as appropriate.   
For the safety interim analysis (DLT review), enrollment of 6 subjects in the ACP-196 
combination arm for DLT review is consistent with sample sizes used in oncology 
studies for determination of MTD.  The trial employs the standard National Cancer 
Institute definition of MTD (dose associated with DLT in ≤ 17% of subjects).  Provided 
the ACP-196 combination arm is not stopped early for toxicity (Section 5.5), then up 
to a total of 60 subjects will be enrolled per arm.   
The sample size for this 2-arm trial was determined by a Z-test for normal 
approximation of binomial distribution, based on one-sided α = 0.10, 80% power, with 
projected response rates of 42% in the ACP-196 combination arm and 23% in the 
nab-paclitaxel/gemcitabine arm (based on the 23% response rate observed in the 
Phase 3 study [nab-paclitaxel prescribing information]).  Accounting for 10% drop-out 
rate (6 in each arm), final sample size is 60 in each arm. 
Independent Radiology Review 


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The IRR will be performed by independent central radiologists in accordance with the 
IRR charter. 
5.2 
DEFINITION OF ANALYSIS SETS 
The following definitions will be used for the efficacy and safety analysis sets. 
• 
Intent-to-treat (ITT) analysis set: All enrolled subjects.  The ITT analysis set will 
be used to summarize demographics, as well as baseline and disease 
characteristics. 
• 
Safety analysis set: All enrolled subjects who receive ≥ 1 dose of study drug.   
The safety analysis set will be used for both safety and efficacy endpoints.  
Subjects will be analyzed as treated. 
• 
Per-protocol (PP) analysis set: A subset of subjects from the ITT analysis set 
who received ≥ 1 dose of study drug and do not have any important protocol 
deviations.  This analysis set may be used for sensitivity analysis relating to the 
efficacy endpoints. 
• 
Response evaluable analysis set: All enrolled subjects who receive ≥ 1 dose of 
study drug, and undergo ≥ 1 tumor assessment after treatment.  This analysis set 
may be used for sensitivity analysis relating to the efficacy endpoints.   
• 
PK/PD analysis set: A subset of subjects from the ITT analysis set who received 
≥ 1 dose of study drug, have sufficient baseline measurements, and 
undergo ≥ 1 PK/PD assessment after treatment.  This analysis set will be used for 
PK/PD parameters. 
5.3 
MISSING DATA HANDLING 
No imputation of values for missing data will be performed except that missing or 
partial start and end dates for AEs and concomitant medication will be imputed 
according to prespecified, conservative imputation rules.  Subjects lost to follow-up (or 
drop out) will be included in statistical analyses to the point of their last evaluation. 
5.4 
ENDPOINT DATA ANALYSIS 
5.4.1 
Safety Endpoint 
Safety summaries will include summaries in the form of tables and listings.  The 
frequency (number and percentage) of treatment emergent AEs will be reported in 
each treatment group by MedDRA System Organ Class and Preferred Term.  


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Summaries will also be presented by the severity of the AE (per CTCAE, v4.03) and 
by relationship to study drug (eg, either ACP-196, nab-paclitaxel/gemcitabine, or 
both). 
Laboratory shift tables containing counts and percentages will be prepared by 
treatment assignment, laboratory parameter, and time.  Summary tables will be 
prepared for each laboratory parameter.  Figures of changes in laboratory parameters 
over time will be generated. 
Results of vital sign assessments and physical exams will be tabulated and 
summarized.   
5.4.2 
Demographics and Baseline Characteristics 
Additional analyses will include summaries of subject demographics, baseline 
characteristics, compliance, and concurrent treatments.  Concomitant medications will 
be coded and tabulated according to the World Health Organization WHO Drug 
Dictionary (WHODRUG). 
5.4.3 
Study Treatment Administration and Compliance 
Descriptive information will be provided regarding the number of ACP-196 and 
nab-paclitaxel/gemcitabine doses prescribed, the total number of doses taken, the 
number of days of treatment, and the number and timing of prescribed dose 
reductions and interruptions.   
For each subject, ACP-196 and nab-paclitaxel/gemcitabine compliance will be 
described in terms of the proportion of study drug actually taken. 
5.4.4 
Analysis of Efficacy Parameters 
Response Rate 
The individual and composite endpoints of response and progression will be 
determined.  Tumor control will be documented at each assessment by response 
category (see Section 4.2) as defined for each response parameter, date that 
response is first documented, and date of disease progression.  ORR will be defined 
as the proportion of subjects who achieve a PR or CR (see Section 4.2).   
ORR will be calculated and the corresponding 2-sided 95% CI will be derived.   
Duration of Response 


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The duration of response defined as the interval from the first documentation of 
response to the earlier of the first documentation of definitive disease progression or 
death from any cause.  Kaplan-Meier methods will be used to estimate event-free 
curves and corresponding quartiles (including the median).  Data from surviving, 
non-progressing subjects will be censored and detailed censoring rules will be 
specified in the statistical analysis plan (SAP).   
Progression-free Survival 
Progression-free survival is defined as the interval from the date of first dose of study 
drug to the earlier of the first documentation of objective disease progression or death 
from any cause.  Kaplan-Meier methods will be used to estimate the event-free 
curves and corresponding quartiles (including the median).  Data from surviving, 
non-progressing subjects will be censored and detailed censoring rules will be 
specified in the SAP.  
Overall Survival 
OS is defined as the time from date of first dose of study drug until date of death due 
to any cause.  Subjects who are known to be alive or whose survival status is 
unknown will be censored at the date last known to be alive.  Subjects who are 
completely lost to follow-up for survival will be censored at date of randomization.  
The analysis methods for OS will be similar to those described for progression-free 
survival.   
Serum cancer antigen 19-9 (CA19-9) 
Changes in CA19-9 will be evaluated using descriptive statistics evaluating the 
absolute and the percent change from baseline in serum CA19-9 levels. 
In addition, several exploratory endpoints will be evaluated.   
5.4.5 
Pharmacodynamic or Biomarker Analyses 
Additional PD, PK and biomarker analyses may be performed, as deemed 
appropriate. 
Correlations between subject characteristics and outcome measures and correlations 
among outcomes measures will be explored using regression models or other 
appropriate techniques. 


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5.5 
FUTILITY AND TOXICITY MONITORING 
The futility and toxicity monitoring will be analyzed for Arm 1 only.  The primary 
efficacy endpoint in Arm 1 is response, which is defined as ORR by RECIST 1.1 (ie, 
CR and PR).  An ORR of at least 23% is clinically meaningful in this population (Von 
Hoff 2013).  The response outcome within 12 weeks will be used in the primary 
analysis.  A Bayesian method (Thall 1995) will be used for futility and toxicity 
monitoring of ACP-196 in combination with nab-paclitaxel/gemcitabine.  The stopping 
rules are as follows: 
Pr(θE < 0.23 | data)  > 0.95 
Pr(TE > 0.30 | data)  > 0.90 
Enrollment will be stopped early if there is > 95% probability that the ORR is < 23% or 
there is > 90% probability that the toxicity rate is higher than 30%.  Where θE denotes 
the marginal response rate, assuming that θE follows a prior distribution of beta (a,b), 
where a and b represent nonresponse and response rates (0.23, 0.77), and TE 
denotes the toxicity rate, assuming that TE has a prior distribution of beta (0.30, 0.70).  
The definition of toxicity of ACP-196 in Arm 1 will follow the same definition used for 
assessing DLTs (see Section 3.7) including the DLT assessment window. 
The above futility and toxicity monitoring rules will be implemented once the first 
10 subjects have been evaluated in Arm 1 and will be applied through the first 
40 subjects enrolled.  The corresponding stopping boundaries for the futility 
monitoring are: enrollment will be stopped early due to futility if (number of subjects 
with ORR/number of subjects evaluated) ≤ 0/(10-13), 1/(14-20), 2/(21-26), 3/(27-32), 
4/(33-38), 5/(39-40).  The corresponding stopping boundaries for toxicity monitoring 
are listed in Table 5-1.  The operating characteristics of the design are presented in 
Table 5-2.  Multc Lean software v2.1 was used for the design. 


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Table 5-1.  Stopping Boundaries for ACP-196 Toxicity Monitoring 
(Applies to Arm 1 Only) 
                  
Stop enrolling if there are this 
many DLTs total: 
No.  Subjects   
(inclusive)        
# Toxicities  (inclusive)    
1-9        
Never stop with this many subjects 
10-12 
6-12 
13-14 
7-14 
15-17 
8-17 
18-20 
9-20 
21-23 
10-23 
24-25 
11-25 
26-28 
12-28 
29-31 
13-31 
32-34 
14-34 
35-37 
15-37 
38-39 
16-39 
Table 5-2.  Operating Characteristics of the Design 
ORR 
Toxicity rate 
Probability of early stop 
Average # of subjects 
treated  
0.23 
0.1 
0.23 
34.8 
0.23 
0.3 
0.42 
30.3 
0.23 
0.5 
0.96 
15.0 
0.33 
0.1 
0.05 
38.8 
0.33 
0.3 
0.28 
33.5 
0.33 
0.5 
0.95 
15.7 
 
 
6.0 
ASSESSMENT OF SAFETY 
All randomized subjects will be evaluated clinically and using standard laboratory 
testing during their participation in this study.  Safety assessments will consist of 
monitoring and recording AEs and SAEs; measurements of protocol-specified 
hematology, clinical chemistry, urinalysis, and other laboratory variables; 
measurement of protocol-specified vital signs; and other protocol-specified tests that 
are deemed critical to the safety evaluation of the study drug(s). 


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6.1 
DEFINITIONS 
6.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational (medicinal) product regardless of 
attribution. 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms associated 
with pancreatic cancer that were not present before the AE reporting period 
(see Section 6.2.1). 
• 
Preexisting medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period. 
Abnormal laboratory values should not be reported as AEs; however, any clinically 
significant laboratory value (ie, requiring medical intervention, reduction or withholding 
of ACP-196 and/or nab-paclitaxel/gemcitabine dose, or leading to study 
discontinuation) will be reported as adverse events. 
6.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the Sponsor to applicable regulatory 
authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
• 
It results in death (ie, the AE actually causes or leads to death). 
• 
It is life-threatening (ie, the AE, in the view of the investigator, places the 
subject at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death). 
• 
It requires or prolongs in-patient hospitalization. 
• 
It results in persistent or significant disability/incapacity (ie, the AE results 
in substantial disruption of the subject’s ability to conduct normal life 
functions). 


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• 
It results in a congenital anomaly/birth defect in a neonate/infant born to 
a mother exposed to the investigational product. 
• 
It is considered a significant medical event by the investigator based on 
medical judgment (eg, may jeopardize the subject or may require 
medical/surgical intervention to prevent 1 of the outcomes listed above). 
6.1.3 
Severity 
Definitions found in the CTCAE version 4.03 or higher will be used for grading the 
severity (intensity) of AEs.  The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each referenced AE.  Should a subject experience 
any AE not listed in the CTCAE, the following grading system should be used to 
assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no 
special treatment, and not interfering with the subject’s daily activities 
• 
Grade 2 (Moderate AE) – experiences which introduce some level of 
inconvenience or concern to the subject, and which may interfere with 
daily activities, but are usually ameliorated by simple therapeutic 
measures 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or 
intolerable, significantly interrupt the subject’s usual daily activity, and 
require systemic drug therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the 
subject to be in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject 
death 
6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed 
or reported during the study, as outlined in the prior sections, are recorded on the 
CRF.  All SAEs must be reported on the SAE/Product Compliant form or clinical 
database. 
6.2.1 
Adverse Event Reporting Period 
The AE reporting period for this study begins when the subject receives the first dose 
of study drug and ends with the safety follow-up visit.  If a fatal AE occurs beyond 
30 days after the last dose of ACP-196 and/or nab-paclitaxel/gemcitabine AND it is 
assessed by the investigator as related to ACP-196 and/or nab-
paclitaxel/gemcitabine, it must be reported as an SAE. 


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6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation 
time points during the study.  All AEs and SAEs whether volunteered by the subject, 
discovered by study personnel during questioning, or detected through physical 
examination, or other means, will be recorded in the subject’s medical record and on 
the AE CRF.   
Disease progression itself is not considered an AE; however, signs and symptoms of 
disease progression may be recorded as AEs or SAEs. 
Each recorded AE or SAE will be described by its duration (eg, start and end dates), 
severity, regulatory seriousness criteria, if applicable, suspected relationship to the 
study drugs (see following guidance), and any actions taken.  The causality of AEs to 
the study drugs will be assessed by means of the question: ‘Is there a reasonable 
possibility that the event may have been caused by the study drug?’  Answer Yes or 
No.   
See Appendix 6 for more detail on assessing causality. 
6.2.3 
Pregnancy 
The investigator should report all pregnancies and pregnancies in the partners of 
subjects within 24 hours using the Pregnancy Report Form.  This form should be 
faxed or emailed to Acerta Pharma Drug Safety.  Any pregnancy-associated SAE 
must be reported to Acerta Pharma, according to the usual timelines and directions 
for SAE reporting (Section 6.2.4). 
Any uncomplicated pregnancy that occurs with the subject or with the partner of a 
treated subject during this study will be reported.  All pregnancies and partner 
pregnancies that are identified during or after this study, wherein the estimated date 
of conception is determined to have occurred from the time of consent to 90 days 
after the last dose of study medication will be reported, followed to conclusion, and 
the outcome reported. 
A pregnancy itself is not regarded as an AE unless there is suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Likewise, elective abortions without complications are not 
considered AEs.  Any SAEs associated with pregnancy (eg, congenital 


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abnormalities/birth defects/spontaneous miscarriage or any other serious events) 
must additionally be reported as such using the SAE report form. 
Subjects should be instructed to immediately notify the investigator of any 
pregnancies.  Any women receiving study drug who become pregnant must 
immediately discontinue study drug.  The investigator should counsel the subject, 
discussing any risks of continuing the pregnancy and any possible effects on the 
fetus. 
Upon completion of the pregnancy, additional information on the mother, pregnancy, 
and baby will be collected and sent to DrugSafety@acerta-pharma.com. 
6.2.4 
Expedited Reporting Requirements for Serious Adverse 
Events 
All SAEs must be reported within 24 hours of discovery.  All initial SAE reports and 
follow-up information will be reported on an SAE/Product Complaint form using the 
protocol-specific electronic data capture system.  If electronic SAE reporting is not 
available, paper SAE/Product Complaint forms may be emailed or faxed to Acerta 
Pharma Drug Safety, or designee.  Acerta Pharma may request follow-up and other 
additional information from the investigator (eg, hospital admission/discharge notes 
and laboratory results). 
All deaths should be reported with the primary cause of death as the AE term, as 
death is typically the outcome of the event, not the event itself.  The primary cause of 
death on the autopsy report should be the term reported.  Autopsy and postmortem 
reports must be forwarded to Acerta Pharma Drug Safety, or designee, as outlined 
above. 
If study drug is discontinued because of an SAE, this information must be included in 
the SAE report. 
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the 
SAE is attributable to the investigational product and is not listed in the current 
Investigator Brochure (ie, an unexpected event).  In this case, Acerta Pharma Drug 
Safety/Designee will forward a formal notification describing the suspected 
unexpected serious adverse reaction (SUSAR) to all investigators.  Each investigator 
must then notify his or her IRB/IEC of the SUSAR. 


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Drug Safety Contact Information 
Fax: 
  
 
 
 
 
Other Safety Issues Requiring Expedited Reporting 
For studies being conducted in Europe expedited reporting is required for 
safety issues that might materially alter the current benefit-risk assessment of 
an investigational medicinal product or that would be sufficient to consider 
changes in the investigational medicinal products administration or in the 
overall conduct of the trial.  For a detailed description of safety issues that may 
qualify for expedited reporting please refer to the European Commission 
guidance titled, “Detailed guidance on the collection, verification and 
presentation of adverse reaction reports arising from clinical trials on medicinal 
products for human use – April 2006” available at 
http://ec.europa.eu/health/files/eudralex/vol-
10/21_susar_rev2_2006_04_11_en.pdf. 
6.2.5 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting 
period should be followed to resolution, or until the investigator assesses the subject 
as stable or the subject is lost to follow-up or withdraws consent. 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
Acerta Pharma retains the right to terminate the study and remove all study materials 
from a study site at any time.  Specific circumstances that may precipitate such 
termination are: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity 
• 
Significant or numerous deviations from study protocol requirements, such as 
failures to perform required evaluations on subjects and maintain adequate 
study records 


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• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 
• 
The incidence and/or severity of AEs in this or other studies indicating a 
potential health hazard caused by the study treatment 
7.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, Investigator Brochure, 
and any other relevant supporting information (eg, all advertising materials) to the 
appropriate IRB/IEC for review and approval before study initiation.  A signed protocol 
approval page; a letter confirming IRB/IEC approval of the protocol and informed 
consent; and a statement that the IRB/IEC is organized and operates according to 
Good Clinical Practice (GCP) and the applicable laws and regulations; must be 
forwarded to Acerta Pharma before screening subjects for the study.  Additionally, 
sites must forward a signed Form FDA 1572 (Investigator Obligation Form) to Acerta 
Pharma before screening subjects for study enrollment.  Amendments to the protocol 
must also be approved by the IRB/IEC and local regulatory agency, as appropriate, 
before the implementation of changes in this study. 
7.2 
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 
INFORMATION AUTHORIZATION 
A copy of the IRB/IEC-approved informed consent must be forwarded to Acerta 
Pharma for regulatory purposes.  The investigator, or designee (designee must be 
listed on the Study Personnel Responsibility/Signature Log, see Section 7.11), must 
explain to each subject the purpose and nature of the study, the study procedures, 
the possible adverse effects, and all other elements of consent as defined in § 21CFR 
Part 50, and other applicable national and local regulations governing informed 
consent form.  Each subject must provide a signed and dated informed consent 
before enrollment into this study.  In the case of a subject who is incapable of 
providing informed consent, the investigator (or designee) must obtain a signed and 
dated informed consent form from the subject’s legal guardian.  Signed consent forms 
must remain in each subject’s study file and be available for verification by study 
monitors at any time. 
In accordance to individual local and national subject privacy regulations, the 
investigator or designee must explain to each subject that for the evaluation of study 
results, the subject’s protected health information obtained during the study may be 


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shared with Acerta Pharma and its designees, regulatory agencies, and IRBs/IECs.  
As the study Sponsor, Acerta Pharma will not use the subject’s protected health 
information or disclose it to a third party without applicable subject authorization.  It is 
the investigator’s or designee’s responsibility to obtain written permission to use 
protected health information from each subject, or if appropriate, the subject’s legal 
guardian.  If a subject or subject’s legal guardian withdraws permission to use 
protected health information, it is the investigator’s responsibility to obtain the 
withdrawal request in writing from the subject or subject’s legal guardian and to 
ensure that no further data will be collected from the subject.  Any data collected on 
the subject before withdrawal will be used in the analysis of study results. 
7.3 
SUBJECT SCREENING LOG 
The investigator must keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects 
subsequently excluded from enrollment, record the reason(s) for exclusion. 
7.4 
CASE REPORT FORMS 
Authorized study site personnel (see Section 7.11) will complete CRFs designed for 
this study according to the completion guidelines that will be provided within the 
clinical database.  The investigator will ensure that the CRFs are accurate, complete, 
legible, and completed promptly.  The investigator will ensure that source documents 
that are required to verify the validity and completeness of data transcribed on the 
CRFs are never obliterated or destroyed. 
7.5 
STUDY MONITORING REQUIREMENTS 
Representatives of Acerta Pharma or its designee will monitor this study until 
completion.  Monitoring will be conducted through personal visits with the investigator 
and site staff as well as any appropriate communications by mail, fax, email, or 
telephone.  The purpose of monitoring is to ensure compliance with the protocol and 
the quality and integrity of the data.  This study is also subject to reviews or audits. 
Every effort will be made to maintain the anonymity and confidentiality of all subjects 
during this clinical study.  However, because of the experimental nature of this 
treatment, the investigator agrees to allow the IRB/IEC, representatives of Acerta 
Pharma, its designated agents, and authorized employees of the appropriate 
regulatory agencies to inspect the facilities used in this study and, for purposes of 


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verification, allow direct access to the hospital or clinic records of all subjects enrolled 
into this study.  This includes providing by fax, email, or regular mail de-identified 
copies of radiology, pathology, and/or laboratory results when requested by the 
sponsor.  A statement to this effect will be included in the informed consent and 
permission form authorizing the use of protected health information. 
7.6 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
ACP-196 capsules must be kept in a locked limited access cabinet or space.  ACP-
196 must not be used outside the context of the protocol.   
Study drug accountability records, for ACP-196 and, when applicable, for nab-
paclitaxel and gemcitabine, must be maintained and readily available for inspection by 
representatives of Acerta Pharma and are open to inspections by regulatory 
authorities at any time.   
Each shipment of study drug will contain a Clinical Supplies Shipping Receipt Form 
(CSSF) that must be appended to the site’s drug accountability records.  Additionally 
a Drug Re-order Form for requesting more study drug is provided in the pharmacy 
binder.  If it is used, then the Drug Re-order Form must also be included in the site’s 
drug accountability records.   
Contents of each shipment must be visually inspected to verify the quantity and 
document the condition of study drug capsules.  The designated recipient completes 
and signs the CSSF.  A copy of the signed CSSF must be faxed or emailed to Acerta 
Pharma at the fax number/email address listed on the form. 
An Investigational Drug Accountability Log must be used for drug accountability.  For 
accurate accountability, the following information must be noted when drug supplies 
are used during the study: 
1. 
study identification number (ACE-ST-004) 
2. 
subject identification number 
3. 
lot number(s) of ACP-196 and nab-paclitaxel/gemcitabine dispensed for that 
subject 
4. 
date and quantity of drug dispensed 
5. 
any unused drug returned by the subject 
At study initiation, the monitor will evaluate and approve the site’s procedure for 
investigational product disposal/destruction to ensure that it complies with Acerta 
Pharma’s requirements.  If the site cannot meet Acerta Pharma’s requirements for 
disposal/destruction, arrangements will be made between the site and Acerta Pharma 


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or its designee, for return of unused investigational product.  Before 
disposal/destruction, final drug accountability and reconciliation must be performed by 
the monitor. 
All study supplies and associated documentation will be regularly reviewed and 
verified by the monitor. 
7.7 
RECORD RETENTION 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of 
study protocols and amendments, each Form FDA 1572, IRB/IEC approval letters, 
signed ICFs, drug accountability records, SAE information transmitted to Acerta 
Pharma, subject files (source documentation) that substantiate entries in CRFs, all 
relevant correspondence and other documents pertaining to the conduct of the study. 
An investigator shall retain records for a period of at least 2 years after the date the 
last marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and 
regulatory authorities have been notified.  The investigator must notify Acerta Pharma 
and obtain written approval from Acerta Pharma before destroying any clinical study 
records at any time.  Acerta Pharma will inform the investigator of the date that study 
records may be destroyed or returned to Acerta Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide 
express written approval of, any change in the maintenance of the foregoing 
documents if the investigator wishes to move study records to another location or 
assign responsibility for record retention to another party.  If the investigator cannot 
guarantee the archiving requirements set forth herein at his or her study site for all 
such documents, special arrangements must be made between the investigator and 
Acerta Pharma to store such documents in sealed containers away from the study 
site so that they can be returned sealed to the investigator for audit purposes. 
7.8 
PROTOCOL AMENDMENTS 
Acerta Pharma will initiate any change to the protocol in a protocol amendment 
document.  The amendment will be submitted to the IRB/IEC together with, if 
applicable, a revised model ICF.  If the change in any way increases the risk to the 


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subject or changes the scope of the study, then written documentation of IRB/IEC 
approval must be received by Acerta Pharma before the amendment may take effect.  
Additionally under this circumstance, information on the increased risk and/or change 
in scope must be provided to subjects already actively participating in the study, and 
they must read, understand, and sign any revised ICF confirming willingness to 
remain in the trial. 
7.9 
PUBLICATION OF STUDY RESULTS 
Authorship, in general, will follow the recommendations of the International 
Committee of Medical Journal Editors (International Committee of Medical Journal 
Editors 2014).   
7.10 CLINICAL TRIAL INSURANCE 
Clinical trial insurance has been undertaken according to the laws of the countries 
where the study will be conducted.  An insurance certificate will be made available to 
the participating sites at the time of study initiation. 
7.11 GENERAL INVESTIGATOR RESPONSIBILITIES 
The principal investigator must ensure that: 
1. He or she will personally conduct or supervise the study. 
2. His or her staff and all persons who assist in the conduct of the study clearly 
understand their responsibilities and have their names included in the Study 
Personnel Responsibility/Signature Log. 
3. The study is conducted according to the protocol and all applicable 
regulations. 
4. The protection of each subject’s rights and welfare is maintained. 
5. Signed and dated informed consent and, when applicable, permission to use 
protected health information are obtained from each subject before conducting 
nonstandard of care study procedures.  If a subject or subject’s legal guardian 
withdraws permission to use protected health information, the investigator will 
obtain a written request from the subject or subject’s legal guardian and will 
ensure that no further data be collected from the subject. 
6. The consent process is conducted in compliance with all applicable 
regulations and privacy acts. 
7. The IRB/IEC complies with applicable regulations and conducts initial and 
ongoing reviews and approvals of the study. 
8. Any amendment to the protocol is submitted promptly to the IRB/IEC. 
9. Any significant protocol deviations are reported to Acerta Pharma and the 
IRB/IEC according to the guidelines at each study site. 


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10. CRF pages are completed promptly. 
11. All Investigational New Drug (IND) Safety Reports/SUSAR Reports are 
submitted promptly to the IRB/IEC. 
12. All SAEs are reported to Acerta Pharma Drug Safety/Designee within 24 hours 
of knowledge via the clinical database and to the IRB/IEC per their 
requirements. 


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8.0 
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Bradshaw JM.  The Src, Syk, and Tec family kinases: distinct types of molecular 
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Cheson BD, Byrd JC, Rai KR, et al.  Novel targeted agents and the need to refine 
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Conroy T, Desseigne F, Ychou M, et al.  Groupe Tumeurs Digestives of Unicancer; 
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9.0 
APPENDICES 
 
 
 
 
 
 


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Appendix 1. 
RECIST 1.1 Guidelines 
 
 
 


New response evaluation criteria in solid tumours:
Revised RECIST guideline (version 1.1)
E.A. Eisenhauera,*, P. Therasseb, J. Bogaertsc, L.H. Schwartzd, D. Sargente, R. Fordf,
J. Danceyg, S. Arbuckh, S. Gwytheri, M. Mooneyg, L. Rubinsteing, L. Shankarg, L. Doddg,
R. Kaplanj, D. Lacombec, J. Verweijk
aNational Cancer Institute of Canada – Clinical Trials Group, 10 Stuart Street, Queen’s University, Kingston, ON, Canada
bGlaxoSmithKline Biologicals, Rixensart, Belgium
cEuropean Organisation for Research and Treatment of Cancer, Data Centre, Brussels, Belgium
dMemorial Sloan Kettering Cancer Center, New York, NY, USA
eMayo Clinic, Rochester, MN, USA
fRadPharm, Princeton, NJ, USA
gDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
hSchering-Plough, Kenilworth, NJ, USA
iEast Surrey Hospital, Redhill, Surrey, UK
jNational Cancer Research Network, Leeds, UK
kErasmus University Medical Center, Rotterdam, The Netherlands
A R T I C L E
I N F O
Article history:
Received 17 October 2008
Accepted 29 October 2008
Keywords:
Response criteria
Solid tumours
Guidelines
A B S T R A C T
Background: Assessment of the change in tumour burden is an important feature of the
clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response)
and disease progression are useful endpoints in clinical trials. Since RECIST was published
in 2000, many investigators, cooperative groups, industry and government authorities have
adopted these criteria in the assessment of treatment outcomes. However, a number of
questions and issues have arisen which have led to the development of a revised RECIST
guideline (version 1.1). Evidence for changes, summarised in separate papers in this special
issue, has come from assessment of a large data warehouse (>6500 patients), simulation
studies and literature reviews.
Highlights of revised RECIST 1.1: Major changes include: Number of lesions to be assessed: based
on evidence from numerous trial databases merged into a data warehouse for analysis pur-
poses, the number of lesions required to assess tumour burden for response determination
has been reduced from a maximum of 10 to a maximum of ﬁve total (and from ﬁve to two
per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes
with a short axis of P15 mm are considered measurable and assessable as target lesions.
The short axis measurement should be included in the sum of lesions in calculation of
tumour response. Nodes that shrink to <10 mm short axis are considered normal. Conﬁrma-
tion of response is required for trials with response primary endpoint but is no longer
required in randomised studies since the control arm serves as appropriate means of inter-
pretation of data. Disease progression is clariﬁed in several aspects: in addition to the previ-
ous deﬁnition of progression in target disease of 20% increase in sum, a 5 mm absolute
increase is now required as well to guard against over calling PD when the total sum is very
0959-8049/$ - see front matter  2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejca.2008.10.026
* Corresponding author: Tel.: +1 613 533 6430; fax: +1 613 533 2411.
E-mail address: eeisenhauer@ctg.queensu.ca (E.A. Eisenhauer).
E U R O P E A N J O U R N A L O F C A N C E R 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
available at www.sciencedirect.com
journal homepage: www.ejconline.com


small. Furthermore, there is guidance offered on what constitutes ‘unequivocal progres-
sion’ of non-measurable/non-target disease, a source of confusion in the original RECIST
guideline. Finally, a section on detection of new lesions, including the interpretation of
FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a
new imaging appendix with updated recommendations on the optimal anatomical assess-
ment of lesions.
Future work: A key question considered by the RECIST Working Group in developing RECIST
1.1 was whether it was appropriate to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment or to functional assessment
with PET or MRI. It was concluded that, at present, there is not sufﬁcient standardisation
or evidence to abandon anatomical assessment of tumour burden. The only exception to
this is in the use of FDG-PET imaging as an adjunct to determination of progression. As
is detailed in the ﬁnal paper in this special issue, the use of these promising newer
approaches requires appropriate clinical validation studies.
 2008 Elsevier Ltd. All rights reserved.
1.
Background
1.1.
History of RECIST criteria
Assessment of the change in tumour burden is an important
feature of the clinical evaluation of cancer therapeutics. Both
tumour shrinkage (objective response) and time to the devel-
opment of disease progression are important endpoints in
cancer clinical trials. The use of tumour regression as the
endpoint for phase II trials screening new agents for evi-
dence of anti-tumour effect is supported by years of evi-
dence suggesting that, for many solid tumours, agents
which produce tumour shrinkage in a proportion of patients
have a reasonable (albeit imperfect) chance of subsequently
demonstrating an improvement in overall survival or other
time to event measures in randomised phase III studies (re-
viewed in [1–4]). At the current time objective response car-
ries with it a body of evidence greater than for any other
biomarker supporting its utility as a measure of promising
treatment effect in phase II screening trials. Furthermore,
at both the phase II and phase III stage of drug development,
clinical trials in advanced disease settings are increasingly
utilising time to progression (or progression-free survival)
as an endpoint upon which efﬁcacy conclusions are drawn,
which is also based on anatomical measurement of tumour
size.
However, both of these tumour endpoints, objective re-
sponse and time to disease progression, are useful only if
based on widely accepted and readily applied standard crite-
ria based on anatomical tumour burden. In 1981 the World
Health Organisation (WHO) ﬁrst published tumour response
criteria, mainly for use in trials where tumour response was
the primary endpoint. The WHO criteria introduced the con-
cept of an overall assessment of tumour burden by summing
the products of bidimensional lesion measurements and
determined response to therapy by evaluation of change from
baseline while on treatment.5 However, in the decades that
followed their publication, cooperative groups and pharma-
ceutical companies that used the WHO criteria often ‘modi-
ﬁed’ them to accommodate new technologies or to address
areas that were unclear in the original document. This led
to confusion in interpretation of trial results6 and in fact,
the application of varying response criteria was shown to lead
to very different conclusions about the efﬁcacy of the same
regimen.7 In response to these problems, an International
Working Party was formed in the mid 1990s to standardise
and simplify response criteria. New criteria, known as RECIST
(Response Evaluation Criteria in Solid Tumours), were pub-
lished in 2000.8 Key features of the original RECIST include
deﬁnitions of minimum size of measurable lesions, instruc-
tions on how many lesions to follow (up to 10; a maximum
ﬁve per organ site), and the use of unidimensional, rather
than bidimensional, measures for overall evaluation of tu-
mour burden. These criteria have subsequently been widely
adopted by academic institutions, cooperative groups, and
industry for trials where the primary endpoints are objective
response or progression. In addition, regulatory authorities
accept
RECIST
as
an
appropriate
guideline
for
these
assessments.
1.2.
Why update RECIST?
Since RECIST was published in 2000, many investigators have
conﬁrmed in prospective analyses the validity of substituting
unidimensional for bidimensional (and even three-dimen-
sional)-based criteria (reviewed in [9]). With rare exceptions
(e.g. mesothelioma), the use of unidimensional criteria seems
to perform well in solid tumour phase II studies.
However, a number of questions and issues have arisen
which merit answers and further clarity. Amongst these
are whether fewer than 10 lesions can be assessed without
affecting the overall assigned response for patients (or the
conclusion about activity in trials); how to apply RECIST in
randomised phase III trials where progression, not response,
is the primary endpoint particularly if not all patients have
measurable disease; whether or how to utilise newer imag-
ing technologies such as FDG-PET and MRI; how to handle
assessment of lymph nodes; whether response conﬁrmation
is truly needed; and, not least, the applicability of RECIST in
trials of targeted non-cytotoxic drugs. This revision of the
RECIST guidelines includes updates that touch on all these
points.
E U R O P E A N J O U R N A L O F C A N C E R 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
229


1.3.
Process of RECIST 1.1 development
The RECIST Working Group, consisting of clinicians with
expertise in early drug development from academic research
organisations, government and industry, together with imag-
ing specialists and statisticians, has met regularly to set the
agenda for an update to RECIST, determine the evidence
needed to justify the various changes made, and to review
emerging evidence. A critical aspect of the revision process
was to create a database of prospectively documented solid
tumour measurement data obtained from industry and aca-
demic group trials. This database, assembled at the EORTC
Data Centre under the leadership of Jan Bogaerts and Patrick
Therasse (co-authors of this guideline), consists of >6500 pa-
tients with >18,000 target lesions and was utilised to investi-
gate the impact of a variety of questions (e.g. number of
target lesions required, the need for response conﬁrmation,
and lymph node measurement rules) on response and pro-
gression-free survival outcomes. The results of this work,
which after evaluation by the RECIST Working Group led to
most of the changes in this revised guideline, are reported
in detail in a separate paper in this special issue.10 Larry Sch-
wartz and Robert Ford (also co-authors of this guideline) also
provided key databases from which inferences have been
made that inform these revisions.11
The publication of this revised guideline is believed to be
timely since it incorporates changes to simplify, optimise
and standardise the assessment of tumour burden in clinical
trials. A summary of key changes is found in Appendix I. Be-
cause the fundamental approach to assessment remains
grounded in the anatomical, rather than functional, assess-
ment of disease, we have elected to name this version RECIST
1.1, rather than 2.0.
1.4.
What about volumetric or functional assessment?
This raises the question, frequently posed, about whether it is
‘time’ to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment
or to functional assessment (e.g. dynamic contrast enhanced
MRI or CT or (18)F-ﬂuorodeoxyglucose positron emission
tomographic (FDG-PET) techniques assessing tumour metab-
olism). As can be seen, the Working Group and particularly
those involved in imaging research, did not believe that there
is at present sufﬁcient standardisation and widespread avail-
ability to recommend adoption of these alternative assess-
ment methods. The only exception to this is in the use of
FDG-PET imaging as an adjunct to determination of progres-
sion, as described later in this guideline. As detailed in paper
in this special issue12, we believe that the use of these prom-
ising newer approaches (which could either add to or substitute
for anatomical assessment as described in RECIST) requires
appropriate and rigorous clinical validation studies. This pa-
per by Sargent et al. illustrates the type of data that will be
needed to be able to deﬁne ‘endpoints’ for these modalities
and how to determine where and when such criteria/modal-
ities can be used to improve the reliability with which truly
active new agents are identiﬁed and truly inactive new agents
are discarded in comparison to RECIST criteria in phase II
screening trials. The RECIST Working Group looks forward
to such data emerging in the next few years to allow the
appropriate changes to the next iteration of the RECIST
criteria.
2.
Purpose of this guideline
This guideline describes a standard approach to solid tumour
measurement and deﬁnitions for objective assessment of
change in tumour size for use in adult and paediatric cancer
clinical trials. It is expected these criteria will be useful in all
trials where objective response is the primary study endpoint,
as well as in trials where assessment of stable disease, tu-
mour progression or time to progression analyses are under-
taken, since all of these outcome measures are based on an
assessment of anatomical tumour burden and its change on
study. There are no assumptions in this paper about the pro-
portion of patients meeting the criteria for any of these end-
points which will signal that an agent or treatment regimen is
active: those deﬁnitions are dependent on type of cancer in
which a trial is being undertaken and the speciﬁc agent(s) un-
der study. Protocols must include appropriate statistical sec-
tions which deﬁne the efﬁcacy parameters upon which the
trial sample size and decision criteria are based. In addition
to providing deﬁnitions and criteria for assessment of tumour
response,
this
guideline
also
makes
recommendations
regarding standard reporting of the results of trials that utilise
tumour response as an endpoint.
While these guidelines may be applied in malignant brain
tumour studies, there are also separate criteria published for
response assessment in that setting.13 This guideline is not in-
tended for use for studies of malignant lymphoma since
international guidelines for response assessment in lym-
phoma are published separately.14
Finally, many oncologists in their daily clinical practice fol-
low their patients’ malignant disease by means of repeated
imaging studies and make decisions about continued therapy
on the basis of both objective and symptomatic criteria. It is
not intended that these RECIST guidelines play a role in that
decision making, except if determined appropriate by the
treating oncologist.
3.
Measurability of tumour at baseline
3.1.
Deﬁnitions
At baseline, tumour lesions/lymph nodes will be categorised
measurable or non-measurable as follows:
3.1.1.
Measurable
Tumour lesions: Must be accurately measured in at least one
dimension (longest diameter in the plane of measurement is
to be recorded) with a minimum size of:
• 10 mm by CT scan (CT scan slice thickness no greater than
5 mm; see Appendix II on imaging guidance).
• 10 mm caliper measurement by clinical exam (lesions
which cannot be accurately measured with calipers should
be recorded as non-measurable).
• 20 mm by chest X-ray.
230
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Malignant lymph nodes: To be considered pathologically en-
larged and measurable, a lymph node must be P15 mm in
short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in
follow-up, only the short axis will be measured and followed
(see Schwartz et al. in this Special Issue15). See also notes be-
low on ‘Baseline documentation of target and non-target le-
sions’ for information on lymph node measurement.
3.1.2.
Non-measurable
All other lesions, including small lesions (longest diameter
<10 mm or pathological lymph nodes with P10 to <15 mm
short axis) as well as truly non-measurable lesions. Lesions
considered truly non-measurable include: leptomeningeal dis-
ease, ascites, pleural or pericardial effusion, inﬂammatory
breast disease, lymphangitic involvement of skin or lung,
abdominal masses/abdominal organomegaly identiﬁed by
physical exam that is not measurable by reproducible imaging
techniques.
3.1.3.
Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated
with local therapy require particular comment:
Bone lesions:.
• Bone scan, PET scan or plain ﬁlms are not considered ade-
quate imaging techniques to measure bone lesions. How-
ever,
these
techniques
can
be
used
to
conﬁrm
the
presence or disappearance of bone lesions.
• Lytic bone lesions or mixed lytic-blastic lesions, with identi-
ﬁable soft tissue components, that can be evaluated by cross
sectional imaging techniques such as CT or MRI can be con-
sidered as measurable lesions if the soft tissue component
meets the deﬁnition of measurability described above.
• Blastic bone lesions are non-measurable.
Cystic lesions:.
• Lesions that meet the criteria for radiographically deﬁned
simple cysts should not be considered as malignant lesions
(neither measurable nor non-measurable) since they are, by
deﬁnition, simple cysts.
• ‘Cystic lesions’ thought to represent cystic metastases can
be considered as measurable lesions, if they meet the deﬁ-
nition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are pre-
ferred for selection as target lesions.
Lesions with prior local treatment:.
• Tumour lesions situated in a previously irradiated area, or
in an area subjected to other loco-regional therapy, are usu-
ally not considered measurable unless there has been dem-
onstrated progression in the lesion. Study protocols should
detail the conditions under which such lesions would be
considered measurable.
3.2.
Speciﬁcations by methods of measurements
3.2.1.
Measurement of lesions
All measurements should be recorded in metric notation,
using calipers if clinically assessed. All baseline evaluations
should be performed as close as possible to the treatment
start and never more than 4 weeks before the beginning of
the treatment.
3.2.2.
Method of assessment
The same method of assessment and the same technique
should be used to characterise each identiﬁed and reported
lesion at baseline and during follow-up. Imaging based evalu-
ation should always be done rather than clinical examination
unless the lesion(s) being followed cannot be imaged but are
assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered mea-
surable when they are superﬁcial and P10 mm diameter as
assessed using calipers (e.g. skin nodules). For the case of skin
lesions, documentation by colour photography including a ru-
ler to estimate the size of the lesion is suggested. As noted
above, when lesions can be evaluated by both clinical exam
and imaging, imaging evaluation should be undertaken since
it is more objective and may also be reviewed at the end of the
study.
Chest X-ray: Chest CT is preferred over chest X-ray, particu-
larly when progression is an important endpoint, since CT is
more sensitive than X-ray, particularly in identifying new le-
sions. However, lesions on chest X-ray may be considered
measurable if they are clearly deﬁned and surrounded by aer-
ated lung. See Appendix II for more details.
CT, MRI: CT is the best currently available and reproducible
method to measure lesions selected for response assessment.
This guideline has deﬁned measurability of lesions on CT
scan based on the assumption that CT slice thickness is
5 mm or less. As is described in Appendix II, when CT scans
have slice thickness greater than 5 mm, the minimum size
for a measurable lesion should be twice the slice thickness.
MRI is also acceptable in certain situations (e.g. for body
scans). More details concerning the use of both CT and MRI
for assessment of objective tumour response evaluation are
provided in Appendix II.
Ultrasound: Ultrasound is not useful in assessment of lesion
size and should not be used as a method of measurement.
Ultrasound examinations cannot be reproduced in their en-
tirety for independent review at a later date and, because
they are operator dependent, it cannot be guaranteed that
the same technique and measurements will be taken from
one assessment to the next (described in greater detail in
Appendix II). If new lesions are identiﬁed by ultrasound in
the course of the study, conﬁrmation by CT or MRI is ad-
vised. If there is concern about radiation exposure at CT,
MRI may be used instead of CT in selected instances.
Endoscopy, laparoscopy: The utilisation of these techniques for
objective tumour evaluation is not advised. However, they
can be useful to conﬁrm complete pathological response
when biopsies are obtained or to determine relapse in trials
where recurrence following complete response or surgical
resection is an endpoint.
Tumour markers: Tumour markers alone cannot be used to as-
sess objective tumour response. If markers are initially above
E U R O P E A N J O U R N A L O F C A N C E R 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
231


the upper normal limit, however, they must normalise for a
patient to be considered in complete response. Because
tumour markers are disease speciﬁc, instructions for their
measurement should be incorporated into protocols on a
disease speciﬁc basis. Speciﬁc guidelines for both CA-125
response (in recurrent ovarian cancer) and PSA response (in
recurrent prostate cancer), have been published.16–18 In addi-
tion, the Gynecologic Cancer Intergroup has developed CA125
progression criteria which are to be integrated with objective
tumour assessment for use in ﬁrst-line trials in ovarian
cancer.19
Cytology, histology: These techniques can be used to differenti-
ate between PR and CR in rare cases if required by protocol
(for example, residual lesions in tumour types such as germ
cell tumours, where known residual benign tumours can re-
main). When effusions are known to be a potential adverse
effect of treatment (e.g. with certain taxane compounds or
angiogenesis inhibitors), the cytological conﬁrmation of the
neoplastic origin of any effusion that appears or worsens dur-
ing treatment can be considered if the measurable tumour
has met criteria for response or stable disease in order to dif-
ferentiate between response (or stable disease) and progres-
sive disease.
4.
Tumour response evaluation
4.1.
Assessment of overall tumour burden and
measurable disease
To assess objective response or future progression, it is nec-
essary to estimate the overall tumour burden at baseline and
use this as a comparator for subsequent measurements.
Only patients with measurable disease at baseline should
be included in protocols where objective tumour response
is the primary endpoint. Measurable disease is deﬁned by
the presence of at least one measurable lesion (as detailed
above in Section 3). In studies where the primary endpoint
is tumour progression (either time to progression or propor-
tion with progression at a ﬁxed date), the protocol must
specify if entry is restricted to those with measurable disease
or whether patients having non-measurable disease only are
also eligible.
4.2.
Baseline documentation of ‘target’ and ‘non-target’
lesions
When more than one measurable lesion is present at baseline
all lesions up to a maximum of ﬁve lesions total (and a max-
imum of two lesions per organ) representative of all involved
organs should be identiﬁed as target lesions and will be re-
corded and measured at baseline (this means in instances
where patients have only one or two organ sites involved a
maximum of two and four lesions respectively will be re-
corded). For evidence to support the selection of only ﬁve tar-
get lesions, see analyses on a large prospective database in
the article by Bogaerts et al.10.
Target lesions should be selected on the basis of their size
(lesions with the longest diameter), be representative of all in-
volved organs, but in addition should be those that lend
themselves to reproducible repeated measurements. It may be
the case that, on occasion, the largest lesion does not lend it-
self to reproducible measurement in which circumstance the
next largest lesion which can be measured reproducibly
should be selected. To illustrate this point see the example
in Fig. 3 of Appendix II.
Lymph nodes merit special mention since they are normal
anatomical structures which may be visible by imaging even
if not involved by tumour. As noted in Section 3, pathological
nodes which are deﬁned as measurable and may be identi-
ﬁed as target lesions must meet the criterion of a short axis
of P15 mm by CT scan. Only the short axis of these nodes
will contribute to the baseline sum. The short axis of the
node is the diameter normally used by radiologists to judge
if a node is involved by solid tumour. Nodal size is normally
reported as two dimensions in the plane in which the image
is obtained (for CT scan this is almost always the axial plane;
for MRI the plane of acquisition may be axial, saggital or
coronal). The smaller of these measures is the short axis.
For example, an abdominal node which is reported as being
20 mm · 30 mm has a short axis of 20 mm and qualiﬁes as a
malignant, measurable node. In this example, 20 mm should
be recorded as the node measurement (See also the example
in Fig. 4 in Appendix II). All other pathological nodes (those
with short axis P10 mm but <15 mm) should be considered
non-target lesions. Nodes that have a short axis <10 mm
are considered non-pathological and should not be recorded
or followed.
A sum of the diameters (longest for non-nodal lesions, short
axis for nodal lesions) for all target lesions will be calculated
and reported as the baseline sum diameters. If lymph nodes
are to be included in the sum, then as noted above, only the
short axis is added into the sum. The baseline sum diameters
will be used as reference to further characterise any objective
tumour regression in the measurable dimension of the
disease.
All other lesions (or sites of disease) including pathological
lymph nodes should be identiﬁed as non-target lesions and
should also be recorded at baseline. Measurements are not re-
quired and these lesions should be followed as ‘present’, ‘ab-
sent’, or in rare cases ‘unequivocal progression’ (more details
to follow). In addition, it is possible to record multiple non-
target lesions involving the same organ as a single item on
the case record form (e.g. ‘multiple enlarged pelvic lymph
nodes’ or ‘multiple liver metastases’).
4.3.
Response criteria
This section provides the deﬁnitions of the criteria used to
determine objective tumour response for target lesions.
4.3.1.
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions.
Any pathological lymph nodes (whether target or
non-target) must have reduction in short axis to
<10 mm.
Partial Response (PR): At least a 30% decrease in the sum of
diameters of target lesions, taking as reference the
baseline sum diameters.
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Progressive Disease (PD): At least a 20% increase in the sum
of diameters of target lesions, taking as reference
the smallest sum on study (this includes the baseline
sum if that is the smallest on study). In addition to
the relative increase of 20%, the sum must also dem-
onstrate an absolute increase of at least 5 mm. (Note:
the appearance of one or more new lesions is also
considered progression).
Stable Disease (SD): Neither sufﬁcient shrinkage to qualify for
PR nor sufﬁcient increase to qualify for PD, taking as
reference the smallest sum diameters while on study.
4.3.2.
Special notes on the assessment of target lesions
Lymph nodes. Lymph nodes identiﬁed as target lesions should
always have the actual short axis measurement recorded (mea-
sured in the same anatomical plane as the baseline examina-
tion), even if the nodes regress to below 10 mm on study. This
means that when lymph nodes are included as target lesions,
the ‘sum’ of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is deﬁned as having
a short axis of <10 mm. Case report forms or other data collec-
tion methods may therefore be designed to have target nodal le-
sions recorded in a separate section where, in order to qualify
for CR, each node must achieve a short axis <10 mm. For PR,
SD and PD, the actual short axis measurement of the nodes is
to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’. While on
study, all lesions (nodal and non-nodal) recorded at baseline
should have their actual measurements recorded at each sub-
sequent evaluation, even when very small (e.g. 2 mm). How-
ever, sometimes lesions or lymph nodes which are recorded
as target lesions at baseline become so faint on CT scan that
the radiologist may not feel comfortable assigning an exact
measure and may report them as being ‘too small to measure’.
When this occurs it is important that a value be recorded on
the case report form. If it is the opinion of the radiologist that
the lesion has likely disappeared, the measurement should be
recorded as 0 mm. If the lesion is believed to be present and is
faintly seen but too small to measure, a default value of 5 mm
should be assigned (Note: It is less likely that this rule will be
used for lymph nodes since they usually have a deﬁnable size
when normal and are frequently surrounded by fat such as in
the retroperitoneum; however, if a lymph node is believed to
be present and is faintly seen but too small to measure, a de-
fault value of 5 mm should be assigned in this circumstance as
well). This default value is derived from the 5 mm CT slice
thickness (but should not be changed with varying CT slice
thickness). The measurement of these lesions is potentially
non-reproducible, therefore providing this default value will
prevent false responses or progressions based upon measure-
ment error. To reiterate, however, if the radiologist is able to
provide an actual measure, that should be recorded, even if
it is below 5 mm.
Lesions that split or coalesce on treatment. As noted in Appen-
dix II, when non-nodal lesions ‘fragment’, the longest diame-
ters of the fragmented portions should be added together to
calculate the target lesion sum. Similarly, as lesions coalesce,
a plane between them may be maintained that would aid in
obtaining maximal diameter measurements of each individ-
ual lesion. If the lesions have truly coalesced such that they
are no longer separable, the vector of the longest diameter
in this instance should be the maximal longest diameter for
the ‘coalesced lesion’.
4.3.3.
Evaluation of non-target lesions
Thissection provides the deﬁnitionsofthe criteriausedtodeter-
mine the tumour response for the group of non-target lesions.
While some non-target lesions may actually be measurable,
they need not be measured and instead should be assessed only
qualitatively at the time points speciﬁed in the protocol.
Complete Response (CR): Disappearance of all non-target le-
sions and normalisation of tumour marker level. All
lymph nodes must be non-pathological in size
(<10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target le-
sion(s) and/or maintenance of tumour marker level
above the normal limits.
Progressive Disease (PD): Unequivocal progression (see com-
ments below) of existing non-target lesions. (Note:
the appearance of one or more new lesions is also
considered progression).
4.3.4.
Special notes on assessment of progression of non-
target disease
The concept of progression of non-target disease requires
additional explanation as follows:
When the patient also has measurable disease. In this setting,
to achieve ‘unequivocal progression’ on the basis of the
non-target disease, there must be an overall level of substan-
tial worsening in non-target disease such that, even in pres-
ence of SD or PR in target disease, the overall tumour
burden has increased sufﬁciently to merit discontinuation
of therapy (see examples in Appendix II and further details
below). A modest ‘increase’ in the size of one or more non-tar-
get lesions is usually not sufﬁcient to quality for unequivocal
progression status. The designation of overall progression so-
lely on the basis of change in non-target disease in the face of
SD or PR of target disease will therefore be extremely rare.
When the patient has only non-measurable disease.This circum-
stance arises in some phase III trials when it is not a criterion of
study entry to have measurable disease. The same general con-
cepts apply here as noted above, however, in this instance there
is no measurable disease assessment to factor into the inter-
pretation of an increase in non-measurable disease burden.
Because worsening in non-target disease cannot be easily
quantiﬁed (by deﬁnition: if all lesions are truly non-measur-
able) a useful test that can be applied when assessing patients
for unequivocal progression is to consider if the increase in
overall disease burden based on the change in non-measurable
disease is comparable in magnitude to the increase that would
berequiredtodeclarePDformeasurabledisease: i.e.anincrease
in tumour burden representing an additional 73% increase in
‘volume’ (which is equivalent to a 20% increase diameter in a
measurable lesion). Examples include an increase in a pleural
effusion from ‘trace’ to ‘large’, an increase in lymphangitic
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233


disease from localised to widespread, or may be described in
protocols as ‘sufﬁcient to require a change in therapy’. Some
illustrative examples are shown in Figs. 5 and 6 in Appendix II.
If ‘unequivocal progression’ is seen, the patient should be con-
sidered to have had overall PD at that point. While it would be
ideal to have objective criteria to apply to non-measurable dis-
ease, the very nature of that disease makes it impossible to do
so, therefore the increase must be substantial.
4.3.5.
New lesions
The appearance of new malignant lesions denotes disease
progression; therefore, some comments on detection of new
lesions are important. There are no speciﬁc criteria for the
identiﬁcation of new radiographic lesions; however, the ﬁnd-
ing of a new lesion should be unequivocal: i.e. not attributable
to differences in scanning technique, change in imaging
modality or ﬁndings thought to represent something other
than tumour (for example, some ‘new’ bone lesions may be
simply healing or ﬂare of pre-existing lesions). This is partic-
ularly important when the patient’s baseline lesions show
partial or complete response. For example, necrosis of a liver
lesion may be reported on a CT scan report as a ‘new’ cystic
lesion, which it is not.
A lesion identiﬁed on a follow-up study in an anatomical
location that was not scanned at baseline is considered a new
lesion andwill indicate diseaseprogression. An example of this
is the patient who has visceral disease at baseline and while on
study has a CTor MRI brain ordered which reveals metastases.
The patient’s brain metastases are considered to be evidence of
PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its
small size, continued therapy and follow-up evaluation will
clarify if it represents truly new disease. If repeat scans con-
ﬁrm there is deﬁnitely a new lesion, then progression should
be declared using the date of the initial scan.
While FDG-PET response assessments need additional
study, it is sometimes reasonable to incorporate the use of
FDG-PET scanning to complement CT scanning in assessment
of progression (particularly possible ‘new’ disease). New le-
sions on the basis of FDG-PET imaging can be identiﬁed
according to the following algorithm:
a. Negative FDG-PET at baseline, with a positivel FDG-PET
at follow-up is a sign of PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at fol-
low-up:
If the positive FDG-PET at follow-up corresponds to a
new site of disease conﬁrmed by CT, this is PD.
If the positive FDG-PET at follow-up is not conﬁrmed as
a new site of disease on CT, additional follow-up CT
scans are needed to determine if there is truly progres-
sion occurring at that site (if so, the date of PD will be
the date of the initial abnormal FDG-PET scan).
If the positive FDG-PET at follow-up corresponds to a
pre-existing site of disease on CT that is not progress-
ing on the basis of the anatomic images, this is not PD.
4.4.
Evaluation of best overall response
The best overall response is the best response recorded from
the start of the study treatment until the end of treatment
taking into account any requirement for conﬁrmation. On oc-
casion a response may not be documented until after the end
of therapy so protocols should be clear if post-treatment
assessments are to be considered in determination of best
overall response. Protocols must specify how any new therapy
introduced before progression will affect best response desig-
nation. The patient’s best overall response assignment will
depend on the ﬁndings of both target and non-target disease
and will also take into consideration the appearance of new
lesions. Furthermore, depending on the nature of the study
and the protocol requirements, it may also require conﬁrma-
tory measurement (see Section 4.6). Speciﬁcally, in non-ran-
domised trials where response is the primary endpoint,
conﬁrmation of PR or CR is needed to deem either one the
‘best overall response’. This is described further below.
4.4.1.
Time point response
It is assumed that at each protocol speciﬁed time point, a re-
sponse assessment occurs. Table 1 on the next page provides
a summary of the overall response status calculation at each
time point for patients who have measurable disease at
baseline.
When patients have non-measurable (therefore non-tar-
get) disease only, Table 2 is to be used.
4.4.2.
Missing assessments and inevaluable designation
When no imaging/measurement is done at all at a particular
time point, the patient is not evaluable (NE) at that time point.
If only a subset of lesion measurements are made at an
assessment, usually the case is also considered NE at that
time point, unless a convincing argument can be made that
the contribution of the individual missing lesion(s) would
not change the assigned time point response. This would be
most likely to happen in the case of PD. For example, if a pa-
tient had a baseline sum of 50 mm with three measured le-
sions and at follow-up only two lesions were assessed, but
those gave a sum of 80 mm, the patient will have achieved
PD status, regardless of the contribution of the missing lesion.
4.4.3.
Best overall response: all time points
The best overall response is determined once all the data for the
patient is known.
Best response determination in trials where conﬁrmation of com-
plete or partial response IS NOT required: Best response in these
trials is deﬁned as the best response across all time points (for
example, a patient who has SD at ﬁrst assessment, PR at sec-
ond assessment, and PD on last assessment has a best overall
response of PR). When SD is believed to be best response, it
must also meet the protocol speciﬁed minimum time from
baseline. If the minimum time is not met when SD is other-
wise the best time point response, the patient’s best response
depends on the subsequent assessments. For example, a pa-
tient who has SD at ﬁrst assessment, PD at second and does
not meet minimum duration for SD, will have a best response
of PD. The same patient lost to follow-up after the ﬁrst SD
assessment would be considered inevaluable.
l A ‘positive’ FDG-PET scan lesion means one which is FDG avid
with an uptake greater than twice that of the surrounding tissue
on the attenuation corrected image.
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Best response determination in trials where conﬁrmation of com-
plete or partial response IS required: Complete or partial re-
sponses may be claimed only if the criteria for each are met
at a subsequent time point as speciﬁed in the protocol (gener-
ally 4 weeks later). In this circumstance, the best overall re-
sponse can be interpreted as in Table 3.
4.4.4.
Special notes on response assessment
When nodal disease is included in the sum of target lesions
and the nodes decrease to ‘normal’ size (<10 mm), they may
still have a measurement reported on scans. This measure-
ment should be recorded even though the nodes are normal
in order not to overstate progression should it be based on
increase in size of the nodes. As noted earlier, this means that
patients with CR may not have a total sum of ‘zero’ on the
case report form (CRF).
In trials where conﬁrmation of response is required, re-
peated ‘NE’ time point assessments may complicate best re-
sponse determination. The analysis plan for the trial must
address how missing data/assessments will be addressed in
determination of response and progression. For example, in
most trials it is reasonable to consider a patient with time
point responses of PR-NE-PR as a conﬁrmed response.
Patients with a global deterioration of health status requir-
ing discontinuation of treatment without objective evidence
of disease progression at that time should be reported as
‘symptomatic deterioration’. Every effort should be made to
document objective progression even after discontinuation
of treatment. Symptomatic deterioration is not a descriptor
of an objective response: it is a reason for stopping study ther-
apy. The objective response status of such patients is to be
determined by evaluation of target and non-target disease
as shown in Tables 1–3.
Conditions that deﬁne ‘early progression, early death and
inevaluability’ are study speciﬁc and should be clearly de-
scribed in each protocol (depending on treatment duration,
treatment periodicity).
In some circumstances it may be difﬁcult to distinguish
residual disease from normal tissue. When the evaluation of
complete response depends upon this determination, it is
recommended that the residual lesion be investigated (ﬁne
Table 3 – Best overall response when conﬁrmation of CR and PR required.
Overall response
Overall response
BEST overall response
First time point
Subsequent time point
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable.
a If a CR is truly met at ﬁrst time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline,
makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum duration
for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in fact the
patient had PR, not CR at the ﬁrst time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
Table 1 – Time point response: patients with target (+/–
non-target) disease.
Target lesions
Non-target lesions
New
lesions
Overall
response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or
not all evaluated
No
PR
SD
Non-PD or
not all evaluated
No
SD
Not all
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease,
PD = progressive disease, and NE = inevaluable.
Table 2 – Time point response: patients with non-target
disease only.
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete
response,
PD = progressive
disease,
and
NE = inevaluable.
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target
disease since SD is increasingly used as endpoint for assessment
of efﬁcacy in some trials so to assign this category when no
lesions can be measured is not advised.
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235


needle aspirate/biopsy) before assigning a status of complete
response. FDG-PET may be used to upgrade a response to a CR
in a manner similar to a biopsy in cases where a residual
radiographic abnormality is thought to represent ﬁbrosis or
scarring. The use of FDG-PET in this circumstance should be
prospectively described in the protocol and supported by dis-
ease speciﬁc medical literature for the indication. However, it
must be acknowledged that both approaches may lead to
false positive CR due to limitations of FDG-PETand biopsy res-
olution/sensitivity.
For equivocal ﬁndings of progression (e.g. very small and
uncertain new lesions; cystic changes or necrosis in existing
lesions), treatment may continue until the next scheduled
assessment. If at the next scheduled assessment, progression
is conﬁrmed, the date of progression should be the earlier
date when progression was suspected.
4.5.
Frequency of tumour re-evaluation
Frequency
of
tumour
re-evaluation
while
on
treatment
should be protocol speciﬁc and adapted to the type and sche-
dule of treatment. However, in the context of phase II studies
where the beneﬁcial effect of therapy is not known, follow-up
every 6–8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals than these could
be justiﬁed in speciﬁc regimens or circumstances. The proto-
col should specify which organ sites are to be evaluated at
baseline (usually those most likely to be involved with meta-
static disease for the tumour type under study) and how often
evaluations are repeated. Normally, all target and non-target
sites are evaluated at each assessment. In selected circum-
stances certain non-target organs may be evaluated less fre-
quently. For example, bone scans may need to be repeated
only when complete response is identiﬁed in target disease
or when progression in bone is suspected.
After the end of the treatment, the need for repetitive tu-
mour evaluations depends on whether the trial has as a goal
the response rate or the time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease-free
survival, progression-free survival) is the main endpoint of
the study, then routine scheduled re-evaluation of protocol
speciﬁed sites of disease is warranted. In randomised com-
parative trials in particular, the scheduled assessments
should be performed as identiﬁed on a calendar schedule
(for example: every 6–8 weeks on treatment or every 3–4
months after treatment) and should not be affected by delays
in therapy, drug holidays or any other events that might lead
to imbalance in a treatment arm in the timing of disease
assessment.
4.6.
Conﬁrmatory measurement/duration of response
4.6.1.
Conﬁrmation
In non-randomised trials where response is the primary end-
point, conﬁrmation of PR and CR is required to ensure re-
sponses identiﬁed are not the result of measurement error.
This will also permit appropriate interpretation of results in
the context of historical data where response has traditionally
required conﬁrmation in such trials (see the paper by Bogaerts
et al. in this Special Issue10). However, in all other circum-
stances, i.e. in randomised trials (phase II or III) or studies
where stable disease or progression are the primary endpoints,
conﬁrmation ofresponseis notrequiredsince itwillnotaddva-
lue to theinterpretationoftrial results.However, eliminationof
the requirement for response conﬁrmation may increase the
importance of central review to protect against bias, in partic-
ular in studies which are not blinded.
In the case of SD, measurements must have met the SD
criteria at least once after study entry at a minimum interval
(in general not less than 6–8 weeks) that is deﬁned in the
study protocol.
4.6.2.
Duration of overall response
The duration of overall response is measured from the time
measurement criteria are ﬁrst met for CR/PR (whichever is ﬁrst
recorded) until the ﬁrst date that recurrent or progressive dis-
ease is objectively documented (taking as reference for progres-
sive disease the smallest measurements recorded on study).
The duration of overall complete response is measured
from the time measurement criteria are ﬁrst met for CR until
the ﬁrst date that recurrent disease is objectively documented.
4.6.3.
Duration of stable disease
Stable disease is measured from the start of the treatment (in
randomised trials, from date of randomisation) until the crite-
ria for progression are met, taking as reference the smallest
sum on study (if the baseline sum is the smallest, this is the
reference for calculation of PD).
The clinical relevance of the duration of stable disease var-
ies in different studies and diseases. If the proportion of pa-
tients achieving stable disease for a minimum period of time
is an endpoint of importance in a particular trial, the protocol
should specify the minimal time interval required between
two measurements for determination of stable disease.
Note: The duration of response and stable disease as well as
theprogression-free survivalareinﬂuencedby thefrequencyof
follow-up after baseline evaluation. It is not in the scope of this
guideline to deﬁne a standard follow-up frequency. The fre-
quency should take into account many parameters including
disease types and stages, treatment periodicity and standard
practice. However, these limitations of the precision of the
measured endpoint should be taken into account if compari-
sons between trials are to be made.
4.7.
Progression-free survival/proportion progression-free
4.7.1.
Phase II trials
This guideline is focused primarily on the use of objective re-
sponse endpoints for phase II trials. In some circumstances, ‘re-
sponse rate’ may not be the optimal method to assess the
potential anticancer activity of new agents/regimens. In such
cases ‘progression-free survival’ (PFS) or the ‘proportion pro-
gression-free’ at landmark time points, might be considered
appropriate alternatives to provide an initial signal of biologic
effect of new agents. It is clear, however, that in an uncontrolled
trial, these measures are subject to criticism since an appar-
ently promising observation may be related to biological factors
such as patient selectionand not theimpactof theintervention.
Thus, phase II screening trials utilising these endpoints are best
designed with a randomised control. Exceptions may exist
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where the behaviour patterns of certain cancers are so consis-
tent (and usually consistently poor), that a non-randomised
trial is justiﬁable (see for example van Glabbeke et al.20). How-
ever, in these cases it will be essential to document with care
the basis for estimating the expected PFS or proportion progres-
sion-free in the absence of a treatment effect.
4.7.2.
Phase III trials
Phase III trials in advanced cancers are increasingly designed
to evaluate progression-free survival or time to progression as
the primary outcome of interest. Assessment of progression
is relatively straightforward if the protocol requires all pa-
tients to have measurable disease. However, restricting entry
to this subset of patients is subject to criticism: it may result
in a trial where the results are less likely to be generalisable if,
in the disease under study, a substantial proportion of pa-
tients would be excluded. Moreover, the restriction to entry
will slow recruitment to the study. Increasingly, therefore, tri-
als allow entry of both patients with measurable disease as
well as those with non-measurable disease only. In this cir-
cumstance, care must be taken to explicitly describe the ﬁnd-
ings which would qualify for progressive disease for those
patients without measurable lesions. Furthermore, in this set-
ting, protocols must indicate if the maximum number of re-
corded target lesions for those patients with measurable
disease may be relaxed from ﬁve to three (based on the data
found in Bogaerts et al.10 and Moskowitz et al.11). As found in
the ‘special notes on assessment of progression’, these guide-
lines offer recommendations for assessment of progression
in this setting. Furthermore, if available, validated tumour mar-
ker measures of progression (as has been proposed for ovarian
cancer) may be useful to integrate into the deﬁnition of pro-
gression. Centralised blinded review of imaging studies or of
source imaging reports to verify ‘unequivocal progression’
may be needed if important drug development or drug ap-
proval decisions are to be based on the study outcome. Finally,
as noted earlier, because the date of progression is subject to
ascertainment bias, timing of investigations in study arms
should be the same. The article by Dancey et al. in this special
issue21 provides a more detailed discussion of the assessment
of progression in randomised trials.
4.8.
Independent review of response and progression
For trials where objective response (CR + PR) is the primary end-
point, and in particular where key drug development deci-
sions are based on the observation of a minimum number of
responders, it is recommended that all claimed responses be
reviewed by an expert(s) independent of the study. If the study
is a randomised trial, ideally reviewers should be blinded to
treatment assignment. Simultaneous review of the patients’
ﬁles and radiological images is the best approach.
Independent review of progression presents some more
complex issues: for example, there are statistical problems
with the use of central-review-based progression time in
place of investigator-based progression time due to the poten-
tial introduction of informative censoring when the former
precedes the latter. An overview of these factors and other
lessons learned from independent review is provided in an
article by Ford et al. in this special issue.22
4.9.
Reporting best response results
4.9.1.
Phase II trials
When response is the primary endpoint, and thus all patients
must have measurable disease to enter the trial, all patients
included in the study must be accounted for in the report of
the results, even if there are major protocol treatment devia-
tions or if they are not evaluable. Each patient will be assigned
one of the following categories:
1. Complete response
2. Partial response
3. Stable disease
4. Progression
5. Inevaluable for response: specify reasons (for example: early
death, malignant disease; early death, toxicity; tumour
assessments not repeated/incomplete; other (specify)).
Normally, all eligible patients should be included in the
denominator for the calculation of the response rate for phase
II trials (in some protocols it will be appropriate to include all
treated patients). It is generally preferred that 95% two-sided
conﬁdence limits are given for the calculated response rate.
Trial conclusions should be based on the response rate for
all eligible (or all treated) patients and should not be based
on a selected ‘evaluable’ subset.
4.9.2.
Phase III trials
Response evaluation in phase III trials may be an indicator
of the relative anti-tumour activity of the treatments eval-
uated and is almost always a secondary endpoint. Ob-
served differences in response rate may not predict the
clinically relevant therapeutic beneﬁt for the population
studied. If objective response is selected as a primary end-
point for a phase III study (only in circumstances where a
direct relationship between objective tumour response and
a clinically relevant therapeutic beneﬁt can be unambigu-
ously demonstrated for the population studied), the same
criteria as those applying to phase II trials should be used
and all patients entered should have at least one measur-
able lesion.
In those many cases where response is a secondary end-
point and not all trial patients have measurable disease, the
method for reporting overall best response rates must be
pre-speciﬁed in the protocol. In practice, response rate may
be reported using either an ‘intent to treat’ analysis (all ran-
domised patients in the denominator) or an analysis where
only the subset of patients with measurable disease at
baseline are included. The protocol should clearly specify
how response results will be reported, including any subset
analyses that are planned.
The original version of RECIST suggested that in phase III
trials one could write protocols using a ‘relaxed’ interpreta-
tion of the RECIST guidelines (for example, reducing the num-
ber of lesions measured) but this should no longer be done
since these revised guidelines have been amended in such a
way that it is clear how these criteria should be applied for
all trials in which anatomical assessment of tumour response
or progression are endpoints.
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237


Appendix I. Summary of major changes RECIST 1.0 to RECIST 1.1
RECIST 1.0
RECIST 1.1
Rationale
Reference in special issue
(if applicable)
Minimum size measurable
lesions
CT: 10 mm spiral
CT 10 mm; delete reference to
spiral scan
Most scans used have 5 mm or less slice
thickness Clearer to give instruction based on
slice interval if it is greater than 5 mm
20 mm non-spiral
Clinical: 20 mm
Clinical: 10 mm (must be
measurable with calipers)
Caliper measurement will make this reliable
Lymph node: not mentioned
CT:
Since nodes are normal structure need to deﬁne
pathological enlargement. Short axis is most
sensitive
Schwartz et al.15
P15 mm short axis for target
P10–<15 mm for non-target
<10 mm is non-pathological
Special considerations on
lesion measurability
–
Notes included on bone
lesions, cystic lesions
Clarify frequently asked questions
Overall tumour burden
10 lesions (5 per organ)
5 lesions (2 per organ)
Data warehouse analysis shows no loss of
information if lesion number reduced from 10 to
5. A maximum of 2 lesions per organ yields
sufﬁcient representation per disease site
Bogaerts et al.10
Response criteria target
disease
CR lymph node not mentioned
CR lymph nodes must be
<10 mm short axis
In keeping with normal size of nodes
Schwartz et al.15
PD 20% increase over smallest sum on
study or new lesions
PD 20% increase over smallest
sum on study (including
baseline if that is smallest) and
at least 5 mm increase or new
lesions
Clariﬁcation that if baseline measurement is
smaller than any on study measurement, it is
reference against which PD is assessed
5 mm absolute increase to guard against over
calling PD when total sum is very small and 20%
increase is within measurement error
Response criteria non-target
disease
‘unequivocal progression’ considered as PD
More detailed description of
‘unequivocal progression’ to
indicate that it should not
normally trump target disease
status. It must be
representative of overall
disease status change, not a
single lesion increase
Confusion with RECIST 1.0 where some were
considering PD if ‘increase’ in any non-target
lesion, even when target disease is stable or
responding
New lesions
–
New section on New lesions
To provide guidance on when a lesion is
considered new (and thus PD)
Overall response
Table integrated target and non-target
lesions
Two tables: one integrating
target and non-target and the
other of non-target only
To account for the fact that RECIST criteria are
now being used in trials where PFS is the
endpoint and not all patients have measurable
(target) disease at baseline
Dancey et al.21
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RECIST 1.0
RECIST 1.1
Rationale
Reference in special issue
(if applicable)
Special notes:
Frequently asked questions on these topics
How to assess and measure
lymph nodes
CR in face of residual tissue
Discussion of ‘equivocal’
progression
Conﬁrmatory measure
For CR and PR: criteria
must be met again 4
weeks after initial
documentation
Retain this requirement ONLY
for
non-randomised trials with
primary endpoint of response
Data warehouse shows that response rates
rise when conﬁrmation is eliminated, but
the only circumstance where this is
important is in trials where there is no
concurrent comparative control and where
this measure is the primary endpoint
Bogaerts et al.10
Progression-free survival
General comments only
More speciﬁc comments on
use of PFS (or proportion
progression-free) as
phase II endpoint
Increasing use of PFS in phase III trials
requires guidance on assessment of PD in
patients with non-measurable disease
Dancey et al.21
Greater detail on PFS
assessment in phase III trials
Reporting of response
results
9 categories suggested for
reporting phase II results
Divided into phase II and phase
III
Simpliﬁes reporting and clariﬁes how to
report phase II and III data consistently
9 categories collapsed into 5
In phase III, guidance given
about reporting response
Response in phase III
trials
More relaxed guidelines
possible if protocol speciﬁed
This section removed and
referenced in section
above: no need to have
different criteria for phase II
and III
Simpliﬁcation of response assessment by
reducing number of lesions and eliminating
need for conﬁrmation in randomised
studies where response is not the primary
endpoint makes separate ‘rules’
unnecessary
Imaging appendix
Appendix I
Appendix II: updated with
detailed guidance on
use of MRI, PET/CT
Evolving use of newer modalities addressed.
Enhanced guidance in response to frequent
questions and from radiology review
experience
Other practical guidance
included
New appendices
Appendix I: comparison of
RECIST 1.0 and 1.1
Appendix III: frequently asked
questions
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239


Conﬂict of interest statement
None declared.
Acknowledgements
The RECIST Working Group would like to thank the following
organisations which made data bases available to us in order
to perform the analyses which informed decisions about
changes to this version of the criteria: Amgen; AstraZeneca;
Breast Cancer International Research Group (BCIRG); Bristol-
Myers
Squibb; European
Organisation for
Research and
Treatment of Cancer (EORTC) Breast Cancer Group and Gas-
trointestinal
Group;
Erasmus
University
Medical
Center,
Rotterdam, The Netherlands; Genentech; Pﬁzer; RadPharm;
Roche; SanoﬁAventis.
We would also like to thank the following individuals from
academic, government, and pharmaceutical organisations for
providing helpful comments on an earlierdraft of these revised
guidelines: Ohad Amit, Phil Murphy, Teri Crofts and Janet Be-
gun, GlaxoSmithKline, USA; Laurence H. Baker, Southwest
Oncology Group, USA; Karla Ballman, Mayo Clinic, USA;
Charles Baum, Darrel Cohen, and Mary Ashford Collier, Pﬁzer,
USA; Gary J. Becker, American Board of Radiology, Tucson,
USA; Jean-Yves Blay, University Claude Pertrand, Lyon France;
Renzo Canetta, Bristol-Myers Squibb, USA; David Chang, Am-
gen Inc., USA; Sandra Chica, Perceptive Informations Inc. (PAR-
EXEL),
USA;
Martin
Edelman,
University
of
Maryland
Greenbaum Cancer Centre, USA; Gwendolyn Fyfe, Genentech,
USA; Bruce Giantonio, Eastern Cooperative Oncology Group,
USA; Gary Gordon, Abbott Pharmaceuticals, USA; Ronald Gott-
lieb, Roswell Park Cancer Institute, USA; Simon Kao, University
of Iowa College of Medicine, USA; Wasaburo Koizumi, Kitasato
University, Japan; Alessandro Riva, Novartis Pharmaceuticals,
USA; Wayne Rackhoff, Ortho Biotech Oncology Research and
Development, USA; Nagahiro Saijo, President Japanese Society
of Medical Oncology, Japan; Mitchell Schnall American College
of Radiology Imaging Network, USA; Yoshik Shimamura, PAR-
EXEL International Inc., Japan; Rajeshwari Sridhara, Centre
for Drug Evaluation and Research, Food and Drug Administra-
tion, USA; Andrew Stone, Alan Barge, AstraZeneca, United
Kingdom; Orhan Suleiman, Centre for Drug Evaluation and Re-
search, Food and Drug Administration, USA; Daniel C. Sullivan,
Duke University Medical Centre, USA; Masakazu Toi, Kyoto
University, Japan; Cindy Welsh, Centre for Drug Evaluation
and Research, Food and Drug Administration, USA.
Finally, the RECIST Working Group would like to thank indi-
vidualswho were not permanent members of the group (which
are all acknowledged as co-authors) but who attended working
group meetings from time to time and made contributions to
the total process over the past 7 years: Richard Pazdur, Food
and Drug Administration, USA; Francesco Pignatti, European
Medicines Agency, London, UK.
Appendix II.
Speciﬁcations for standard
anatomical radiological imaging
These protocols for image acquisition of computed tomogra-
phy (CT) and magnetic resonance imaging (MRI) are recom-
mendations intended for patients on clinical trials where
RECIST assessment will be performed. Standardisation of
imaging requirements and image acquisition parameters is
ideal to allow for optimal comparability of subjects within a
study and results between studies. These recommendations
are designed to balance optimised image acquisition proto-
cols with techniques that should be feasible to perform glob-
ally at imaging facilities in all types of radiology practices.
These guidelines are not applicable to functional imaging
techniques or volumetric assessment of tumour size.
Scanner quality control is highly recommended and should
follow
standard
manufacturer
and
facility
maintenance
schedules using commercial phantoms. It is likely that for RE-
CIST unidimensional measurements this will be adequate to
produce reproducible measurements. Imaging quality control
for CT includes an analysis of image noise and uniformity and
CT number as well as spatial resolution. The frequency of
quality control analysis is also variable and should focus on
clinically relevant scanning parameters. Dose analysis is al-
ways important and the use of imaging should follow the
ALARA principle, ‘As Low As Reasonably Achievable’, which
refers to making every reasonable effort to maintain radiation
exposures as far below the dose limits as possible.
Speciﬁc.notes
Chest X-ray measurement of lesions surrounded by pulmon-
ary
parenchyma
is
feasible,
but
not
preferable
as
the
measurement represents a summation of densities. Further-
more, there is poor identiﬁcation of new lesions within the
chest on X-ray as compared with CT. Therefore, measure-
ments of pulmonary parenchymal lesions as well as medias-
tinal disease are optimally performed with CT of the chest.
MRI of the chest should only be performed in extenuating cir-
cumstances. Even if IV contrast cannot be administered (for
example, in the situation of allergy to contrast), a non-con-
trast CT of the chest is still preferred over MRI or chest X-ray.
CT scans: CT scans of the chest, abdomen, and pelvis should
be contiguous throughout all the anatomic region of interest.
As a general rule, the minimum size of a measurable lesion at
baseline should be no less than double the slice thickness and
also have a minimum size of 10 mm (see below for minimum
size when scanners have a slice thickness more than 5 mm).
While the precise physics of lesion size and partial volume
averaging is complex, lesions smaller than 10 mm may be dif-
ﬁcult to accurately and reproducibly measure. While this rule
is applicable to baseline scans, as lesions potentially decrease
in size at follow-up CT studies, they should still be measured.
Lesions which are reported as ‘too small to measure’ should
be assigned a default measurement of 5 mm if they are still
visible.
The most critical CT image acquisition parameters for opti-
mal tumour evaluation using RECIST are anatomic coverage,
contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most
solid tumours is the chest, abdomen and pelvis. Cover-
age should encompass all areas of known predilection
for metastases in the disease under evaluation and
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should additionally investigate areas that may be
involved based on signs and symptoms of individual
patients. Because a lesion later identiﬁed in a body part
not scanned at baseline would be considered as a new
lesion representing disease progression, careful consid-
eration should begiven to the extent of imaging coverage
at baseline and at subsequent follow-up time points.
This will enable better consistency not only of tumour
measurements but also identiﬁcation of new disease.
b. IV contrast administration: Optimal visualisation and
measurement of metastases in solid tumours requires
consistent administration (dose and rate) of IV contrast
as well as timing of scanning. Typically, most abdomi-
nal imaging is performed during the portal venous
phase and (optimally) about the same time frame after
injection on each examination (see Fig. 1 for impact of
different phase of IV contrast on lesion measurement).
Most solid tumours may be scanned with a single
phase after administration of contrast. While triphasic
CT scans are sometimes performed on other types of
vascular tumours to improve lesion conspicuity, for
consistency and uniformity, we would recommend tri-
phasic
CT
for
hepatocellular
and
neuroendocrine
tumours for which this scanning protocol is generally
standard of care, and the improved temporal resolution
of the triphasic scan will enhance the radiologists’ abil-
ity to consistently and reproducibly measure these
lesions. The precise dose and rate of IV contrast is
dependent upon the CT scanning equipment, CT acqui-
sition protocol, the type of contrast used, the available
venous
access
and
the
medical
condition
of
the
patient. Therefore, the method of administration of
intravenous contrast agents is variable. Rather than
try to institute rigid rules regarding methods for
administering contrast agents and the volume injected,
it is appropriate to suggest that an adequate volume of
a suitable contrast agent should be given so that the
metastases are demonstrated to best effect and a con-
sistent method is used on subsequent examinations for
any given patient (ideally, this would be speciﬁed in
the protocol or for an institution). It is very important
that the same technique be used at baseline and on fol-
low-up examinations for a given patient. This will
greatly enhance the reproducibility of the tumour mea-
surements. If prior to enrolment it is known a patient is
not able to undergo CT scans with IV contrast due to
allergy
or
renal
insufﬁciency,
the
decision
as
to
whether a non-contrast CT or MRI (with or without IV
contrast) should be used to evaluate the subject at
baseline and follow-up should be guided by the tumour
type under investigation and the anatomic location of
the disease. For patients who develop contraindica-
tions to contrast after baseline contrast CT is done,
the decision as to whether non-contrast CT or MRI
(enhanced or non-enhanced) should be performed
should also be based on the tumour type, anatomic
location of the disease and should be optimised to
allow for comparison to the prior studies if possible.
Each case should be discussed with the radiologist to
determine if substitution of these other approaches is
possible and, if not, the patient should be considered
not evaluable from that point forward. Care must be
taken in measurement of target lesions on a different
modality and interpretation of non-target disease or
new lesions, since the same lesion may appear to have
a different size using a new modality (see Fig. 2 for a
comparison of CT and MRI of the same lesion). Oral
contrast is recommended to help visualise and differ-
entiate structures in the abdomen.
c. Slice thickness and reconstruction interval: RECIST measure-
ments may be performed at most clinically obtained
slice thicknesses. It is recommended that CT scans be
performed at 5 mm contiguous slice thickness or less
and indeed this guideline presumes a minimum 5 mm
thickness in recommendations for measurable lesion
deﬁnition. Indeed, variations in slice thickness can have
an impact on lesion measurement and on detection of
new lesions. However, consideration should also be
given for minimising radiation exposure. With these
parameters, a minimum 10 mm lesion is considered
measurable at baseline. Occasionally, institutions may
perform medically acceptable scans at slice thicknesses
greater than 5 mm. If this occurs, the minimum size of
measurable lesions at baseline should be twice the slice
Fig. 1 – Difference in measurement/visualisation with different phases of IV contrast administration. Hypervascular
metastases imaged in the arterial phase (left) and the portal venous phase (right). Note that the number of lesions visible
differs greatly between the two phases of contrast administration as does any potential lesion measurement. Consistent CT
scan acquisition, including phase of contrast administration, is important for optimal and reproducible tumour
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241


thickness of the baseline scans. Most contemporary CT
scanners are multidetector which have many imaging
options for these acquisition parameters.23 The equip-
ment vendor and scanning manual should be reviewed
if there are any speciﬁc system questions.
d. Alternative contrast agents: There are a number of other,
new contrast agents, some organ speciﬁc.24 They may
be used as part of patient care for instance, in liver
lesion assessment, or lymph node characterisation25,
but should not as yet be used in clinical trials.
FDG-PET has gained acceptance as a valuable tool for
detecting, staging and restaging several malignancies. Criteria
for incorporating (or substituting) FDG-PET into anatomical
assessment of tumour response in phase II trials are not yet
available, though much research is ongoing. Nevertheless,
FDG-PET is being used in many drug development trials both
as a tool to assess therapeutic efﬁcacy and also in assessment
of progression. If FDG-PET scans are included in a protocol, by
consensus, an FDG uptake period of 60 min prior to imaging
has been decided as the most appropriate for imaging of pa-
tients with malignancy.26 Whole-body acquisition is impor-
tant since this allows for sampling of all areas of interest
and can assess if new lesions have appeared thus determining
the possibility of interval progression of disease. Images from
the base of the skull to the level of the mid-thigh should be ob-
tained 60 min post injection. PET camera speciﬁcations are
variable and manufacturer speciﬁc, so every attempt should
be made to use the same scanner, or the same model scanner,
for serial scans on the same patient. Whole-body acquisitions
can be performed in either 2- or 3-dimensional mode with
attenuation correction, but the method chosen should be con-
sistent across all patients and serial scans in the clinical trial.
PET/CT scans: Combined modality scanning such as with
PET–CT is increasingly used in clinical care, and is a modal-
ity/technology that is in rapid evolution; therefore, the recom-
mendations in this paper may change rather quickly with
time. At present, low dose or attenuation correction CT por-
tions of a combined PET–CT are of limited use in anatomically
based efﬁcacy assessments and it is therefore suggested that
they should not be substituted for dedicated diagnostic con-
trast enhanced CT scans for anatomically based RECIST mea-
surements. However, if a site can document that the CT
performed as part of a PET–CT is of identical diagnostic qual-
ity to a diagnostic CT (with IV and oral contrast) then the CT
portion of the PET–CT can be used for RECIST measurements.
Note, however, that the PET portion of the CT introduces addi-
tional data which may bias an investigator if it is not routinely
or serially performed.
Ultrasound examinations should not be used in clinical trials
to measure tumour regression or progression of lesions be-
cause the examination is necessarily subjective and operator
dependent. The reasons for this are several: Entire examina-
tions cannot be reproduced for independent review at a later
date, and it must be assumed, whether or not it is the case,
that the hard-copy ﬁlms available represent a true and accu-
rate reﬂection of events. Furthermore, if, for example, the
only measurable lesion is in the para-aortic region of the
abdomen and if gas in the bowel overlies the lesion, the lesion
will not be detected because the ultrasound beam cannot
penetrate the gas. Accordingly, the disease staging (or restag-
ing for treatment evaluation) for this patient will not be
accurate.
While evaluation of lesions by physical examination is also
of limited reproducibility, it is permitted when lesions are
superﬁcial, at least 10 mm size, and can be assessed using
calipers. In general, it is preferred if patients on clinical trials
have at least one lesion that is measurable by CT. Other skin
or palpable lesions may be measured on physical examina-
tion and be considered target lesions.
Use of MRI remains a complex issue. MRI has excellent
contrast, spatial and temporal resolution; however, there
are many image acquisition variables involved in MRI, which
greatly impact image quality, lesion conspicuity and mea-
surement. Furthermore, the availability of MRI is variable
globally. As with CT, if an MRI is performed, the technical
speciﬁcations of the scanning sequences used should be
optimised for the evaluation of the type and site of disease.
Furthermore, as with CT, the modality used at follow-up
should be the same as was used at baseline and the lesions
should be measured/assessed on the same pulse sequence.
Generally, axial imaging of the abdomen and pelvis with T1
and T2 weighted imaging along with gadolinium enhanced
imaging should be performed. The ﬁeld of view, matrix,
number of excitations, phase encode steps, use of fat sup-
pression and fast sequences should be optimised for the spe-
Fig. 2 – CT versus MRI of same lesions showing apparent ‘progression’ due only to differing method of measurement.
242
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ciﬁc body part being imaged as well as the scanner utilised. It
is beyond the scope of this document or appendix to pre-
scribe speciﬁc MRI pulse sequence parameters for all scan-
ners, body parts and diseases. Ideally, the same type of
scanner should be used and the image acquisition protocol
should be followed as closely as possible to prior scans. Body
scans should be performed with breath-hold scanning tech-
niques if possible.
Selection of target lesions: In general, the largest lesions rep-
resentative of involved organs (up to a maximum of two per
organ and ﬁve total) are selected to follow as target lesions.
However, in some cases, the largest lesions may not be easily
measured and are not suitable for follow-up because of their
conﬁguration. In these cases, identiﬁcation of the largest most
reproducible lesions is advised. Fig. 3 provides an illustrative
example where the largest lesion is not the most reproducible
and another lesion is better to select and follow:
Measurement of lesions
The longest diameter of selected lesions should be measured
in the plane in which the images were acquired. For body CT,
this is the axial plane. In the event isotropic reconstructions
are performed, measurements can be made on these recon-
structed images; however, it should be cautioned that not
all radiology sites are capable of producing isotropic recon-
structions. This could lead to the undesirable situation of
measurements in the axial plane at one assessment point
and in a different plane at a subsequent assessment. There
are some tumours, for instance paraspinal lesions, which
are better measured in the coronal or sagittal plane. It would
be acceptable to measure these lesions in these planes if the
reconstructions in those planes were isotropic or the images
were acquired with MRI in those planes. Using the same plane
of evaluation, the maximal diameter of each target lesion
should always be measured at subsequent follow-up time
points even if this results in measuring the lesion at a differ-
ent slice level or in a different orientation or vector compared
with the baseline study. Software tools that calculate the
maximal diameter for a perimeter of a tumour may be em-
ployed and may even reduce variability.
The only exception to the longest diameter rule is lymph
node measurement. Because malignant nodes are identiﬁed
by the length of their short axis, this is the guide used to
determine not only whether they are pathological but is also
the dimension measured for adding into the sum of target le-
sions. Fig. 4 illustrates this point: the large arrow identiﬁes a
malignant node: the shorter perpendicular axis is P15 mm
and will be recorded. Close by (small arrow) there is a normal
node: note here the long axis is greater than 10 mm but the
short axis is well below 10 mm. This node should be consid-
ered non-pathological.
If a lesion disappears and reappears at a subsequent time
point it should continue to be measured. However, the pa-
tient’s response at the point in time when the lesion reap-
pears will depend upon the status of his/her other lesions.
For example, if the patient’s tumour had reached a CR status
and the lesion reappeared, then the patient would be consid-
ered PD at the time of reappearance. In contrast, if the tumour
status was a PR or SD and one lesion which had disappeared
then reappears, its maximal diameter should be added to the
sum of the remaining lesions for a calculated response: in
other words, the reappearance of an apparently ‘disappeared’
single lesion amongst many which remain is not in itself en-
Fig. 3 – Largest lesion may not be most reproducible: most reproducible should be selected as target. In this example, the
primary gastric lesion (circled at baseline and at follow-up in the top two images) may be able to be measured with thin
section volumetric CT with the same degree of gastric distention at baseline and follow-up. However, this is potentially
challenging to reproduce in a multicentre trial and if attempted should be done with careful imaging input and analysis. The
most reproducible lesion is a lymph node (circled at baseline and at follow-up in the bottom two images).
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243


ough to qualify for PD: that requires the sum of all lesions to
meet the PD criteria. The rationale for such a categorisation is
based upon the realisation that most lesions do not actually
‘disappear’ but are not visualised because they are beyond
the resolving power of the imaging modality employed.
The identiﬁcation of the precise boundary deﬁnition of a
lesion may be difﬁcult especially when the lesion is embed-
ded in an organ with a similar contrast such as the liver, pan-
creas, kidney, adrenal or spleen. Additionally, peritumoural
oedema may surround a lesion and may be difﬁcult to distin-
guish on certain modalities between this oedema and actual
tumour. In fact, pathologically, the presence of tumour cells
within the oedema region is variable. Therefore, it is most
critical that the measurements be obtained in a reproducible
manner from baseline and all subsequent follow-up time-
points. This is also a strong reason to consistently utilise
the same imaging modality.
When lesions ‘fragment’, the individual lesion diameters
should be added together to calculate the target lesion
sum. Similarly, as lesions coalesce, a plane between them
may be maintained that would aid in obtaining maximal
diameter measurements of each individual lesion. If the le-
sions have truly coalesced such that they are no longer sep-
arable, the vector of the longest diameter in this instance
should be the maximal longest diameter for the ‘merged
lesion’.
Progression of non-target lesions
To achieve ‘unequivocal progression’ there must be an overall
level of substantial worsening in non-target disease that is of
a magnitude that, even in the presence of SD or PR in target
disease, the treating physician would feel it important to
change therapy. Examples of unequivocal progression are
shown in Figs. 5 and 6.
Fig. 5 – Example of unequivocal progression in non-target lesions in liver.
Fig. 6 – Example of unequivocal progression in non-target lesion (nodes).
Fig. 4 – Lymph node assessment: large arrow illustrates a
pathological node with the short axis shown as a solid line
which should be measured and followed. Small arrow illus-
trates a non-pathological node which has a short axis
<10 mm.
244
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Appendix III. Frequently asked questions
Question
Answer
What should be done if several unique lesions at
baseline become conﬂuent at a follow-up
evaluation?
Measure the longest diameter of the conﬂuent mass and record to add into the sum of
the longest diameters
How large does a new lesion have to be to count
as progression? Does any small subcentimetre
lesion qualify, or should the lesion be at least
measurable?
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is
clear on previous images (with the same technique) that a lesion was absent then its
deﬁnitive appearance implies progression. If there is any doubt (because of the
techniques or conditions) then it is suggested that treatment continue until next
scheduled assessment when, generally, all should be clear. Either it gets bigger and the
date of progression is the date of the ﬁrst suspicion, or it disappears and one may then
consider it an artefact with the support of the radiologists
How should one lesion be measured if on
subsequent exams it is split into two?
Measure the longest diameter of each lesion and add this into the sum
Does the deﬁnition of progression depend on
the status of all target lesions or only one?
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of
diameters of all target lesions AND a minimum absolute increase of 5 mm in the sum
Are RECIST criteria accepted by regulatory
agencies?
Many cooperative groups and members of pharma were involved in preparing RECIST
1.0 and have adopted them. The FDA was consulted in their development and supports
their use, though they don’t require it. The European and Canadian regulatory
authorities also participated and the RECIST criteria are now integrated in the European
note for guidance for the development of anticancer agents. Many pharmaceutical
companies are also using them. RECIST 1.1 was similarly widely distributed before
publication
What is the criterion for a measurable lesion if
the CT slice thickness is >5 mm?
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and the
minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is
<5 mm). If scanners with slice thickness >5 mm are used, the minimum lesion size must
have a longest diameter twice the actual slice thickness
What should we record when target lesions
become so small they are below the 10 mm
‘measurable’ size?
Target lesion measurability is deﬁned at baseline. Thereafter, actual measurements,
even if <10 mm, should be recorded. If lesions become very small, some radiologists
indicate they are ‘too small to measure’. This guideline advises that when this occurs, if
the lesion is actually still present, a default measurement of 5 mm should be applied. If
in fact the radiologist believes the lesion has gone, a default measurement of 0 mm
should be recorded
If a patient has several lesions which have
decreased in size to meet PR criteria and one
has actually disappeared, does that patient have
PD if the ‘disappeared’ lesion reappears?
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR (or
SD) is not PD. The lesion should simply be added into the sum.
If the patients had had a CR, clearly reappearance of an absent lesion would qualify for
PD
When measuring the longest diameter of target
lesions in response to treatment, is the same
axis that was used initially used subsequently,
even if there is a shape change to the lesion that
may have produced a new longest diameter?
The longest diameter of the lesion should always be measured even if the actual axis is
different from the one used to measure the lesion initially (or at different time point
during follow-up)
The only exception to this is lymph nodes: as per RECIST 1.1 the short axis should
always be followed and as in the case of target lesions, the vector of the short axis may
change on follow-up
Target lesions have been selected at baseline
and followed but then one of these target
lesions then becomes non-evaluable (i.e.
different technique used)
What may be done in such cases is one of the following:
What is the effect this has on the other target
lesions and the overall response?
(a) If the patient is still being treated, call the centre to be sure that future evaluations are
done with the baseline technique so at least SOME courses are fully evaluable
(b) If that is not possible, check if there IS a baseline exam by the same technique which
was used to follow patients...in which case if you retrieve the baseline measures from
that technique you retrieve the lesion evaluability
(c) If neither (a) nor (b) is possible then it is a judgement call about whether you delete
the lesion from all forms or consider the impact of the lesion overall is so important that
its being non-evaluable makes the overall response interpretation inevaluable without
it. Such a decision should be discussed in a review panel
It is NOT recommended that the lesion be included in baseline sums and then excluded
from follow-up sums since this biases in favour of a response
(continued on next page)
E U R O P E A N J O U R N A L O F C A N C E R 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
245


R E F E R E N C E S
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8. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines
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11. Moskowitz CS, Jia X, Schwartz LH, Go¨nen M. A simulation
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12. Sargent D, Rubinstein L, Schwartz L, et al. Validation of novel
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Appendix III – continued
Question
Answer
What if a single non-target lesion cannot be reviewed, for
whatever reason; does this negate the overall assessment?
Sometimes the major contribution of a single non-target lesion may be in
the setting of CR having otherwise been achieved: failure to examine one
non-target in that setting will leave you unable to claim CR. It is also
possible that the non-target lesion has undergone such substantial
progression that it would override the target disease and render patient
PD. However, this is very unlikely, especially if the rest of the measurable
disease is stable or responding
A patient has a 32% decrease in sum cycle 2, a 28% decrease cycle
4 and a 33% decrease cycle 6. Does conﬁrmation of PR have to
take place in sequential scans or is a case like this conﬁrmed PR?
It is not infrequent that tumour shrinkage hovers around the 30% mark.
In this case, most would consider PR to have been conﬁrmed looking at
this overall case. Had there been two or three non-PR observations
between the two time point PR responses, the most conservative
approach would be to consider this case SD
In the setting of a breast cancer neoadjuvant study, would
mammography not be used to assess lesions? Is CT preferred in
this setting?
Neither CT nor mammography are optimal in this setting. MRI is the
preferred modality to follow breast lesions in a neoadjuvant setting
A patient has a lesion measurable by clinical exam and by CT
scan. Which should be followed?
CT scan. Always follow by imaging if that option exists since it can be
reviewed and veriﬁed
A lesion which was solid at baseline has become necrotic in the
centre. How should this be measured?
The longest diameter of the entire lesion should be followed. Eventually,
necrotic lesions which are responding to treatment decrease in size. In
reporting the results of trials, you may wish to report on this
phenomenon if it is seen frequently since some agents (e.g. angiogenesis
inhibitors) may produce this effect
If I am going to use MRI to follow disease, what is minimum size
for measurability?
MRI may be substituted for contrast enhanced CT for some sites, but not
lung. The minimum size for measurability is the same as for CT (10 mm)
as long as the scans are performed with slice thickness of 5 mm and no
gap. In the event the MRI is performed with thicker slices, the size of a
measurable lesion at baseline should be two times the slice thickness. In
the event there are inter-slice gaps, this also needs to be considered in
determining the size of measurable lesions at baseline
Can PET–CT be used with RECIST?
At present, the low dose or attenuation correction CT portion of a
combined PET–CT is not always of optimal diagnostic CT quality for use
with RECIST measurements. However, if your site has documented that
the CT performed as part of a PET–CT is of the same diagnostic quality as
a diagnostic CT (with IV and oral contrast) then the PET–CT can be used
for RECIST measurements. Note, however, that the PET portion of the CT
introduces additional data which may bias an investigator if it is not
routinely or serially performed
246
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13. Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG.
Response criteria for phase II studies of supratentorial
malignant glioma. J Clin Oncol 1990;8:1277–80.
14. Cheson BD, Pﬁstner B, Juweid ME, et al. Revised response
criteria for malignant lymphoma. J Clin Oncol 2007;10:579–86.
15. Schwartz LH, Bogaerts J, Ford R, et al. Evaluation of lymph
nodes with RECIST 1.1. Eur J Cancer 2009;45:261–7.
16. Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to
evaluate the response to treatment in solid tumors (ovarian
cancer). J Natl Cancer Inst 2004;96:487–8.
17. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response
guidelines for phase II clinical trials in androgen-independent
prostate cancer: recommendations from the Prostate-Speciﬁc
Antigen Working Group. J Clin Oncol 1999;17:3461–7.
18. Scher H, Halabi S, Tannock I, et al. Design and end points of
clinical trials for patients with progressive prostate cancer
and castrate levels of testosterone: recommendations of the
Prostate Cancer Clinical Trials Working Group. J Clin Oncol
2008;26:1148–59.
19. Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines
to evaluate the response to treatment in solid tumors [ovarian
cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst
2000;92:1534–5.
20. Van Glabbeke M, Verweij J, Judson I, Nielsen OS. EORTC Soft
Tissue and Bone Sarcoma Group: Progression-free rate as the
principal end-point for phase II trials in soft-tissue sarcomas.
Eur J Cancer 2002;38:543–9.
21. Dancey JE, Dodd LE, Ford R, et al. Recommendations for the
assessment of progression in randomised cancer treatment
trials. Eur J Cancer 2009;45:281–9.
22. Ford R, Schwartz L, Dancey J, et al. Lessons learned
from independent central review. Eur J Cancer 2009;45:
268–74.
23. Catalano C, Francone M, Ascarelli A, Mangia M, Iacucci I,
Passariello R. Optimizing radiation dose and image quality.
Eur Radiol 2007;17(Suppl 6):F26–32.
24. Low RN. Abdominal MRI advances in the detection of liver
tumours and characterization. Lancet Oncol 2007;8(6):525–35.
25. Barrett T, Choyke PL, Kobayashi H. Imaging of the lymphatic
system: new horizons. Contrast Media Mol Imaging
2006;1(6):230–45.
26. Shankar LK, Hoffman JM, Bacharach S, et al. National
Cancer Institute. Consensus recommendations for the use
of 18F-FDG PET as an indicator of therapeutic response
in patients in National Cancer Institute Trials.
J Nucl Med 2006;47(6):1059–66.
E U R O P E A N J O U R N A L O F C A N C E R 4 5 ( 2 0 0 9 ) 2 2 8 –2 4 7
247


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
Acerta Pharma 
Confidential 
Page 111 of 160 
Appendix 2. 
Nab-paclitaxel Prescribing Information 
 


ABRAXANE- paclitaxel injection, powder, lyophilized, for suspension  
Abraxis BioScience, LLC
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ABRAXANE safely and effectively.  See full
prescribing information for ABRAXANE.
ABRAXANE  for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension)
(albumin-bound)
Initial U.S. Approval: 2005
WARNING: NEUTROPENIA
See full prescribing information for complete boxed warning.
Do not administer ABRAXANE therapy to patients with baseline neutrophil counts of less than 1,500
cells/mm . (4)
It is recommended that frequent peripheral blood cell counts be performed to monitor the
occurrence of bone marrow suppression. (4, 5.1, 6.1, 6.2, 6.3)
DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.
RECENT MAJOR CHANGES
 •  Dosage and Administration (2.4, 2.8)    
12/2014
 •  Dosage and Administration (2.7)    
07/2015
 •  Warnings and Precautions, Hepatic Impairment (5.6)    12/2014
INDICATIONS AND USAGE
ABRAXANE is a microtubule inhibitor indicated for the treatment of:
Metastatic breast cancer, after failure of combination chemotherapy for metastatic disease or relapse within 6 months of
adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. (1.1)
Locally advanced or metastatic non-small cell lung cancer (NSCLC), as first-line treatment in combination with
carboplatin, in patients who are not candidates for curative surgery or radiation therapy. (1.2)
Metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with gemcitabine. (1.3)
DOSAGE AND ADMINISTRATION
Metastatic Breast Cancer: Recommended dosage of ABRAXANE is 260 mg/m  intravenously over 30 minutes every 3
weeks. (2.1)
Non-Small Cell Lung Cancer: Recommended dosage of ABRAXANE is 100 mg/m  intravenously over 30 minutes on
Days 1, 8, and 15 of each 21-day cycle; administer carboplatin on Day 1 of each 21-day cycle immediately after
ABRAXANE. (2.2)
Adenocarcinoma of the Pancreas: Recommended dosage of ABRAXANE is 125 mg/m  intravenously over 30-40
minutes on Days 1, 8 and 15 of each 28-day cycle; administer gemcitabine on Days 1, 8 and 15 of each 28-day cycle
immediately after ABRAXANE. (2.3)
Do not administer ABRAXANE to any patient with AST > 10 x ULN or bilirubin > 5 x ULN. Do not administer
ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic
impairment. For diseases other than metastatic adenocarcinoma of the pancreas, reduce starting dose in patients with
moderate to severe hepatic impairment. (2.4)
Dose Reductions: Dose reductions or discontinuation may be needed based on severe hematologic, neurologic,
cutaneous, or gastrointestinal toxicities. (2.5)
Use caution when handling cytotoxic drugs. Closely monitor the infusion site for extravasation and infiltration. No
premedication is required prior to administration. (2.6)
DOSAGE FORMS AND STRENGTHS
For injectable suspension: lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in
single-use vial for reconstitution. (3)
CONTRAINDICATIONS
Neutrophil counts of < 1,500 cells/mm . (4)
Severe hypersensitivity reaction to ABRAXANE. (4)
WARNINGS AND PRECAUTIONS
ABRAXANE causes myelosuppression. Monitor CBC and withhold and/or reduce the dose as needed. (5.1)
Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. (5.2)
Sepsis occurred in patients with or without neutropenia who received ABRAXANE in combination with gemcitabine;
interrupt ABRAXANE and gemcitabine until sepsis resolves, and if neutropenia, until neutrophils are at least 1500
cells/mm , then resume treatment at reduced dose levels. (5.3)
Pneumonitis occurred with the use of ABRAXANE in combination with gemcitabine; permanently discontinue
treatment with ABRAXANE and gemcitabine. (5.4)
Severe hypersensitivity reactions with fatal outcome have been reported. Do not re-challenge with this drug. (5.5)
Exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment; therefore administer with
caution. (5.6)
ABRAXANE contains albumin derived from human blood, which has a theoretical risk of viral transmission. (5.7)
Fetal harm may occur when administered to a pregnant woman. Advise women of childbearing potential to avoid
becoming pregnant while receiving ABRAXANE. (5.8)
Advise men not to father a child while on ABRAXANE. (5.9)
®
3
2
2
2
3
3


(
)
ADVERSE REACTIONS
The most common adverse reactions (≥ 20%) in metastatic breast cancer are alopecia, neutropenia, sensory
neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia,
nausea, infections, and diarrhea. (6.1)
The most common adverse reactions (≥ 20%) in NSCLC are anemia, neutropenia, thrombocytopenia, alopecia,
peripheral neuropathy, nausea, and fatigue. (6.2)
The most common (≥ 20%) adverse reactions of ABRAXANE in adenocarcinoma of the pancreas are neutropenia,
fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite,
rash, and dehydration. (6.3)
To report SUSPECTED ADVERSE REACTIONS, contact Celgene Corporation at 1-888-423-5436 or FDA at 1-
800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Use caution when concomitantly administering ABRAXANE with inhibitors or inducers of either CYP2C8 or CYP3A4.
(7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 7/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: NEUTROPENIA
1 INDICATIONS AND USAGE
1.1 Metastatic Breast Cancer
1.2 Non-Small Cell Lung Cancer
1.3 Adenocarcinoma of the Pancreas
2 DOSAGE AND ADMINISTRATION
2.1 Metastatic Breast Cancer
2.2 Non-Small Cell Lung Cancer
2.3 Adenocarcinoma of the Pancreas
2.4 Dosage in Patients with Hepatic Impairment
2.5 Dose Reduction/Discontinuation Recommendations
2.6 Preparation and Administration Precautions
2.7 Preparation for Intravenous Administration
2.8 Stability
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hematologic Effects
5.2 Nervous System
5.3 Sepsis
5.4 Pneumonitis
5.5 Hypersensitivity
5.6 Hepatic Impairment
5.7 Albumin (Human)
5.8 Use in Pregnancy
5.9 Use in Men
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience in Metastatic Breast Cancer
6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer
6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas
6.4 Postmarketing Experience with ABRAXANE and other Paclitaxel Formulations
6.5 Accidental Exposure
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Patients with Hepatic Impairment
8.7 Patients with Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action


12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Metastatic Breast Cancer
14.2 Non-Small Cell Lung Cancer
14.3 Adenocarcinoma of the Pancreas
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage
16.3 Handling and Disposal
17 PATIENT COUNSELING INFORMATION
*
FULL PRESCRIBING INFORMATION
ABRAXANE  for Injectable Suspension (paclitaxel protein-bound particles for injectable
suspension) (albumin-bound)
WARNING: NEUTROPENIA
Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts
of less than 1,500 cells/mm . In order to monitor the occurrence of bone marrow
suppression, primarily neutropenia, which may be severe and result in infection, it is
recommended that frequent peripheral blood cell counts be performed on all patients
receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and
Adverse Reactions (6.1, 6.2, 6.3)].
Note: An albumin form of paclitaxel may substantially affect a drug’s functional
properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR
WITH OTHER PACLITAXEL FORMULATIONS.
1 INDICATIONS AND USAGE
1.1 Metastatic Breast Cancer
ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy
for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have
included an anthracycline unless clinically contraindicated.
1.2 Non-Small Cell Lung Cancer
ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell
lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or
radiation therapy.
1.3 Adenocarcinoma of the Pancreas
ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the
pancreas, in combination with gemcitabine.
2 DOSAGE AND ADMINISTRATION
2.1 Metastatic Breast Cancer
After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of
adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m  administered
intravenously over 30 minutes every 3 weeks.
2.2 Non-Small Cell Lung Cancer
The recommended dose of ABRAXANE is 100 mg/m  administered as an intravenous infusion over 30
minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day
cycle immediately after ABRAXANE [see Clinical Studies (14.2)].
2.3 Adenocarcinoma of the Pancreas
Sections or subsections omitted from the full prescribing information are not listed.
®
3
2
2


The recommended dose of ABRAXANE is 125 mg/m  administered as an intravenous infusion over 30-
40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after
ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].
2.4 Dosage in Patients with Hepatic Impairment
For patients with mild hepatic impairment (total bilirubin greater than ULN and less than or equal to 1.5 x
ULN and aspartate aminotransferase [AST] less than or equal to 10 x ULN), no dose adjustments are
required, regardless of indication.
Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have
moderate to severe hepatic impairment.
Do not administer ABRAXANE to patients with total bilirubin greater than 5 x ULN or AST greater
than 10 x ULN regardless of indication as these patients have not been studied.
Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.
Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment
MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer.
 Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be
based on individual tolerance.
 A dose increase to 260 mg/m  for patients with metastatic breast cancer or 100 mg/m  for patients with non-small cell lung cancer in
subsequent courses should be considered if the patient tolerates the reduced dose for two cycles.
 Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.
SGOT (AST) Levels
Bilirubin Levels
ABRAXANE Dose
MBC
NSCLC 
Pancreatic  
Adenocarcinoma
Mild
< 10 x ULN
AND
> ULN to ≤ 1.5 x ULN
260 mg/m
100 mg/m
125 mg/m
Moderate
< 10 x ULN
AND
>1.5 to ≤ 3 x ULN
200 mg/m
80 mg/m
not recommended
Severe
< 10 x ULN
AND
> 3 to ≤ 5 x ULN
200 mg/m
80 mg/m
not recommended
> 10 x ULN
OR
> 5 x ULN
not recommended
not recommended
not recommended
2.5 Dose Reduction/Discontinuation Recommendations
Metastatic Breast Cancer 
Patients who experience severe neutropenia (neutrophils less than 500 cells/mm  for a week or longer)
or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m
for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory
neuropathy, additional dose reduction should be made to 180 mg/m . For Grade 3 sensory neuropathy
hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses
of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions
(6.1)].
Non-Small Cell Lung Cancer
Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least
1500 cells/mm  and platelet count is at least 100,000 cells/mm  [see Contraindications (4),Warnings
and Precautions (5.1) and Adverse Reactions (6.2)].
In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts
recover to an absolute neutrophil count of at least 1500 cells/mm  and platelet count of at least
100,000 cells/mm  on Day 1 or to an absolute neutrophil count of at least 500 cells/mm  and platelet
count of at least 50,000 cells/mm  on Days 8 or 15 of the cycle. Upon resumption of dosing,
permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.
Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin
at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely
resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].
Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC
Adverse Drug Reaction
Occurrence
Weekly
ABRAXANE Dose
(mg/m )
Every 3-Week
Carboplatin Dose
(AUC mg•min/mL)
Neutropenic Fever (ANC less than 500/mm  with fever >38°C)
                                                      OR
Delay of next cycle by more than 7 days for ANC less than 1500/mm  
                                                      OR
ANC less than 500/mm  for more than 7 days
First
75
4.5
Second
50
3
Third
Discontinue Treatment
Platelet count less than 50 000/mm
First
75
4.5
2
a
b
2
2
c
a
c
c
2
2
2
2 b
2 b
2 b
2 b
3
2
2
3
3
3
3
3
3
2
3
3
3
3


Platelet count less than 50,000/mm
Second
Discontinue Treatment
Severe sensory Neuropathy – Grade 3 or 4
First
75
4.5
Second
50
3
Third
Discontinue Treatment
Adenocarcinoma of the Pancreas 
Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and
5, are provided in Table 3.
Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas
  Dose Level
ABRAXANE (mg/m )
Gemcitabine (mg/m )
   Full dose
125
1000
   1  dose reduction
100
800
   2
 dose reduction
75
600
   If additional dose reduction required
Discontinue
Discontinue
Recommended dose modifications for neutropenia and thrombocytopenia for patients with
adenocarcinoma of the pancreas are provided in Table 4.
Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within
a Cycle for Patients with Adenocarcinoma of the Pancreas
ANC = Absolute Neutrophil Count
Cycle
Day
ANC (cells/mm )
   
Platelet count (cells/mm )
ABRAXANE / Gemcitabine
Day 1
  < 1500
  OR   
  < 100,000
Delay doses until recovery
Day 8
  500 to < 1000
  OR   
  50,000 to < 75,000
Reduce 1 dose level
   
  < 500
  OR   
  < 50,000
Withhold doses
Day 15: If Day 8 doses were reduced or given without modification:
   
  500 to < 1000
  OR   
  50,000 to < 75,000
Reduce 1 dose level from Day 8
   
  < 500
  OR   
  < 50,000
Withhold doses
Day 15: If Day 8 doses were withheld:
   
  ≥ 1000
  OR   
  ≥ 75,000
Reduce 1 dose level from Day 1
   
  500 to < 1000
  OR   
  50,000 to < 75,000
Reduce 2 dose levels from Day 1
   
  < 500
  OR   
  < 50,000
Withhold doses
Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of
the pancreas are provided in Table 5.
Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas
Adverse Drug Reaction
ABRAXANE
Gemcitabine
Febrile Neutropenia:
   Grade 3 or 4
Withhold until fever resolves and ANC ≥ 1500; resume at next lower dose level
Peripheral Neuropathy:
   Grade 3 or 4
Withhold until improves to ≤ Grade 1; 
resume at next lower dose level
No dose reduction
Cutaneous Toxicity:
   Grade 2 or 3
Reduce to next lower dose level; discontinue treatment if toxicity persists
Gastrointestinal Toxicity:
   Grade 3 mucositis or diarrhea
Withhold until improves to ≤ Grade 1; 
resume at next lower dose level
2.6 Preparation and Administration Precautions
ABRAXANE is a cytotoxic drug and, as with other potentially toxic paclitaxel compounds, caution
should be exercised in handling ABRAXANE. The use of gloves is recommended. If ABRAXANE
(lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and
thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling,
burning and redness. If ABRAXANE contacts mucous membranes, the membranes should be flushed
thoroughly with water.
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible
infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed,
reduces the likelihood of infusion-related reactions [see Adverse Reactions (6.4)].
Premedication to prevent hypersensitivity reactions is generally not needed prior to the administration
3
2
2
st
nd
3
3


of ABRAXANE. Premedication may be needed in patients who have had prior hypersensitivity
reactions to ABRAXANE. Patients who experience a severe hypersensitivity reaction to ABRAXANE
should not be re-challenged with this drug [see Warnings and Precautions (5.5)].
2.7 Preparation for Intravenous Administration
ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID
ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO
RECONSTITUTION.
1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.
2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute,
using the
sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL.
3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as
this
will result in foaming.
4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper
wetting of
the lyophilized cake/powder.
5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any
cake/powder
occurs. Avoid generation of foam.
6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.
Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
The reconstituted suspension should be milky and homogenous without visible particulates. If
particulates or settling are visible, the vial should be gently inverted again to ensure complete
resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard
any unused portion.
Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient and slowly
withdraw the dosing volume of the reconstituted suspension from the vial(s) into a syringe: Dosing
volume (mL)=Total dose (mg)/5 (mg/mL).
Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile intravenous bag
[plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type intravenous bag]. The use of
specialized DEHP-free solution containers or administration sets is not necessary to prepare or
administer ABRAXANE infusions. The use of medical devices containing silicone oil as a lubricant
(ie, syringes and intravenous bags) to reconstitute and administer ABRAXANE may result in the
formation of proteinaceous strands.
Visually inspect the reconstituted ABRAXANE suspension in the intravenous bag prior to
administration. Discard the reconstituted suspension if proteinaceous strands, particulate matter or
discoloration are observed.
2.8 Stability
Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between
20°C to 25°C (68°F to 77°F) in the original package. Neither freezing nor refrigeration adversely
affects the stability of the product.
Stability of Reconstituted Suspension in the Vial 
Reconstituted ABRAXANE in the vial should be used immediately, but may be refrigerated at 2°C to
8°C (36°F to 46°F) for a maximum of 24 hours if necessary. If not used immediately, each vial of
reconstituted suspension should be replaced in the original carton to protect it from bright light.
Discard any unused portion.
Stability of Reconstituted Suspension in the Infusion Bag 
The suspension for infusion when prepared as recommended in an infusion bag should be used
immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a
maximum of 24 hours.
The total combined refrigerated storage time of reconstituted ABRAXANE in the vial and in the


infusion bag is 24 hours. This may be followed by storage in the infusion bag at ambient temperature
(approximately 25°C) and lighting conditions for a maximum of 4 hours.
Discard any unused portion.
3 DOSAGE FORMS AND STRENGTHS
For injectable suspension: lyophilized powder containing 100 mg of paclitaxel formulated as albumin-
bound particles in single-use vial for reconstitution.
4 CONTRAINDICATIONS
ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500
cells/mm .
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be
rechallenged with the drug.
5 WARNINGS AND PRECAUTIONS
5.1 Hematologic Effects
Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of
ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic
breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients
with pancreatic cancer.
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to
dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not
administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500
cells/mm . In the case of severe neutropenia (<500 cells/mm  for seven days or more) during a course
of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either
MBC or NSCLC.
In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers
to a level >1,500 cells/mm  and platelets recover to a level >100,000 cells/mm .
In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at
permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC
recovers to at least 1500 cells/mm  and platelet count of at least 100,000 cells/mm  on Day 1 or to an
ANC of at least 500 cells/mm  and platelet count of at least 50,000 cells/mm  on Days 8 or 15 of the
cycle [see Dosage and Administration (2.5)].
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is
less than 500 cells/mm  or platelets are less than 50,000 cells/mm  and delay initiation of the next cycle
if the ANC is less than 1500 cells/mm  or platelet count is less than 100,000 cells/mm  on Day 1 of the
cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and
Administration (2.5)].
5.2 Nervous System
Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The
occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥
Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2
for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed
by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].
5.3 Sepsis
Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in
combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for
severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad
spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever
resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration
(2.5)].
5.4 Pneumonitis
Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE
in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt
ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious
etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with
ABRAXANE and gemcitabine.
3
3
3
3
3
3
3
3
3
3
3
3
3


5.5 Hypersensitivity
Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been
reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be
rechallenged with this drug.
5.6 Hepatic Impairment
Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment,
administration of ABRAXANE in patients with hepatic impairment should be performed with caution.
Patients with hepatic impairment may be at increased risk of toxicity, particularly from
myelosuppression; such patients should be closely monitored for development of profound
myelosuppression. ABRAXANE is not recommended in patients who have total bilirubin >5 x ULN or
AST >10 x ULN. In addition, ABRAXANE is not recommended in patients with metastatic
adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin >1.5 x
ULN and AST ≤10 x ULN). The starting dose should be reduced for patients with moderate or severe
hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical
Pharmacology (12.3)].
5.7 Albumin (Human)
ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor
screening and product manufacturing processes, it carries a remote risk for transmission of viral
diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered
extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for
albumin.
5.8 Use in Pregnancy
ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel
formulated as albumin-bound particles to rats during pregnancy at doses lower than the maximum
recommended human dose, based on body surface area, caused embryo-fetal toxicities, including
intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.
There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this
drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient
should be apprised of the potential hazard to the fetus. Women of childbearing potential should be
advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations
(8.1)].
5.9 Use in Men
Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology
(13.1)].
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice.
The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast
cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia,
myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and
diarrhea [see Adverse Reactions (6.1)].
The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-
small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy,
nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of
ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and
pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of
ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most
common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%),
thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding
or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).
In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic
adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher
incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea,
alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The
most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia
(6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions
resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%)


and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of
ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse
reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%),
thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).
6.1 Clinical Trials Experience in Metastatic Breast Cancer
Table 6 shows the frequency of important adverse events in the randomized comparative trial for the
patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of
metastatic breast cancer.
Table 6: Frequency  of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast
Cancer Study on an Every-3-Weeks Schedule
Percent of Patients
ABRAXANE
260 mg/m  over 30 min
(n=229)
Paclitaxel Injection
175 mg/m  over 3 h  
(n=225)
Bone Marrow
 Neutropenia
   < 2.0 x 10 /L
80
82
   < 0.5 x 10 /L
9
22
 Thrombocytopenia
   < 100 x 10 /L
2
3
   < 50 x 10 /L
<1
<1
 Anemia
   < 11 g/dL
33
25
   < 8 g/dL
1
<1
 Infections
24
20
 Febrile Neutropenia
2
1
 Neutropenic Sepsis
<1
<1
 Bleeding
2
2
Hypersensitivity Reaction
 All
4
12
 Severe
0
2
Cardiovascular
 Vital Sign Changes During Administration
   Bradycardia
<1
<1
   Hypotension
5
5
 Severe Cardiovascular Events
3
4
Abnormal ECG
 All Patients
60
52
 Patients with Normal Baseline
35
30
Respiratory
 Cough
7
6
 Dyspnea
12
9
Sensory Neuropathy
 Any Symptoms
71
56
 Severe Symptoms
10
2
Myalgia / Arthralgia
 Any Symptoms
44
49
 Severe Symptoms
8
4
Asthenia
 Any Symptoms
47
39
 Severe Symptoms
8
3
Fluid Retention/Edema
 Any Symptoms
10
8
 Severe Symptoms
0
<1
Gastrointestinal
 Nausea
   Any Symptoms
30
22
   Severe Symptoms
3
<1
 Vomiting
a
2
2
b
9
9
9
9
c
d
d
d
d
d
d
d


 Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2.
 Paclitaxel injection patients received premedication.
 Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that
began on a day of dosing.
 Severe events are defined as at least grade 3 toxicity.
   Any Symptoms
18
10
   Severe Symptoms
4
1
 Diarrhea
   Any Symptoms
27
15
   Severe Symptoms
<1
1
  Mucositis
   Any Symptoms
7
6
   Severe Symptoms
<1
0
Alopecia
90
94
Hepatic (Patients with Normal Baseline)
 Bilirubin Elevations
7
7
 Alkaline Phosphatase Elevations
36
31
 AST (SGOT) Elevations
39
32
Injection Site Reaction
<1
1
Adverse Event Experiences by Body System
Hematologic Disorders 
Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the
randomized trial, neutrophil counts declined below 500 cells/mm  (Grade 4) in 9% of the patients
treated with a dose of 260 mg/m  compared to 22% in patients receiving paclitaxel injection at a dose of
175 mg/m . Pancytopenia has been observed in clinical trials.
Infections 
Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis,
respiratory tract infections and pneumonia were the most frequently reported infectious complications.
Hypersensitivity Reactions (HSRs) 
Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%)
and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE 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 ABRAXANE 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 ABRAXANE.
Neurologic 
The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy
was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%)
treated with ABRAXANE 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
ABRAXANE 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 ABRAXANE and 1%
a
b
c
d
d
d
d
3
2
2


were severe. The severe cases (keratitis and blurred vision) were reported in patients who received
higher doses than those recommended (300 or 375 mg/m ). These effects generally have been
reversible.
Arthralgia/Myalgia 
The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and
resolved within a few days.
Hepatic 
Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE 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.
6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer
Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel
injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage
IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label
trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m
on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous
infusion over 3 hours at a dose of 200 mg/m , following premedication. In both treatment arms
carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day
cycle after completion of ABRAXANE/paclitaxel infusion.
The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose-
and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median
age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell
lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of
treatment.
The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in
ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia
56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea
15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus
carboplatin treatment group).
Table 7 provides the frequency and severity of laboratory-detected abnormalities which occurred with
a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus
carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.
Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for
Grade 3-4 Toxicity Between Treatment Groups
 508 patients assessed in ABRAXANE/carboplatin-treated group
 514 patients assessed in paclitaxel injection/carboplatin-treated group
 513 patients assessed in paclitaxel injection/carboplatin-treated group
ABRAXANE (100 mg/m  weekly)
plus carboplatin
Paclitaxel Injection (200 mg/m  every 3 weeks)
plus carboplatin
Grades 1-4 (%)
Grade 3-4 (%)
Grades 1-4 (%)
Grade 3-4 (%)
Anemia
98
28
91
7
Neutropenia
85
47
83
58
Thrombocytopenia
68
18
55
9
Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of
≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514
ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel
injection plus carboplatin.
Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between
Treatment Groups
ABRAXANE (100 mg/m  weekly)
+ carboplatin
(N=514)
Paclitaxel Injection (200 mg/m  
every 3 weeks) + carboplatin
(N=524)
2
2
2
1
2
3
2
2
1,2
1,3
1,3
2
2


 Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).
System Organ
Class
MedDRA v 12.1
Preferred Term
Grade 1-4
Toxicity
(%)
Grade 3-4
Toxicity
(%)
Grades 1-4
Toxicity
(%)
Grade 3-4
Toxicity
(%)
Nervous system
disorders
Peripheral neuropathy
48
3
64
12
General disorders
and administration
site conditions
Edema peripheral
10
0
4
<1
Respiratory
thoracic and
mediastinal
disorders
Epistaxis
7
0
2
0
Musculoskeletal
and connective
tissue disorders
Arthralgia
13
<1
25
2
Myalgia
10
<1
19
2
For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3
peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy
improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of
ABRAXANE.
6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas
Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402
patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of
the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a
median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the
gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was
75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative
dose intensity of ABRAXANE was 81%.
Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a
higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus
gemcitabine-treated patients.
Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5%
for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm
 405 patients assessed in ABRAXANE/gemcitabine-treated group
 388 patients assessed in gemcitabine-treated group
 404 patients assessed in ABRAXANE/gemcitabine-treated group
 Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine
group.
ABRAXANE(125 mg/m )/
Gemcitabine
Gemcitabine
Grades 1-4
(%)
Grade 3-4
(%)
Grades 1-4
(%)
Grade 3-4
(%)
Neutropenia
73
38
58
27
Thrombocytopenia
74
13
70
9
Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of
≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group
compared to the gemcitabine group.
Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher
Toxicity) in the ABRAXANE/Gemcitabine Arm
System Organ Class
Adverse Reaction
ABRAXANE (125 mg/m ) and
gemcitabine (N=421)
Gemcitabine (N=402)
All Grades
Grade 3 or 
Higher
All Grades
Grade 3 or 
Higher
General disorders and
administration site conditions
Fatigue
248 (59%)
77 (18%)
183 (46%)
37 (9%)
Peripheral edema
194 (46%)
13 (3%)
122 (30%)
12 (3%)
Pyrexia
171 (41%)
12 (3%)
114 (28%)
4 (1%)
a
a
a
b
c
d
2
d
a,b
b,c
2


 Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope).
 Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial,
and urinary tract infection enterococcal.
Asthenia
79 (19%)
29 (7%)
54 (13%)
17 (4%)
Mucositis
42 (10%)
6 (1%)
16 (4%)
1 (<1%)
Gastrointestinal disorders
Nausea
228 (54%)
27 (6%)
192 (48%)
14 (3%)
Diarrhea
184 (44%)
26 (6%)
95 (24%)
6 (1%)
Vomiting
151 (36%)
25 (6%)
113 (28%)
15 (4%)
Skin and subcutaneous
tissue disorders
Alopecia
212 (50%)
6 (1%)
21 (5%)
0
Rash
128 (30%)
8 (2%)
45 (11%)
2 (<1%)
Nervous system disorders
Peripheral neuropathy
227 (54%)
70 (17%)
51 (13%)
3 (1%)
Dysgeusia
68 (16%)
0
33 (8%)
0
Headache
60 (14%)
1 (<1%)
38 (9%)
1 (<1%)
Metabolism and nutrition
disorders
Decreased appetite
152 (36%)
23 (5%)
104 (26%)
8 (2%)
Dehydration
87 (21%)
31 (7%)
45 (11%)
10 (2%)
Hypokalemia
52 (12%)
18 (4%)
28 (7%)
6 (1%)
Respiratory, thoracic and 
mediastinal disorders
Cough
72 (17%)
0
30 (7%)
0
Epistaxis
64 (15%)
1 (<1%)
14 (3%)
1 (<1%)
Infections and infestations
Urinary tract infections 
47 (11%)
10 (2%)
20 (5%)
1 (<1%)
Musculoskeletal and
connective tissue disorders
Pain in extremity
48 (11%)
3 (1%)
24 (6%)
3 (1%)
Arthralgia
47 (11%)
3 (1%)
13 (3%)
1 (<1%)
Myalgia
44 (10%)
4 (1%)
15 (4%)
0
Psychiatric disorders
Depression
51 (12%)
1 (<1%)
24 (6%)
0
Additional clinically relevant adverse reactions that were reported in < 10% of the patients with
adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included:
Infections & infestations: oral candidiasis, pneumonia
Vascular disorders: hypertension
Cardiac disorders: tachycardia, congestive cardiac failure
Eye disorders: cystoid macular edema
Peripheral Neuropathy 
Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitabine
compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral
neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE
arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from
Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade
3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.
Sepsis 
Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients
who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk
factors for sepsis included biliary obstruction or presence of biliary stent.
Pneumonitis 
Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of
patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis
died.
6.4 Postmarketing Experience with ABRAXANE and other Paclitaxel Formulations
Unless otherwise noted, the following discussion refers to the adverse reactions that have been
identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure. In some instances, severe events observed with
paclitaxel injection may be expected to occur with ABRAXANE.
Hypersensitivity Reactions 
Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use
of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human
albumin has not been studied.
Cardiovascular 
a
b
a
b


There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular
block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such
as anthracyclines, or had underlying cardiac history.
Respiratory 
There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients
receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent
radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of
paclitaxel injection safety and may also be observed with ABRAXANE.
Neurologic 
Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy
resulting in paralytic ileus.
Vision Disorders 
Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection
suggest persistent optic nerve damage. These may also be observed with ABRAXANE.
Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with
ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual
acuity may return to baseline.
Hepatic 
Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of
the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE
treatment.
Gastrointestinal (GI) 
There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic
colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis
(typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection
alone and in combination with other chemotherapeutic agents.
Injection Site Reaction 
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is
advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug
administration.
Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part
of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site
reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a
week to ten days. Recurrence of skin reactions at a site of previous extravasation following
administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.
Other Clinical Events 
Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed
with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall
phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar
erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.
There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.
6.5 Accidental Exposure
No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of
paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following
topical exposure, events have included tingling, burning, and redness.
7 DRUG INTERACTIONS
The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised when
administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other
imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir,
and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either
CYP2C8 or CYP3A4.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.8)].
There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its
mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a


pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while
receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of
childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE.
Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on
gestation days 7 to 17 at doses of 6 mg/m  (approximately 2% of the daily maximum recommended
human dose on a mg/m  basis) caused embryofetal toxicities, as indicated by intrauterine mortality,
increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body
weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations,
such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of
soft tissue and skeletal malformations were also exhibited at 3 mg/m  (approximately 1% of the daily
maximum recommended human dose on a mg/m  basis).
8.3 Nursing Mothers
It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were
excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of
the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue
nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.
8.5 Geriatric Use
Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic
breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities
occurred notably more frequently among patients who received ABRAXANE.
A subsequent pooled analysis was conducted in 981 patients receiving ABRAXANE monotherapy for
metastatic breast cancer, of which 15% were 65 years of age or older and 2% were 75 years of age or
older. A higher incidence of epistaxis, diarrhea, dehydration, fatigue and peripheral edema was found in
patients 65 years of age or older.
Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-
line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or
older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years
or older compared to patients younger than 65 years old. No overall difference in effectiveness, as
measured by response rates, was observed between patients 65 years or older compared to patients
younger than 65 years old.
Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-
line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or
older. No overall differences in effectiveness were observed between patients who were 65 years of
age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more
frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies
of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years
and older to determine whether they respond differently from younger patients.
8.6 Patients with Hepatic Impairment
The exposure to paclitaxel may be higher in patients with hepatic impairment than in patients with normal
hepatic function. Reduce ABRAXANE starting dose in patients with moderate to severe hepatic
impairment. Do not administer ABRAXANE to patients with total bilirubin > 5 x ULN or AST > 10 x
ULN [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology
(12.3)]. Do not administer to patients with metastatic adenocarcinoma of the pancreas who have moderate
to severe hepatic impairment [see Dosage and Administration (2.4)].
8.7 Patients with Renal Impairment
Adjustment of the starting ABRAXANE dose is not required for patients with mild to moderate renal
impairment (estimated creatinine clearance ≥30 to <90 mL/min) [see Clinical Pharmacology (12.3)].
There are insufficient data to permit dosage recommendations in patients with severe renal impairment
or end stage renal disease (estimated creatinine clearance <30 mL/min).
10 OVERDOSAGE
There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of
overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.
11 DESCRIPTION
2
2
2
2


ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension)
(albumin-bound) is paclitaxel formulated as albumin-bound nanoparticles with a mean particle size of
approximately 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state.
ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20
mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial
contains 100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of human albumin
(containing sodium caprylate and sodium acetyltryptophanate). Each milliliter (mL) of reconstituted
suspension contains 5 mg paclitaxel formulated as albumin-bound particles. ABRAXANE is free of
solvents.
The active agent in ABRAXANE is paclitaxel, a microtubule inhibitor. The chemical name for
paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate
13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
Paclitaxel has the following structural formula:
Paclitaxel is a white to off-white crystalline powder with the empirical formula C
H
NO
 and a
molecular weight of 853.91. It is highly lipophilic, insoluble in water, and melts at approximately
216°C to 217°C.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ABRAXANE is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers
and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the
normal dynamic reorganization of the microtubule network that is essential for vital interphase and
mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout
the cell cycle and multiple asters of microtubules during mitosis.
12.3 Pharmacokinetics
Absorption 
The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of ABRAXANE at
dose levels of 80 to 375 mg/m  were determined in clinical studies. Dose levels of mg/m  refer to mg
of paclitaxel in ABRAXANE. Following intravenous administration of ABRAXANE, paclitaxel plasma
concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the
peripheral compartment and the slower second phase representing drug elimination.
The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m  and the pharmacokinetics of
paclitaxel for ABRAXANE were independent of the duration of intravenous administration.
The pharmacokinetic data of 260 mg/m  ABRAXANE administered over a 30-minute infusion was
compared to the pharmacokinetics of 175 mg/m  paclitaxel injection over a 3-hour infusion. Clearance
was larger (43%) and the volume of distribution was higher (53%) for ABRAXANE than for paclitaxel
injection. There were no differences in terminal half-lives.
Distribution 
Following ABRAXANE administration to patients with solid tumors, paclitaxel is evenly distributed
into blood cells and plasma and is highly bound to plasma proteins (94%). In a within-patient comparison
study, the fraction of unbound paclitaxel in plasma was significantly higher with ABRAXANE (6.2%)
than with solvent-based paclitaxel (2.3%). This contributes to significantly higher exposure to unbound
paclitaxel with ABRAXANE compared with solvent-based paclitaxel, when the total exposure is
comparable. In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging
from 0.1 to 50 µg/mL, indicated that the presence of cimetidine, ranitidine, dexamethasone, or
diphenhydramine did not affect protein binding of paclitaxel. The total volume of distribution is
approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution
and/or tissue binding of paclitaxel.
Metabolism 
In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized
47
51
14
2
2
2
2
2


primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel
and 6α, 3’-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-
hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine,
dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used
exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol,
retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-
hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of
interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 [see
Drug Interactions (7)].
Elimination 
At the clinical dose range of 80 to 300 mg/m , the mean total clearance of paclitaxel ranges from 13 to
30 L/h/m , and the mean terminal half-life ranges from 13 to 27 hours.
After a 30-minute infusion of 260 mg/m  doses of ABRAXANE, the mean values for cumulative
urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the
total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3’-p-
hydroxypaclitaxel.
Fecal excretion was approximately 20% of the total dose administered.
Specific Populations
Pharmacokinetics in Hepatic Impairment 
The effect of hepatic impairment on the pharmacokinetics of paclitaxel following ABRAXANE
administration was studied in patients with advanced solid tumors. The results showed that mild hepatic
impairment (total bilirubin >1 to ≤1.5 x ULN, AST ≤10 x ULN, n=8) had no clinically important effect
on pharmacokinetics of paclitaxel. Patients with moderate (total bilirubin >1.5 to ≤ 3 x ULN, AST ≤10 x
ULN, n=7) or severe (total bilirubin >3 to ≤5 x ULN, n=5) hepatic impairment had a 22% to 26%
decrease in the maximum elimination rate of paclitaxel and approximately 20% increase in mean
paclitaxel AUC compared with patients with normal hepatic function (total bilirubin ≤ULN, AST ≤ULN,
n=130). [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].
Elimination of paclitaxel shows an inverse correlation with total bilirubin and a positive correlation
with serum albumin. Pharmacokinetic/pharmacodynamic modeling indicates that there is no correlation
between hepatic function (as indicated by the baseline albumin or total bilirubin level) and neutropenia
after adjusting for ABRAXANE exposure. Pharmacokinetic data are not available for patients with total
bilirubin >5 x ULN or for patients with metastatic adenocarcinoma of the pancreas [see Dosage and
Administration (2.4) and Use in Specific Populations (8.6)].
Pharmacokinetics in Renal Impairment 
The effect of pre-existing mild (creatinine clearance ≥60 to <90 mL/min, n=61) or moderate (creatinine
clearance ≥30 to <60 mL/min, n=23) renal impairment on the pharmacokinetics of paclitaxel following
ABRAXANE administration was studied in patients with advanced solid tumors. Mild to moderate renal
impairment had no clinically important effect on the maximum elimination rate and systemic exposure
(AUC and C
) of paclitaxel [see Use in Specific Populations (8.7)].
Other Intrinsic Factors 
Population pharmacokinetic analyses for ABRAXANE show that body weight (40 to 143 kg), body
surface area (1.3 to 2.4 m ), gender, race (Asian vs. White), age (24 to 85 years) and type of solid
tumors do not have a clinically important effect on the maximum elimination rate and systemic exposure
(AUC and C
) of paclitaxel.
Pharmacokinetic Interactions between ABRAXANE and Carboplatin 
Administration of carboplatin immediately after the completion of the ABRAXANE infusion to patients
with NSCLC did not cause clinically meaningful changes in paclitaxel exposure. The observed mean
AUC
 of free carboplatin was approximately 23% higher than the targeted value (6 min*mg/mL), but its
mean half-life and clearance were consistent with those reported in the absence of paclitaxel.
Pharmacokinetic Interactions between ABRAXANE and Gemcitabine 
Pharmacokinetic interactions between ABRAXANE and gemcitabine have not been studied in humans.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of ABRAXANE has not been studied.
Paclitaxel was clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo
(micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene
mutation assay.
Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m  on a weekly
basis (approximately 16% of the daily maximum recommended human exposure on a body surface area
2
2
2
max
2
max
inf
2


basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility
accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low
incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m /week
in this study (approximately 1 to 5% of the daily maximum recommended human exposure on a mg/m
basis). Testicular atrophy/degeneration was observed in single-dose toxicology studies in rodents
administered paclitaxel formulated as albumin-bound particles at doses lower than the recommended
human dose; doses were 54 mg/m  in rodents and 175 mg/m  in dogs.
14 CLINICAL STUDIES
14.1 Metastatic Breast Cancer
Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a
randomized comparative study were available to support the use of ABRAXANE in metastatic breast
cancer.
Single Arm Open Label Studies 
In one study, ABRAXANE was administered as a 30-minute infusion at a dose of 175 mg/m  to 43
patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m  as a 30-minute
infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3-week intervals.
Objective responses were observed in both studies.
Randomized Comparative Study 
This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were
randomized to receive ABRAXANE at a dose of 260 mg/m  given as a 30-minute infusion, or paclitaxel
injection at 175 mg/m  given as a 3-hour infusion. Sixty-four percent of patients had impaired
performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of
metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received
chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and
adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy.
Seventy-seven percent of the patients had been previously exposed to anthracyclines.
In this trial, patients in the ABRAXANE treatment arm had a statistically significantly higher reconciled
target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to 26.7%), compared to
11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection treatment arm. See Table 11.
There was no statistically significant difference in overall survival between the two study arms.
Table 11: Efficacy Results from Randomized Metastatic Breast Cancer Trial
 Reconciled Target Lesion Response Rate (TLRR) was the prospectively defined protocol specific endpoint, based on independent
radiologic assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the
first 6 cycles of therapy. The reconciled TLRR was lower than the investigator Reported Response Rates, which are based on all
cycles of therapy.
 From Cochran-Mantel-Haenszel test stratified by 1  line vs. > 1  line therapy.
 Prior therapy included an anthracycline unless clinically contraindicated.
 
ABRAXANE 
260 mg/m
Paclitaxel
Injection
175 mg/m
Reconciled Target Lesion Response Rate (primary endpoint)
All randomized patients
Response
Rate 
[95% CI]
50/233 (21.5%) 
[16.19% –
26.73%]
25/227 (11.1%) 
[6.94% –
15.09%]
p-value
0.003
Patients who had failed combination chemotherapy or relapsed within 6 months of
adjuvant chemotherapy
Response
Rate 
[95% CI]
20/129 (15.5%) 
[9.26% –
21.75%]
12/143 (8.4%) 
[3.85% –
12.94%]
14.2 Non-Small Cell Lung Cancer
A multicenter, randomized, open-label study was conducted in 1052 chemonaive patients with Stage
IIIb/IV non-small cell lung cancer to compare ABRAXANE in combination with carboplatin to
paclitaxel injection in combination with carboplatin as first-line treatment in patients with advanced non-
small cell lung cancer. ABRAXANE was administered as an intravenous infusion over 30 minutes at a
dose of 100 mg/m  on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as
an intravenous infusion over 3 hours at a dose of 200 mg/m , following premedication. In both treatment
arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-
day cycle after completion of ABRAXANE/paclitaxel infusion. Treatment was administered until
disease progression or development of an unacceptable toxicity. The major efficacy outcome measure
was overall response rate as determined by a central independent review committee using RECIST
2
2
2
2
2
2
2
2
a
b
st
st
c
2
2
a
b
c
2
2


guidelines (Version 1.0).
In the intent-to-treat (all-randomized) population, the median age was 60 years, 75% were men, 81%
were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1,
and 73% were current or former smokers. Patients received a median of 6 cycles of treatment in both
study arms.
Patients in the ABRAXANE/carboplatin arm had a statistically significantly higher overall response rate
compared to patients in the paclitaxel injection/carboplatin arm [(33% versus 25%) see Table 12]. There
was no statistically significant difference in overall survival between the two study arms.
Table 12: Efficacy Results from Randomized Non-Small Cell Lung Cancer Trial (Intent-to-Treat Population)
CI = confidence interval; DoR= Duration of response
ABRAXANE (100 mg/m  
weekly)
+ carboplatin
(N=521)
Paclitaxel Injection
(200 mg/m  every 3 weeks)
+ carboplatin
(N=531)
Overall Response Rate (ORR)
Confirmed complete or partial overall response, n (%)
170 (33%)
132 (25%)
      95% CI
28.6, 36.7
21.2, 28.5
      P-value (Chi-Square test)
0.005
   
   
   
Median DoR in months (95% CI)
6.9 (5.6, 8.0)
6.0 (5.6, 7.1)
   
   
   
Overall Response Rate by Histology
Carcinoma/Adenocarcinoma
66/254 (26%)
71/264 (27%)
Squamous Cell Carcinoma
94/229 (41%)
54/221 (24%)
Large Cell Carcinoma
3/9 (33%)
2/13 (15%)
Other
7/29 (24%)
5/33 (15%)
14.3 Adenocarcinoma of the Pancreas
A multicenter, multinational, randomized, open-label study was conducted in 861 patients comparing
ABRAXANE plus gemcitabine versus gemcitabine monotherapy as first-line treatment of metastatic
adenocarcinoma of the pancreas. Key eligibility criteria were Karnofsky Performance Status (KPS) ≥70,
normal bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the
ULN for patients with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting or for
metastatic disease, no ongoing active infection requiring systemic therapy, and no history of interstitial
lung disease. Patients with rapid decline in KPS (≥10%) or serum albumin (≥20%) during the 14 day
screening period prior to study randomization were ineligible.
A total of 861 patients were randomized (1:1) to the ABRAXANE/gemcitabine arm (N=431) or to the
gemcitabine arm (N=430). Randomization was stratified by geographic region (Australia, Western
Europe, Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence of liver
metastasis (yes versus no). Patients randomized to ABRAXANE/gemcitabine received ABRAXANE
125 mg/m  as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m  as an
intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients randomized
to gemcitabine received 1000 mg/m  as an intravenous infusion over 30-40 minutes weekly for 7 weeks
followed by a 1-week rest period in Cycle 1 then as 1000 mg/m  on Days 1, 8 and 15 of each
subsequent 28-day cycle. Patients in both arms received treatment until disease progression or
unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional
outcome measures were progression-free survival (PFS) and overall response rate (ORR), both
assessed by independent, central, blinded radiological review using RECIST (version 1.0).
In the intent to treat (all randomized) population, the median age was 63 years (range 27-88 years) with
42% ≥ 65 years of age; 58% were men; 93% were White and KPS was 90-100 in 60%. Disease
characteristics included 46% of patients with 3 or more metastatic sites; 84% of patients had liver
metastasis; and the location of the primary pancreatic lesion was in the head of pancreas (43%), body
(31%), or tail (25%).
Results for overall survival, progression-free survival, and overall response rate are shown in Table
13.
Table 13: Efficacy Results from Randomized Study in Patients with Adenocarcinoma of the Pancreas (ITT
Population)
ABRAXANE (125 mg/m )
and gemcitabine
Gemcitabine
(N = 430)
2
2
2
2
2
2
2


CI = confidence interval, HR = hazard ratio of ABRAXANE plus gemcitabine / gemcitabine, ITT = intent-to-treat
population.
 Stratified Cox proportional hazard model.
 Stratified log-rank test stratified by geographic region (North America versus Others), Karnofsky performance score
(70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no).
 Based on Independent Radiological Reviewer Assessment.
 Chi-square test.
(N = 431)
(N = 430)
Overall Survival
Number of deaths, n (%)
333 (77)
359 (83)
      Median Overall Survival (months)
8.5
6.7
      95% CI
7.9, 9.5
6.0, 7.2
      HR (95% CI) 
0.72 (0.62, 0.83)
      P-value
<0.0001
Progression-free Survival
Death or progression, n (%)
277 (64)
265 (62)
      Median Progression-free Survival (months)
5.5
3.7
      95% CI
4.5, 5.9
3.6, 4.0
      HR (95% CI) 
0.69 (0.58, 0.82)
      P-value
<0.0001
Overall Response Rate
Confirmed complete or partial overall response, n (%)
99 (23)
31 (7)
      95% CI
19.1, 27.2
5.0, 10.1
      P-value 
<0.0001
In exploratory analyses conducted in clinically relevant subgroups with a sufficient number of subjects,
the treatment effects on overall survival were similar to that observed in the overall study population.
Figure 1: Kaplan-Meier Curve of Overall Survival (Intent-to-treat Population)
15 REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in
healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service,
Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health,
a
b
c
d
a
b
c
a
b
c
d


DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure
to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous
Drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines
and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Product No.: 103450 
NDC No.: 68817-134-50        100 mg of paclitaxel in a single-use vial, individually packaged in a
carton.
16.2 Storage
Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to
protect from bright light.
16.3 Handling and Disposal
Procedures for proper handling and disposal of anticancer drugs should be considered. Several
guidelines on this subject have been published [see References (15)]. There is no general agreement that
all of the procedures recommended in the guidelines are necessary or appropriate.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling
ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while
receiving this drug. Women of childbearing potential should use effective contraceptives while
receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].
Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].
Patients must be informed of the risk of low blood cell counts and severe and life-threatening
infections and instructed to contact their physician immediately for fever or evidence of infection.
[see Warnings and Precautions (5.1), (5.3)].
Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of
dehydration.
Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients
should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see
Warnings and Precautions (5.2)].
Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with
ABRAXANE
Instruct patients to contact their physician for signs of an allergic reaction, which could be severe
and sometimes fatal. [see Warnings and Precautions (5.5)].
Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or
shortness of breath [see Warnings and Precautions (5.4)].
Manufactured for:       Celgene Corporation
                                  Summit, NJ 07901
ABRAXANE  is a registered trademark of Abraxis BioScience, LLC.
©2005-2015 Abraxis BioScience, LLC.
All Rights Reserved.
Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.
U.S. Patent Numbers: See www.celgene.com.
ABRPI.009/PPI.009 07/15
Patient Information
ABRAXANE  (ah-BRAKS-ane) 
(paclitaxel protein-bound particles for injectable suspension)
(albumin-bound)
Read this Patient Information before you start receiving ABRAXANE and before each infusion. This
information does not take the place of talking with your doctor about your medical condition or your
treatment.
®
®


What is ABRAXANE?
ABRAXANE is a prescription medicine used to treat:
advanced breast cancer in people who have already received certain other medicines for their
cancer.
advanced non-small cell lung cancer, in combination with carboplatin in people who cannot be
treated with surgery or radiation.
and advanced pancreatic cancer, when used in combination with gemcitabine as the first medicine for
advanced pancreatic cancer.
It is not known if ABRAXANE is safe or effective in children.
Who should not receive ABRAXANE?
Do not receive ABRAXANE if:
your white blood cell count is below 1,500 cells/ mm .
you have had a severe allergic reaction to ABRAXANE.
What should I tell my doctor before receiving ABRAXANE? 
Before you receive ABRAXANE, tell your doctor if you:
have liver or kidney problems.
have any other medical conditions.
are a man planning to father a child. You should not father a child during your treatment with
ABRAXANE. ABRAXANE can harm the unborn baby of your partner. Talk to your doctor if this is
a concern to you.
are pregnant or plan to become pregnant. ABRAXANE can harm your unborn baby. You should not
become pregnant while receiving ABRAXANE. Women who may become pregnant should use
effective birth control (contraception). Talk to your doctor about the best way to prevent pregnancy
while receiving ABRAXANE.
are breastfeeding or plan to breastfeed. It is not known if ABRAXANE passes into your breast milk.
You and your doctor should decide if you will receive ABRAXANE or breastfeed.
Tell your doctor about all the medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list to show your doctor and pharmacist when you get a new
medicine.
How will I receive ABRAXANE?
Your doctor will prescribe ABRAXANE in an amount that is right for you.
Premedication to prevent allergic reactions is generally not needed to receive ABRAXANE.
Premedication may be needed if you have had an allergic reaction to ABRAXANE. In case of
severe allergic reaction, ABRAXANE should not be used again.
ABRAXANE will be given to you by intravenous infusion into your vein.
Your doctor should do regular blood tests while you receive ABRAXANE.
What are the possible side effects of ABRAXANE?
ABRAXANE may cause serious side effects, including:
decreased blood cell counts. ABRAXANE can cause a severe decrease in neutrophils (a type of
white blood cells important in fighting against bacterial infections) and platelets (important for
clotting and to control bleeding). Your doctor will check your blood cell count during your
treatment with ABRAXANE and after you have stopped your treatment.
numbness, tingling, pain, or weakness in your hands or feet (neuropathy).
severe infection (sepsis). If you receive ABRAXANE in combination with gemcitabine, infections
can be severe and lead to death. Tell your doctor right away if you have a fever (temperature of
greater than 100.4° F) or develop signs of infection.
lung or breathing problems. If you receive ABRAXANE in combination with gemcitabine, lung or
breathing problems may be severe and can lead to death. Tell your doctor right away if you have a
sudden onset of persistent dry cough or shortness of breath.
allergic reactions. Allergic reactions to ABRAXANE may be severe and can lead to death.
The most common side effects of ABRAXANE include:
hair loss
numbness, tingling, pain, or weakness in the hands or feet
abnormal heart beat
tiredness
joint and muscle pain
changes in your liver function tests
3


rash
low red blood cell count (anemia). Red blood cells carry oxygen to your body tissues. Tell your
doctor if you feel weak, tired or short of breath.
nausea and vomiting
infections. If you have a fever (temperature of greater than 100.4° F) or other signs of infection, tell
your doctor right away.
Diarrhea
Loss of body fluid (dehydration)
Swelling in the hands or feet
These are not all the possible side effects of ABRAXANE. For more information, ask your doctor or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-
FDA-1088.
General information about the safe and effective use of ABRAXANE.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
This Patient Information leaflet summarizes the important information about ABRAXANE. If you would
like more information, talk to your doctor. You can ask your doctor or pharmacist for information about
ABRAXANE that is written for health professionals.
For more information, call 1-888-423-5436.
What are the ingredients in ABRAXANE?
Active ingredient: paclitaxel (bound to human albumin).
Other ingredient: human albumin (containing sodium caprylate and sodium acetyltryptophanate)
This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: July 2015
Manufactured for:      Celgene Corporation
                                 Summit, NJ 07901
ABRAXANE  is a registered trademark of Abraxis BioScience, LLC. 
©2005-2015 Abraxis BioScience, LLC. 
All Rights Reserved.
Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.
U.S. Patent Numbers: See www.celgene.com.
ABRPPI.009 07/15
PRINCIPAL DISPLAY PANEL - 100 mg Vial
NDC 68817-134-50
103450
Abraxane  
for Injectable Suspension
(paclitaxel protein-bound particles for injectable suspension)
(albumin-bound)
100 mg per vial 
Single Use Vial
Discard any unused portion.
For Intravenous Use Only
Rx only
Functional properties differ from other
paclitaxel products. DO NOT SUBSTITUTE.
®
®


Product: ACP-196 (acalabrutinib) 
Date:  01 February 2016 
Protocol: ACE-ST-004 
 
 
Acerta Pharma 
Confidential 
Page 135 of 160 
Appendix 3. 
Gemcitabine Prescribing Information 
 


1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use 
Gemzar safely and effectively. See full prescribing information for 
Gemzar.
GEMZAR (gemcitabine for injection), for intravenous use
Initial U.S. Approval: 1996
--------------------------- RECENT MAJOR CHANGES --------------------------
Dosage and Administration:
Dose Modifications for Non-Hematologic Adverse Reactions (2.5)
6/2014
Warnings and Precautions:
Posterior Reversible Encephalopathy Syndrome (5.9)
6/2014
---------------------------- INDICATIONS AND USAGE ---------------------------
Gemzar
® is a nucleoside metabolic inhibitor indicated:
•
in combination with carboplatin, for the treatment of advanced 
ovarian cancer that has relapsed at least 6 months after 
completion of platinum- based therapy. (1.1)
•
in combination with paclitaxel, for first-line treatment of metastatic 
breast cancer after failure of prior anthracycline-containing 
adjuvant chemotherapy, unless anthracyclines were clinically 
contraindicated. (1.2)
•
in combination with cisplatin for the treatment of non-small cell 
lung cancer. (1.3)
•
as a single agent for the treatment of pancreatic cancer. (1.4)
------------------------DOSAGE AND ADMINISTRATION-----------------------
Gemzar is for intravenous use only.
•
Ovarian Cancer: 1000 mg/m
2 over 30 minutes on Days 1 and 8 of 
each 21-day cycle. (2.1)
•
Breast Cancer: 1250 mg/m
2 over 30 minutes on Days 1 and 8 of 
each 21-day cycle. (2.2)
•
Non-Small Cell Lung Cancer: 1000 mg/m
2 over 30 minutes on 
Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m
2 over 30 
minutes on Days 1 and 8 of each 21-day cycle. (2.3)
•
Pancreatic Cancer: 1000 mg/m
2 over 30 minutes once weekly for 
the first 7 weeks, then one week rest, then once weekly for 3 
weeks of each 28-day cycle. (2.4)
----------------------DOSAGE FORMS AND STRENGTHS---------------------
•
200 mg/single-use vial (3)
•
1 g/single-use vial (3)
------------------------------- CONTRAINDICATIONS ------------------------------
Patients with a known hypersensitivity to gemcitabine. (4)
------------------------ WARNINGS AND PRECAUTIONS -----------------------
•
Schedule-dependent toxicity: Increased toxicity with infusion time 
greater than 60 minutes or dosing more frequently than once 
weekly. (5.1)
•
Myelosuppression: Monitor for myelosuppression prior to each 
cycle and reduce or withhold dose for severe myelosuppression.
(5.2, 5.7)
•
Pulmonary Toxicity and Respiratory Failure: Discontinue Gemzar
immediately for unexplained new or worsening dyspnea or 
evidence of severe pulmonary toxicity. (5.3)
•
Hemolytic-Uremic Syndrome (HUS): Monitor renal function prior 
to initiation and during therapy. Discontinue Gemzar for HUS or 
severe renal impairment. (5.4)
•
Hepatic Toxicity: Monitor hepatic function prior to initiation and 
during therapy. Discontinue Gemzar for severe hepatic toxicity.
(5.5)
•
Embryofetal Toxicity: Can cause fetal harm. Advise women of 
potential risk to the fetus. (5.6, 8.1)
•
Exacerbation of Radiation Therapy Toxicity: May cause severe 
and life-threatening toxicity when administered during or within 7 
days of radiation therapy. (5.7)
•
Capillary Leak Syndrome: Discontinue Gemzar. (5.8)
•
Posterior reversible encephalopathy syndrome (PRES): 
Discontinue Gemzar. (5.9)
-------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions for the single agent (≥20%) are 
nausea/vomiting, anemia, hepatic transaminitis, neutropenia, 
increased alkaline phosphatase, proteinuria, fever, hematuria, rash, 
thrombocytopenia, dyspnea, and peripheral edema. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly 
and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-
FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 6/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Ovarian Cancer
1.2
Breast Cancer
1.3
Non-Small Cell Lung Cancer
1.4
Pancreatic Cancer
2
DOSAGE AND ADMINISTRATION
2.1
Ovarian Cancer
2.2
Breast Cancer
2.3
Non-Small Cell Lung Cancer
2.4
Pancreatic Cancer
2.5
Dose Modifications for Non-Hematologic Adverse 
Reactions
2.6
Preparation and Administration Precautions
2.7
Preparation for Intravenous Infusion Administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Schedule-dependent Toxicity
5.2
Myelosuppression
5.3
Pulmonary Toxicity and Respiratory Failure
5.4
Hemolytic Uremic Syndrome
5.5
Hepatic Toxicity
5.6
Embryofetal Toxicity
5.7
Exacerbation of Radiation Therapy Toxicity
5.8
Capillary Leak Syndrome
5.9
Posterior Reversible Encephalopathy Syndrome
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Post-Marketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
8.8
Gender
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1
Ovarian Cancer
14.2
Breast Cancer
14.3
Non-Small Cell Lung Cancer (NSCLC)
14.4
Pancreatic Cancer
16
HOW SUPPLIED/STORAGE AND HANDLING


2
16.1
How Supplied
16.2
Storage and Handling
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information 
are not listed
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Ovarian Cancer
Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that 
has relapsed at least 6 months after completion of platinum-based therapy.
1.2
Breast Cancer
Gemzar in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast 
cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically 
contraindicated.
1.3
Non-Small Cell Lung Cancer
Gemzar is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally 
advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer.
1.4
Pancreatic Cancer
Gemzar is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or 
metastatic (Stage IV) adenocarcinoma of the pancreas. Gemzar is indicated for patients previously treated with 5-FU.
2
DOSAGE AND ADMINISTRATION
2.1
Ovarian Cancer
Recommended Dose and Schedule
The recommended dose of Gemzar is 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of 
each 21-day cycle, in combination with carboplatin AUC 4 intravenously after Gemzar administration on Day 1 of each 21-
day cycle. Refer to carboplatin prescribing information for additional information.
Dose Modifications
Recommended Gemzar dose modifications for myelosuppression are described in Table 1 and Table 2 [see 
Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic 
adverse reactions.
Table 1: Dosage Reduction Guidelines for Gemzar for Myelosuppression on Day of Treatment in Ovarian Cancer
Treatment Day
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
Day 1
≥1500
<1500
and
or
≥100,000
<100,000
100%
Delay Treatment Cycle
Day 8
≥1500
1000-1499
<1000
and
or
or
≥100,000
75,000-99,999
<75,000
100%
50%
Hold
Table 2: Gemzar Dose Modification for Myelosuppression in Previous Cycle In Ovarian Cancer
Occurrence
Myelosuppression During Treatment Cycle
Dose Modification
Initial 
Occurrence
Absolute granulocyte count less than 500 x 106/L for 
more than 5 days
Absolute granulocyte count less than 100 x 106/L for 
more than 3 days
Febrile neutropenia
Platelets less than 25,000x106/L
Cycle delay of more than one week due to toxicity
Permanently reduce Gemzar to 800 mg/m2 on 
Days 1 and 8
Subsequent 
Occurrence
If any of the above toxicities occur after the initial dose 
reduction
Permanently reduce Gemzar dose to 
800 mg/m2 on Day 1 only 
2.2
Breast Cancer
Recommended Dose and Schedule
The recommended dose of Gemzar is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day 
cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion 
before Gemzar administration.
Dose Modifications


3
Recommended dose modifications for Gemzar for myelosuppression are described in Table 3 [see Warnings and 
Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
Table 3: Recommended Dose Reductions for Gemzar for Myelosuppression on Day of Treatment in Breast 
Cancer
Treatment Day
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
Day 1
≥1500
and
≥100,000
100%
less than 1500
or
less than 100,000
Hold
Day 8
≥1200
and
>75,000
100%
1000-1199
or
50,000-75,000
75%
700-999
and
≥50,000
50%
<700
or
<50,000
Hold
2.3
Non-Small Cell Lung Cancer
Recommended Dose and Schedule
Every 4-week schedule
The recommended dose of Gemzar is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in 
combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar.
Every 3-week schedule
The recommended dose of Gemzar is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination 
with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar.
Dose Modifications
Recommended dose modifications for Gemzar myelosuppression are described in Table 4 [see Warnings and 
Precautions (5.2)]. Refer to Dosage and Administration (2.5) for Gemzar recommendations for non-hematologic adverse 
reactions.
2.4
Pancreatic Cancer
Recommended Dose and Schedule
The recommended dose of Gemzar is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment 
schedule is as follows:
•
Weeks 1-8: weekly dosing for the first 7 weeks followed by one week rest.
•
After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles.
Dose Modifications
Recommended dose modifications for Gemzar for myelosuppression are described in Table 4 [see Warnings and 
Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including 
differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to 
the guidelines in Table 4.
Table 4: Recommended Dose Reductions for Gemzar for Myelosuppression in Pancreatic Cancer and Non-Small 
Cell Lung Cancer
Absolute granulocyte count
(x 106/L)
Platelet count
(x 106/L)
% of full dose
≥1000
And
≥100,000
100%
500-999
Or
50,000-99,999
75%
<500
Or
<50,000
Hold
2.5
Dose Modifications for Non-Hematologic Adverse Reactions
Permanently discontinue Gemzar for any of the following:
•
Unexplained dyspnea or other evidence of severe pulmonary toxicity
•
Severe hepatic toxicity
•
Hemolytic-uremic syndrome
•
Capillary leak syndrome
•
Posterior reversible encephalopathy syndrome
Withhold Gemzar or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. 
No dose modifications are recommended for alopecia, nausea, or vomiting.
2.6
Preparation and Administration Precautions


4
Exercise caution and wear gloves when preparing Gemzar solutions. Immediately wash the skin thoroughly or 
rinse the mucosa with copious amounts of water if Gemzar contacts the skin or mucus membranes. Death has occurred
in animal studies due to dermal absorption. For further guidance on handling Gemzar go to “OSHA Hazardous Drugs”
(refer to antineoplastic weblinks including OSHA Technical Manual) at OSHA. 
http://www.osha.gov/SLTC/hazardousdrugs/index.html
2.7
Preparation for Intravenous Infusion Administration
Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives.
Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. These dilutions each yield a Gemzar concentration of 
38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g of Gemzar. Prior to administration the 
appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 
0.1 mg/mL.
Reconstituted Gemzar is a clear, colorless to light straw-colored solution. Inspect visually prior to administration 
and discard for particulate matter or discoloration. Gemzar solutions are stable for 24 hours at controlled room 
temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur.
No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
3
DOSAGE FORMS AND STRENGTHS
Gemzar (gemcitabine for injection USP) is a white to off-white lyophilized powder available in sterile single-use 
vials containing 200 mg or 1 g gemcitabine.
4
CONTRAINDICATIONS
Gemzar is contraindicated in patients with a known hypersensitivity to gemcitabine.
5
WARNINGS AND PRECAUTIONS
5.1
Schedule-dependent Toxicity
In clinical trials evaluating the maximum tolerated dose of Gemzar, prolongation of the infusion time beyond 60 
minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, 
severe flu-like symptoms, myelosuppression, and asthenia. The half-life of Gemzar is influenced by the length of the 
infusion [see Clinical Pharmacology (12.3)].
5.2
Myelosuppression
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with Gemzar as a single 
agent and the risks are increased when Gemzar is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 
neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent
Gemzar. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, 
and 5 to 55%, respectively, in patients receiving Gemzar in combination with another drug.
5.3
Pulmonary Toxicity and Respiratory Failure
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory 
distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory 
failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose 
of Gemzar. Discontinue Gemzar in patients who develop unexplained dyspnea, with or without bronchospasm, or have 
any evidence of pulmonary toxicity [see Adverse Reactions (6.1 and 6.2)].
5.4
Hemolytic Uremic Syndrome
Hemolytic uremic syndrome, including fatalities from renal failure or the requirement for dialysis, can occur in 
patients treated with Gemzar. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal 
failure were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Assess renal function prior to initiation of Gemzar and 
periodically during treatment. Consider the diagnosis of HUS in patients who develops anemia with evidence of 
microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of 
renal failure (elevation of serum creatinine or BUN) [see Dosage and Administration (2.5) and Use in Specific Populations 
(8.6)]. Permanently discontinue Gemzar in patients with HUS or severe renal impairment. Renal failure may not be 
reversible even with discontinuation of therapy.
5.5
Hepatic Toxicity
Drug-induced liver injury, including liver failure and death, has been reported in patients receiving Gemzar alone or 
in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Administration of Gemzar in 
patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can
lead to exacerbation of the underlying hepatic insufficiency [see Use in Specific Populations (8.7)]. Assess hepatic 
function prior to initiation of Gemzar and periodically during treatment. Discontinue Gemzar in patients that develop
severe liver injury.
5.6
Embryofetal Toxicity
Gemzar can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. 
Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a 


5
woman becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to a fetus [see Use 
in Specific Populations (8.1)].
5.7
Exacerbation of Radiation Therapy Toxicity
Gemzar is not indicated for use in combination with radiation therapy.
Concurrent (given together or ≤7 days apart) — Life-threatening mucositis, especially esophagitis and pneumonitis
occurred in a trial in which Gemzar was administered at a dose of 1000 mg/m2 to patients with non-small cell lung cancer
for up to 6 consecutive weeks concurrently with thoracic radiation.
Non-concurrent (given >7 days apart) — Excessive toxicity has not been observed when Gemzar is administered 
more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemzar after prior 
radiation.
5.8
Capillary Leak Syndrome
Capillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemzar as a 
single agent or in combination with other chemotherapeutic agents. Discontinue Gemzar if CLS develops during therapy.
5.9
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving Gemzar as a single 
agent or in combination with other chemotherapeutic agents. PRES can present with headache, seizure, lethargy, 
hypertension, confusion, blindness, and other visual and neurologic disturbances. Confirm the diagnosis of PRES with 
magnetic resonance imaging (MRI) and discontinue Gemzar if PRES develops during therapy.
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in another section of the label
•
Schedule-dependent Toxicity [see Warnings and Precautions (5.1)]
•
Myelosuppression [see Warnings and Precautions (5.2)]
•
Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.3)]
•
Hemolytic Uremic Syndrome [see Warnings and Precautions (5.4)]
•
Hepatic Toxicity [see Warnings and Precautions (5.5)]
•
Embryofetal Toxicity [see Warnings and Precautions (5.6), Use in Specific Populations (8.1), and Nonclinical 
Toxicology (13.1)]
•
Exacerbation of Radiation Toxicity [see Warnings and Precautions (5.7)]
•
Capillary Leak Syndrome [see Warnings and Precautions (5.8)]
•
Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.9)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the
rates observed in clinical practice.
Single-Agent Use:
The data described below reflect exposure to Gemzar as a single agent administered at doses between 
800 mg/m2 to 1250 mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The 
most common (≥20%) adverse reactions of single-agent Gemzar are nausea/vomiting, anemia, increased ALT, increased 
AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and 
edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, 
increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients 
discontinued Gemzar due to adverse reactions. Adverse reactions resulting in discontinuation of Gemzar in 2% of 979 
patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and 
hypertension) and adverse reactions resulting in discontinuation of Gemzar in less than 1% of the 979 patients were 
anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, 
infection, stomatitis, somnolence, flu-like syndrome, and edema.
Table 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving 
single-agent Gemzar across 5 clinical trials. Table 5 includes all clinical adverse reactions, reported in at least 10% of 
patients. A listing of clinically significant adverse reactions is provided following the table.
Table 5: Selected Per-Patient Incidence of Adverse Events in Patients Receiving Single-Agent Gemzara
All Patientsb
All Grades
Grade 3
Grade 4
Laboratoryc
Hematologic
Anemia
68
7
1
Neutropenia
63
19
6
Thrombocytopenia
24
4
1
Hepatic


6
Increased ALT
68
8
2
Increased AST
67
6
2
Increased Alkaline Phosphatase
55
7
2
Hyperbilirubinemia
13
2
<1
Renal
Proteinuria
45
<1
0
Hematuria
35
<1
0
Increased BUN
16
0
0
Increased Creatinine
8
<1
0
Non-laboratoryd
Nausea and Vomiting
69
13
1
Fever
41
2
0
Rash
30
<1
0
Dyspnea
23
3
<1
Diarrhea
19
1
0
Hemorrhage
17
<1
<1
Infection
16
1
<1
Alopecia
15
<1
0
Stomatitis
11
<1
0
Somnolence
11
<1
<1
Paresthesias
10
<1
0
a Grade based on criteria from the World Health Organization (WHO).
b N=699-974; all patients with laboratory or non-laboratory data.
c Regardless of causality.
d For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-
related.
•
Transfusion requirements — Red blood cell transfusions (19%); platelet transfusions (<1%)
•
Fever — Fever occurred in the absence of clinical infection and frequently in combination with other flu-like 
symptoms.
•
Pulmonary — Dyspnea unrelated to underlying disease and sometimes accompanied by bronchospasm.
•
Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%); <1% of patients.
discontinued Gemzar due to edema.
•
Flu-like Symptoms — Characterized by fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia 
insomnia, rhinitis, sweating, and/or malaise (19%); <1% of patients discontinued Gemzar due to flu-like 
symptoms
•
Infection — Sepsis (<1%)
•
Extravasation — Injection-site reactions (4%)
•
Allergic — Bronchospasm (<2%); anaphylactoid reactions [see Contraindications (4)].
Non-Small Cell Lung Cancer:
Table 6 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at 
a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=262) 
administered in 28-day cycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally 
advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)].
Patients randomized to Gemzar plus cisplatin received a median of 4 cycles of treatment and those randomized to 
cisplatin received a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus
16%), discontinuation of treatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized 
(36% versus 23%) were all higher for patients receiving Gemzar plus cisplatin arm compared to those receiving cisplatin 
alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias
(3% versus <1%) were all higher in the Gemzar plus cisplatin arm compared to the cisplatin alone arm. The two-drug 
combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from 
myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due 
to treatment were reported on the cisplatin arm.
Table 6: Per-Patient Incidence of Selected Adverse Reactions from Randomized Trial of Gemzar plus Cisplatin 
versus Single-Agent Cisplatin in Patients with NSCLC Occurring at Higher Incidence in Gemzar-Treated Patients
[Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]a
Gemzar plus Cisplatinb
Cisplatinc
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratoryd


7
Hematologic
Anemia
89
22
3
67
6
1
RBC Transfusione
39
13
Neutropenia
79
22
35
20
3
1
Thrombocytopenia
85
25
25
13
3
1
Platelet Transfusionse
21
<1
Lymphopenia
75
25
18
51
12
5
Hepatic
Increased 
Transaminases
22
2
1
10
1
0
Increased Alkaline 
Phosphatase
19
1
0
13
0
0
Renal
Proteinuria
23
0
0
18
0
0
Hematuria
15
0
0
13
0
0
Elevated creatinine
38
4
<1
31
2
<1
Other Laboratory
Hyperglycemia
30
4
0
23
3
0
Hypomagnesemia
30
4
3
17
2
0
Hypocalcemia
18
2
0
7
0
<1
Non-laboratoryf
Nausea
93
25
2
87
20
<1
Vomiting
78
11
12
71
10
9
Alopecia
53
1
0
33
0
0
Neuro Motor
35
12
0
15
3
0
Diarrhea
24
2
2
13
0
0
Neuro Sensory
23
1
0
18
1
0
Infection
18
3
2
12
1
0
Fever
16
0
0
5
0
0
Neuro Cortical
16
3
1
9
1
0
Neuro Mood
16
1
0
10
1
0
Local
15
0
0
6
0
0
Neuro Headache
14
0
0
7
0
0
Stomatitis
14
1
0
5
0
0
Hemorrhage 
14
1
0
4
0
0
Hypotension
12
1
0
7
1
0
Rash
11
0
0
3
0
0
a National Cancer Institute Common Toxicity Criteria (CTC) for severity grading.
b N=217-253; all Gemzar plus cisplatin patients with laboratory or non-laboratory data Gemzar at 1000 mg/m2 on Days 1, 
8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days.
c N=213-248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days.
d Regardless of causality.
e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
f Non-laboratory events were graded only if assessed to be possibly drug-related.
Table 7 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at 
a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=69) 
administered in 21-day cycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line 
treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)]. A listing of 
clinically significant adverse reactions is provided following the table.
Patients in the Gemzar cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) 
arm received a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose 
adjustments; 81% in the (GC) arm and 68% in the (EC) arm. The incidence of hospitalizations for treatment-related 
adverse events was 22% (GC) and 27% in the (EC) arm. The proportion of discontinuation of treatment for treatment-
related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients 
hospitalized for febrile neutropenia was lower in the (GC) arm (7% versus 12%). There was one death attributed to 
treatment, a patient with febrile neutropenia and renal failure, which occurred in the Gemzar/cisplatin arm.
Table 7: Per-Patient Incidence of Selected Adverse Reactions in Randomized Trial of Gemzar plus Cisplatin 
versus Etoposide plus Cisplatin in Patients with NSCLCa


8
Gemzar plus Cisplatinb
Etoposide plus Cisplatinc
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratoryd
Hematologic
Anemia
88
22
0
77
13
2
RBC Transfusionse
29
-
-
21
-
-
Neutropenia
88
36
28
87
20
56
Thrombocytopenia
81
39
16
45
8
5
Platelet Transfusionse
3
-
-
8
-
-
Hepatic
Increased ALT
6
0
0
12
0
0
Increased AST
3
0
0
11
0
0
Increased Alkaline 
Phosphatase
16
0
0
11
0
0
Bilirubin
0
0
0
0
0
0
Renal
Proteinuria
12
0
0
5
0
0
Hematuria
22
0
0
10
0
0
BUN
6
0
0
4
0
0
Creatinine
2
0
0
2
0
0
Non-laboratoryf
Nausea and Vomiting
96
35
4
86
19
7
Fever
6
0
0
3
0
0
Rash
10
0
0
3
0
0
Dyspnea
1
0
1
3
0
0
Diarrhea
14
1
1
13
0
2
Hemorrhage
9
0
3
3
0
3
Infection
28
3
1
21
8
0
Alopecia
77
13
0
92
51
0
Stomatitis
20
4
0
18
2
0
Somnolence
3
0
0
3
2
0
Paresthesias
38
0
0
16
2
0
Flu-like syndromeg
3
-
-
0
-
-
Edemag
12
-
-
2
-
-
a Grade based on criteria from the World Health Organization (WHO).
b N=67-69; all Gemzar plus cisplatin patients with laboratory or non-laboratory data. Gemzar at 1250 mg/m2 on Days 1 
and 8 and cisplatin at 100 mg/m2 on Day 1 every 21 days.
c N=57-63; all cisplatin plus etoposide patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 
and intravenous etoposide at 100 mg/m2 on Days 1, 2, and 3 every 21 days.
d Regardless of causality.
e WHO grading scale not applicable to proportion of patients with transfusions.
f Non-laboratory events were graded only if assessed to be possibly drug-related. Pain data were not collected.
g Flu-like syndrome and edema were not graded.
Breast Cancer
Table 8 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at 
a higher incidence in the Gemzar plus paclitaxel arm, reported in a randomized trial of Gemzar plus paclitaxel (n=262) 
compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who 
received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were 
contraindicated [see Clinical Studies (14.2)].
The requirement for dose reduction of paclitaxel were higher for patients in the Gemzar/paclitaxel arm (5% versus
2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for treatment-
related adverse reactions (7% versus 5%), and the number of treatment-related deaths (1 patient in each arm) were 
similar between the two arms.
Table 8: Per-Patient Incidence of Selected Adverse Reactions from Comparative Trial of Gemzar plus Paclitaxel 
versus Single-Agent Paclitaxel in Breast Cancera Occurring at Higher Incidence in Gemzar-Treated Patients
[Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]
Gemzar plus Paclitaxel
Paclitaxel


9
(N=262)
(N=259)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratoryb
Hematologic
Anemia
69
6
1
51
3
<1
Neutropenia
69
31
17
31
4
7
Thrombocytopenia
26
5
<1
7
<1
<1
Hepatobiliary
Increased ALT
18
5
<1
6
<1
0
Increased AST
16
2
0
5
<1
0
Non-laboratoryc
Alopecia
90
14
4
92
19
3
Neuropathy-sensory
64
5
<1
58
3
0
Nausea
50
1
0
31
2
0
Fatigue
40
6
<1
28
1
<1
Vomiting
29
2
0
15
2
0
Diarrhea
20
3
0
13
2
0
Anorexia
17
0
0
12
<1
0
Neuropathy-motor
15
2
<1
10
<1
0
Stomatitis/pharyngitis
13
1
<1
8
<1
0
Fever
13
<1
0
3
0
0
Rash/desquamation
11
<1
<1
5
0
0
Febrile neutropenia
6
5
<1
2
1
0
a Severity grade based on National Cancer Institute Common Toxicity Criteria (CTC) Version 2.0.
b Regardless of causality.
c Non-laboratory events were graded only if assessed to be possibly drug-related.
Clinically relevant Grade 3 or 4 dyspnea occurred with a higher incidence in the Gemzar plus paclitaxel arm 
compared with the paclitaxel arm (1.9% versus 0).
Ovarian Cancer
Table 9 presents the incidence of selected adverse reactions, occurring in ≥10% of gemcitabine-treated patients 
and at a higher incidence in the Gemzar plus carboplatin arm, reported in a randomized trial of Gemzar plus carboplatin 
(n=175) compared to carboplatin alone (n=174) for the second-line treatment of ovarian cancer in women with disease 
that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)]. 
Additional clinically significant adverse reactions, occurring in less than 10% of patients, are provided following Table 9.
The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted 
(0.2% versus 0), and discontinuing treatment for treatment-related adverse reactions (10.9% versus 9.8%), were similar 
between arms. Dose adjustment for Gemzar occurred in 10.4% of patients and Gemzar dose was omitted in 13.7% of 
patients in the Gemzar /carboplatin arm.
Table 9: Per-Patient Incidence of Adverse Reactions in Randomized Trial of Gemzar plus Carboplatin versus
Carboplatin in Ovarian Cancera Occurring at Higher Incidence in Gemzar-Treated Patients
[Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]
Gemzar plus Carboplatin
(N=175)
Carboplatin
(N=174)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Laboratoryb
Hematologic
Neutropenia
90
42
29
58
11
1
Anemia
86
22
6
75
9
2
Thrombocytopenia
78
30
5
57
10
1
RBC Transfusionsc
38
15
Platelet Transfusionsc
9
3
Non-laboratoryb
Nausea
69
6
0
61
3
0
Alopecia
49
0
0
17
0
0
Vomiting
46
6
0
36
2
<1
Constipation
42
6
1
37
3
0
Fatigue
40
3
<1
32
5
0
Diarrhea
25
3
0
14
<1
0


10
Stomatitis/pharyngitis
22
<1
0
13
0
0
a Grade based on Common Toxicity Criteria (CTC) Version 2.0.
b Regardless of causality.
c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both 
packed red blood cells and whole blood.
Hematopoietic growth factors were administered more frequently in the Gemzar-containing arm: granulocyte growth 
factors (23.6% and 10.1%) and erythropoietic agents (7.3% and 3.9%).
The following clinically relevant, Grade 3 and 4 adverse reactions occurred more frequently in the Gemzar plus 
carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1
%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).
6.2
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of Gemzar. Because these 
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their 
frequency or establish a causal relationship to drug exposure.
Cardiovascular — Congestive heart failure, myocardial infarction, arrhythmias, supraventricular arrhythmias
Vascular Disorders — Peripheral vasculitis, gangrene, and capillary leak syndrome [see Warnings and 
Precautions (5.8)]
Skin — Cellulitis, severe skin reactions, including desquamation and bullous skin eruptions
Hepatic — Hepatic failure, hepatic veno-occlusive disease
Pulmonary — Interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress 
syndrome (ARDS)
Nervous System — Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.9)]
7
DRUG INTERACTIONS
No drug interaction studies have been conducted.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category D. [See Warnings and Precautions (5.6)].
Risk Summary
Gemzar can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, 
Gemzar is expected to result in adverse reproductive effects. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in 
mice and rabbits. If Gemzar is used during pregnancy, or if the patient becomes pregnant while taking Gemzar, the patient 
should be apprised of the potential hazard to a fetus.
Animal Data
Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 
1.5 mg/kg/day in mice (approximately 0.005 times the recommended human dose on a mg/m2 basis). Gemcitabine is 
fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in 
rabbits (about 0.002 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by 
decreased fetal viability, reduced live litter sizes, and developmental delays. [See Warnings and Precautions (5.6)].
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and 
because of the potential for serious adverse reactions in nursing infants from Gemzar, a decision should be made whether 
to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4
Pediatric Use
The safety and effectiveness of Gemzar have not been established in pediatric patients. The safety and 
pharmacokinetics of gemcitabine were evaluated in a trial in pediatric patients with refractory leukemia. The maximum 
tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. The safety and 
activity of Gemzar were evaluated in a trial of pediatric patients with relapsed acute lymphoblastic leukemia (22 patients) 
and acute myelogenous leukemia (10 patients) at a dose of 10 mg/m2/min administered over 360 minutes three times 
weekly followed by a one-week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, 
elevation of serum transaminases, nausea, and rash/desquamation. No meaningful clinical activity was observed in this 
trial.
8.5
Geriatric Use
In clinical studies of GEMZAR, enrolling 979 patients with various cancers who received GEMZAR as a single 
agent, no overall differences in safety were observed between patients aged 65 and older and younger patients, with the 
exception of a higher rate of Grade 3-4 thrombocytopenia in older patients as compared to younger patients. In a 
randomized trial in women with ovarian cancer, 175 women received GEMZAR plus carboplatin, of which 29% were age 


11
65 years or older. Similar effectiveness was observed between older and younger women. There was significantly higher 
Grade 3/4 neutropenia in women 65 years of age or older.
GEMZAR clearance is affected by age, however there are no recommended dose adjustments based on patients’ 
age [see Clinical Pharmacology (12.3)].
8.6
Renal Impairment
No clinical studies have been conducted with gemcitabine in patients with decreased renal function.
8.7
Hepatic Impairment
No clinical studies have been conducted with gemcitabine in patients with decreased hepatic function.
8.8
Gender
Gemzar clearance is affected by gender [see Clinical Pharmacology (12.3)]. In single-agent studies of Gemzar, 
women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 
neutropenia and thrombocytopenia.
10
OVERDOSAGE
Myelosuppression, paresthesias, and severe rash were the principal toxicities seen when a single dose as high as 
5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a dose-
escalation study.
11
DESCRIPTION
Gemzar (gemcitabine for injection, USP) is a nucleoside metabolic inhibitor that exhibits antitumor activity. 
Gemcitabine HCl is 2´-deoxy-2´,2´-difluorocytidine monohydrochloride (-isomer).
The structural formula is as follows:
The empirical formula for gemcitabine HCl is C9H11F2N3O4 • HCl. It has a molecular weight of 299.66.
Gemcitabine HCl is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar 
organic solvents.
Gemzar is supplied in a sterile form for intravenous use only. Vials of Gemzar contain either 200 mg or 1 g of 
gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate 
(12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have 
been added for pH adjustment.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase 
boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) 
nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the 
reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide 
concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction 
in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine 
triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional 
nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death.
12.3
Pharmacokinetics
Absorption and Distribution
The pharmacokinetics of gemcitabine were examined in 353 patients, with various solid tumors. Pharmacokinetic 
parameters were derived using data from patients treated for varying durations of therapy given weekly with periodic rest 


12
weeks and using both short infusions (<70 minutes) and long infusions (70 to 285 minutes). The total Gemzar dose varied 
from 500 to 3600 mg/m2.
The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2
following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m2.
Gemcitabine pharmacokinetics are linear and are described by a 2-compartment model. Population 
pharmacokinetic analyses of combined single and multiple dose studies showed that the volume of distribution of 
gemcitabine was significantly influenced by duration of infusion and gender. Gemcitabine plasma protein binding is 
negligible.
Metabolism
Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m2/30 minute infusion of 
radiolabeled drug. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine 
(<10%) and the inactive uracil metabolite, 2´-deoxy-2´,2´-difluorouridine (dFdU), accounted for 99% of the excreted dose. 
The metabolite dFdU is also found in plasma.
The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The 
half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.
Elimination
Clearance of gemcitabine was affected by age and gender. The lower clearance in women and the elderly results 
in higher concentrations of gemcitabine for any given dose. Differences in either clearance or volume of distribution based 
on patient characteristics or the duration of infusion result in changes in half-life and plasma concentrations. Table 10
shows plasma clearance and half-life of gemcitabine following short infusions for typical patients by age and gender.
Table 10: Gemcitabine Clearance and Half-Life for the “Typical” Patient
Age
Clearance Men
(L/hr/m2)
Clearance Women
(L/hr/m2)
Half-Lifea Men
(min)
Half-Lifea Women
(min)
29
92.2
69.4
42
49
45
75.7
57.0
48
57
65
55.1
41.5
61
73
79
40.7
30.7
79
94
a Half-life for patients receiving <70 minute infusion.
Gemcitabine half-life for short infusions ranged from 42 to 94 minutes, and the value for long infusions varied from 
245 to 638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer 
infusions.
Drug Interactions
When Gemzar (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were administered in NSCLC 
patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on Day 8 was 107 L/hr/m2. Analysis of data from 
metastatic breast cancer patients shows that, on average, Gemzar has little or no effect on the pharmacokinetics 
(clearance and half-life) of paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data 
from NSCLC patients demonstrate that Gemzar and carboplatin given in combination does not alter the pharmacokinetics 
of gemcitabine or carboplatin compared to administration of either single agent. However, due to wide confidence 
intervals and small sample size, interpatient variability may be observed.
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies to evaluate the carcinogenic potential of Gemzar have not been conducted. Gemcitabine 
was mutagenic in an in vitro mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus 
assay. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an 
effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In 
female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day administered intravenously 
(about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day 
administered intravenously (about 1/1300 the human dose on a mg/m2 basis).
14
CLINICAL STUDIES
14.1
Ovarian Cancer
The safety and efficacy of Gemzar was studied in a randomized trial of 356 women with advanced ovarian cancer 
that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either 
Gemzar 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar infusion on 
Day 1 of each cycle (n=178) or to carboplatin AUC 5 administered on Day 1 of each 21-day cycle (n=178). The primary 
efficacy outcome measure was progression free survival (PFS).


13
Patient characteristics are shown in Table 11. The addition of Gemzar to carboplatin resulted in statistically 
significant improvements in PFS and overall response rate as shown in Table 12 and Figure 1. Approximately 75% of 
patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin 
alone arm received Gemzar for treatment of disease progression. There was no significant difference in overall survival 
between the treatment arms.
Table 11: Randomized Trial of Gemzar plus Carboplatin versus Carboplatin in Ovarian Cancer - Baseline 
Demographics and Clinical Characteristics
Gemzar/Carboplatin
Carboplatin
Number of randomized patients
178
178
Median age, years
59
58
Range
36 to 78
21 to 81
Baseline ECOG performance status 0-1a
94%
95%
Disease Status
Evaluable
8%
3%
Bidimensionally measurable
92%
96%
Platinum-free intervalb
6-12 months
40%
40%
>12 months
59%
60%
First-line therapy
Platinum-taxane combination
70%
71%
Platinum-non-taxane combination
29%
28%
Platinum monotherapy
1%
1%
a 5 patients on Gemzar plus carboplatin arm and 4 patients on carboplatin arm with no baseline Eastern Cooperative 
Oncology Group (ECOG) performance status.
b 2 on Gemzar plus carboplatin arm and 1 on carboplatin arm had platinum-free interval <6 months.
Table 12: Randomized Trial of Gemzar plus Carboplatin versus Carboplatin in Ovarian Cancer - Efficacy 
Outcomes
Gemzar/Carboplatin
(N=178)
Carboplatin
(N=178)
Progression-free Survival
Median (95% CIa) months
8.6 (8.0, 9.7)
5.8 (5.2, 7.1)
Hazard Ratio (95% CI)
0.72 (0.57, 0.90)
p-valueb
p=0.0038
Overall Survival
Median (95% CI) months
18.0 (16.2, 20.3)
17.3 (15.2, 19.3)
Hazard Ratio (95% CI)
0.98 (0.78, 1.24)
p-valueb
p=0.8977
Investigator Reviewed
Overall Response Rate
47.2%
30.9%
p-valuec
p=0.0016
CRd
14.6%
6.2%
PR plus PRNMe
32.6%
24.7%
Independently Reviewed
Overall Response Ratef
46.3%
35.6%
p-valuec
p=0.11
CRd
9.1%
4.0%
PR plus PRNMe
37.2%
31.7%
a CI=confidence interval.
b Log rank, unadjusted.
c Chi square.
d CR=Complete response.
e PR plus PRNM=Partial response plus partial response, non-measurable disease.
f Independently reviewed cohort - Gemzar/carboplatin (n=121), carboplatin (n=101); independent reviewers unable to 
measure disease detected by sonography or physical exam.


14
Figure 1: Kaplan-Meier Curve of Progression Free Survival in Gemzar plus Carboplatin versus Carboplatin in 
Ovarian Cancer (N=356).
14.2
Breast Cancer
The safety and efficacy of Gemzar were evaluated in a multi-national, randomized, open-label trial conducted in 
women receiving initial treatment for metastatic breast cancer in women who have received prior adjuvant/neoadjuvant 
anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive Gemzar 1250 mg/m2
on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m2 administered prior to Gemzar on Day 1 of each cycle (n=267) 
or to receive paclitaxel 175 mg/m2 was administered on Day 1 of each 21-day cycle (n=262). The primary efficacy 
outcome measure was time to documented disease progression.
A total of 529 patients were enrolled; 267 were randomized to Gemzar and paclitaxel and 262 to paclitaxel alone. 
Demographic and baseline characteristics were similar between treatment arms (see Table 13). Efficacy results are 
presented in Table 13 and Figure 2. The addition of Gemzar to paclitaxel resulted in statistically significant improvement in 
time to documented disease progression and overall response rate compared to paclitaxel alone. There was no significant 
difference in overall survival.
Table 13: Randomized Trial of Gemzar plus Paclitaxel versus Paclitaxel in Breast Cancer
Gemzar/Paclitaxel
Paclitaxel
Number of patients
267
262
Demographic/Entry Characteristics
Median age (years)
53
52
Range
26 to 83
26 to 75
Metastatic disease
97%
97%
Baseline KPSa ≥90
70%
74%
Number of tumor sites
1-2
57%
59%
≥3
43%
41%
Visceral disease
73%
73%
Prior anthracycline
97%
96%
Efficacy Outcomes
Time to Documented Disease Progressionb
Median in months
(95% CI)
5.2
(4.2, 5.6)
2.9
(2.6, 3.7)
Hazard Ratio (95% CI)
0.650 (0.524, 0.805)
p-value
p<0.0001
Overall Survivalc
Median Survival in months
(95% CI)
18.6
(16.5, 20.7)
15.8
(14.1, 17.3)


15
Hazard Ratio (95% CI)
0.86 (0.71, 1.04)
p-value
Not Significant
Overall Response Rate
40.8%
22.1%
(95% CI)
(34.9, 46.7)
(17.1, 27.2)
p-value
p<0.0001
a Karnofsky Performance Status.
b These represent reconciliation of investigator and Independent Review Committee assessments according to a 
predefined algorithm.
c Based on the ITT population.
Figure 2: Kaplan-Meier Curve of Time to Documented Disease Progression in Gemzar plus Paclitaxel versus
Paclitaxel Breast Cancer Study (N=529).
14.3
Non-Small Cell Lung Cancer (NSCLC)
The safety and efficacy of Gemzar was evaluated in two randomized, multicenter trials.
28-Day Schedule
A multinational, randomized trial compared Gemzar plus cisplatin to cisplatin alone in the treatment of patients with 
inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive 
Gemzar 1000 mg/m2 on Days 1, 8, and 15 of a 28-day cycle with cisplatin 100 mg/m2 administered on Day 1 of each cycle 
or to receive cisplatin 100 mg/m2 on Day 1 of each 28-day cycle. The primary efficacy outcome measure was overall 
survival. A total of 522 patients were enrolled at clinical centers in Europe, the US, and Canada. Patient demographics 
and baseline characteristics (shown in Table 14) were similar between arms with the exception of histologic subtype of 
NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the Gemzar plus cisplatin arm having 
adenocarcinoma. Efficacy results are presented in Table 14 and Figure 3 for overall survival.
21-Day Schedule
A randomized (1:1), multicenter trial was conducted in 135 patients with Stage IIIB or IV NSCLC. Patients were 
randomized to receive Gemzar 1250 mg/m2 on Days 1 and 8, and cisplatin 100 mg/m2 on Day 1 of a 21-day cycle or to
receive etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 and cisplatin 100 mg/m2 on Day 1 of a 21 -day cycle.
There was no significant difference in survival between the two treatment arms (Log rank p=0.18, two- sided, see 
Table 14). The median survival was 8.7 months for the Gemzar plus cisplatin arm versus 7.0 months for the etoposide 
plus cisplatin arm. Median time to disease progression for the Gemzar plus cisplatin arm was 5.0 months compared to 4.1 
months on the etoposide plus cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the Gemzar
plus cisplatin arm was 33% compared to 14% on the etoposide plus cisplatin arm (Fisher’s Exact p=0.01, two-sided).


16
Figure 3: Kaplan-Meier Survival Curve in Gemzar plus Cisplatin versus Cisplatin in Patients with NSCLC Study 
(N=522).
Table 14: Randomized Trials of Gemzar plus Cisplatin in Patients with NSCLC
Trial
28-day Schedulea
21-day Scheduleb
Treatment Arm
Gemzar plus 
Cisplatin
Cisplatin
Gemzar plus 
Cisplatin
Etoposide plus 
Cisplatin 
Number of patients
260
262
69
66
Demographic/Entry 
Characteristics
Male
70%
71%
93%
92%
Median age, years
62
63
58
60
Range
36 to 88
35 to 79
33 to 76
35 to 75
Stage IIIA
7%
7%
N/Ac
N/Ac
Stage IIIB
26%
23%
48%
52%
Stage IV
67%
70%
52%
49%
Baseline KPSd 70 to 80
41%
44%
45%
52%
Baseline KPSd 90 to 
100
57%
55%
55%
49%
Efficacy Outcomes
Survival
Median in months
9.0
7.6
8.7
7.0
(95% CIe) months
8.2, 11.0
6.6, 8.8
7.8, 10.1
6.0, 9.7
p-valuef
p=0.008
p=0.18
Time to Disease 
Progression
Median in months
5.2
3.7
5.0
4.1
(95% CIe) months
4.2, 5.7
3.0, 4.3
4.2, 6.4
2.4, 4.5
p-valuef
p=0.009
p=0.015
Tumor Response
26%
10%
33%
14%
p-valuef
p<0.0001
p=0.01
a 28-day schedule — Gemzar plus cisplatin: Gemzar 1000 mg/m2 on Days 1, 8, and 15 and cisplatin 100 mg/m2 on Day 1 
every 28 days; Single-agent cisplatin: cisplatin 100 mg/m2 on Day 1 every 28 days.
b 21-day schedule — Gemzar plus cisplatin: Gemzar 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 
every 21 days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and intravenous etoposide 100 mg/m2 on Days 
1, 2, and 3 every 21 days.
c N/A Not applicable.


17
d Karnofsky Performance Status.
e CI=confidence intervals.
f p-value two-sided Fisher’s Exact test for difference in binomial proportions; log rank test for time-to-event analyses.
14.4
Pancreatic Cancer
The safety and efficacy of Gemzar was evaluated in two trials, a randomized, single-blind, two-arm, active-
controlled trial conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior 
chemotherapy and in a single-arm, open-label, multicenter trial conducted in patients with locally advanced or metastatic 
pancreatic cancer previously treated with 5-FU or a 5-FU-containing regimen. The first trial randomized patients to receive 
Gemzar 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once 
weekly dosing for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or to 5-fluorouracil (5-FU) 600 mg/m2
intravenously over 30 minutes once weekly (n=63). In the second trial, all patients received Gemzar 1000 mg/m2
intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly dosing for 3 
consecutive weeks every 28-days in subsequent cycles.
The primary efficacy outcome measure in both trials was “clinical benefit response”. A patient was considered to 
have had a clinical benefit response if either of the following occurred:
•
The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic 
consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for 
a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other 
parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain 
intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12
weeks of therapy.
OR
•
The patient was stable on all of the aforementioned parameters, and showed a marked, sustained weight gain 
(≥7% increase maintained for ≥4 weeks) not due to fluid accumulation.
The randomized trial enrolled 126 patients across 17 sites in the US and Canada. The demographic and entry 
characteristics were similar between the arms (Table 15). The efficacy outcome results are shown in Table 15 and for 
overall survival in Figure 4. Patients treated with Gemzar had statistically significant increases in clinical benefit response, 
survival, and time to disease progression compared to those randomized to receive 5-FU. No confirmed objective tumor 
responses were observed in either treatment arm.
Table 15: Randomized Trial of Gemzar versus 5-Fluorouracil in Pancreatic Cancer
Gemzar
5-FU
Number of patients
63
63
Demographic/Entry Characteristics
Male
54%
54%
Median age
62 years
61 years
Range
37 to 79
36 to 77
Stage IV disease
71%
76%
Baseline KPSa ≤70
70%
68%
Efficacy Outcomes
Clinical benefit response
22.2%
4.8%
p-valueb
p=0.004
Survival
Median
5.7 months
4.2 months
(95% CI)
(4.7, 6.9)
(3.1, 5.1)
p-valueb
p=0.0009
Time to Disease Progression
Median
2.1 months
0.9 months
(95% CI)
(1.9, 3.4)
(0.9, 1.1)
p-valueb
p=0.0013
a Karnofsky Performance Status.
b p-value for clinical benefit response calculated using the two-sided test for difference in binomial proportions. All other 
p-values are calculated using log rank test.


18
Figure 4: Kaplan-Meier Survival Curve.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
Gemzar (gemcitabine for injection, USP), is available in sterile single-use vials individually packaged in a carton 
containing:
200 mg white to off-white, lyophilized powder in a 10-mL size sterile single-use vial – NDC 0002-7501-01 (No.
7501)
1 g white to off-white, lyophilized powder in a 50-mL size sterile single-use vial – NDC 0002-7502-01 (No. 7502)
16.2
Storage and Handling
Unopened vials of Gemzar are stable until the expiration date indicated on the package when stored at controlled 
room temperature 20° to 25°C (68° to 77°F) and that allows for excursions between 15° and 30°C (59° and 86°F) [see 
USP Controlled Room Temperature] [see Dosage and Administration (2.6 and 2.7)].
17
PATIENT COUNSELING INFORMATION
•
Advise patients of the risks of low blood cell counts and the potential need for blood transfusions and 
increased susceptibility to infections. Instruct patients to immediately contact their healthcare provided for 
development of signs or symptoms of infection, fever, prolonged or unexpected bleeding, bruising, or 
shortness of breath [see Warnings and Precautions (5.2)].
•
Advise patients of the risks of pulmonary toxicity including respiratory failure and death. Instruct patients to 
immediately contact their healthcare provider for development of shortness of breath, wheezing, or cough [see 
Warnings and Precautions (5.3)].
•
Advise patients of the risks of hemolytic-uremic syndrome and associated renal failure. Instruct patients to 
immediately contact their healthcare provider for changes in the color or volume of urine output or for 
increased bruising or bleeding [see Warnings and Precautions (5.4)].
•
Advise patients of the risks of hepatic toxicity including liver failure and death. Instruct patients to immediately 
contact their healthcare provider for signs of jaundice or for pain/tenderness in the right upper abdominal 
quadrant [see Warnings and Precautions (5.5)].
Marketed by: Lilly USA, LLC
Indianapolis, IN 46285, USA
Copyright © 1996, 2014, Eli Lilly and Company. All rights reserved.
GEM-0001-USPI-20140610


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Appendix 4. 
Performance Status Scores  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, eg, light 
house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair 
5 
Dead 
As published in Am J Clin Oncol: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group.  Am J Clin Oncol 5:649-655, 1982. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 
 
 
 
 


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Appendix 5. 
Known Strong In Vivo Inhibitors or Inducers of CYP3A 
or CYP2C8 
 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ae 
boceprevir 
carbamazepinef 
clarithromycinb 
phenytoinf 
conivaptinb 
rifampinf 
grapefruit juicec 
St John's wortf  
indinavir 
 
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradild 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
Strong Inhibitors of CYP2C8a 
Strong Inducers of CYP2C8e 
gemfibrozil 
 
a. 
A strong inhibitor for is defined as an inhibitor that increases the AUC of a substrate for by ≥ 5-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” 
when a certain preparation was used (eg, high dose, double strength) or as a “moderate CYP3A 
inhibitor” when another preparation was used (eg, low dose, single strength). 
d. 
Withdrawn from the United States market because of safety reasons. 
e. 
A strong inducer is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate. 
f. 
In vivo inducer of P-glycoprotein.   
 
Note: The list of drugs in these tables is not exhaustive.  Any questions about drugs not on this list 
should be addressed to the medical monitor of the protocol. 
Source: 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.  Web 
link Accessed 21 January 2015: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsL
abeling/ucm093664.htm#inVivo 
 


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Appendix 6. 
Adverse Event Assessment of Causality 
 
Is there a reasonable possibility that the event may have been caused by study 
drugs?  No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making 
the decision to choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by 
study drugs. 
The adverse event: 
• 
may be judged to be due to extraneous causes such as disease or 
environment or toxic factors 
• 
may be judged to be due to the subject’s clinical state or other therapy being 
administered 
• 
is not biologically plausible 
• 
does not reappear or worsen when study drug is re-administered 
• 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by 
study drugs. 
The adverse event: 
• 
follows a temporal sequence from administration of study drug 
• 
is a known response to the study drug based on clinical or preclinical data 
• 
could not be explained by the known characteristics of the subject’s clinical 
state, environmental or toxic factors, or other therapy administered to the 
subject 
• 
disappears or decreases upon cessation or reduction of dose of study drug 
• 
reappears or worsens when study drug is re-administered 
 
 
 


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Appendix 7. 
Schedule of Assessments 
 
Treatment Phase 
Safety 
Follow-up 
Visitb 
Follow-up 
Phasec 
Cycles 
 
Cycle 1 
Cycle 2 
Cycles 3+ 
TT 
+ 30 days 
after last 
dose 
Q12W 
Study Days 
Screening
a 
-1 
1 
8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
Study Window 
-21 days 
 
± 3 days 
± 3 days 
± 3 days 
+ 7 days 
+ 7 days 
± 10 days 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEd/Vital signse/Weight 
x 
xn 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
x 
x 
 
ECOG status 
x 
xn 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
ECGf 
x 
xn 
x 
 
x 
 
 
 
 
 
 
 
 
 
x 
x 
 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or serum 
pregnancy testg 
x 
xn,t 
xp,s 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
 
Hematologyh 
x 
xn,t 
xp 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
Serum chemistry/ 
 
CA19-9i 
x 
xn,t 
xp 
 
 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
 
Serum lipase/amylase 
x 
xn 
xp 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
x 
x 
 
 
Coagulation panelj 
x 
xn,t 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
Hepatitis serologyu 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRv 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
QM 
 
Urinalysisk 
x 
xn 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
T/B/NK/monocyte cell 
countl 
 
xn 
xp 
 
 
 
 
 
x 
 
Day 1 every 3 cycles 
 
 
 
Pharmacokineticsm 
(Arm 1 only) 
 
xn 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
PD/Biomarkers 
Tumor 
sampleo 
xn 
xp 
xp 
xp 
xp 
 
 
xp 
 
Cycle 3 Day 8 and 
Cycle 4 Day 1 onlyp 
xq 
 
 
ACP-196 100 mg BID 
 
xn 
Continuous Twice Daily Dosing 
 
 
 
Nab-paclitaxel/gemcitabine 
IV 
 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
 
 
Study drug compliance 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
Tumor assessmentr 
x 
 
 
 
 
 
 
 
 
 
 Day 1 every other 
cycle (eg, Cycle 3 
Day 1, Cycle 5 Day 1) 
 
 
x 


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Concomitant medications 
x 
xn 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
x 
 
Adverse events 
 
xn 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
x 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 


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Abbreviations: BID = twice per day; CA 19-9 = cancer antigen 19-9; CR = complete remission; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology 
Group; HBV = hepatitis B virus; IV = intravenous; MRI = magnetic resonance imaging; NK = natural killer; PCR = polymerase chain reaction; PD = pharmacodynamics; 
PE = physical exam; Q12W = every 12 weeks; QM = every month; TT = treatment termination. 
 
Footnotes for ACE-ST-004 Schedule of Study Activities: 
a.   Screening tests should be performed within 21 days before the first administration of study drug, unless otherwise indicated. 
b. 
A 30-day (+ 7 days) safety follow-up visit is required when subjects discontinue study drug unless they start another anticancer therapy within that timeframe.  
c. 
Subjects who discontinue study therapy will continue on study for time-to-next therapy and survival unless they withdraw consent or are lost to follow up or the sponsor ends 
the study. Subjects who discontinue study drug for any reason other than disease progression, death, lost to follow-up, or withdrawal of consent will also be followed for 
tumor assessment until disease progression or initiation of any other anticancer therapies, whichever comes first. 
d. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of the skin, 
eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed physical exams, including 
tumor assessments by palpation, are done thereafter.   
e. 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be assessed after the subject has rested in the sitting position.   
f. 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related ECGs.  The screening ECGs will be done in triplicate taken ≥ 1 minute apart.  At 
Cycle 1 Day 1 and Cycle 1 Day 15, a single ECG will be done 1 hour after ACP-196 administration.  In addition, a single ECG will also be performed 1 hour after ACP-196 
administration at Cycle 1 Day -1 for the first 6 subjects enrolled to Arm 1.  The window is ± 10 minutes for the ECGs at the Cycle 1 Day 1 and Cycle 1 Day 15 visits.  At the 
treatment termination and/or safety follow-up visit, a single ECG will be done at any time during the visit. 
g. 
Women of childbearing potential only.   
h. 
Hematology includes complete blood count with differential and platelet counts.  Cycle 1 Day 1 hematology does not need to be repeated if screening hematology was done 
within 7 days.  For subjects in Arm 1 who discontinue nab-paclitaxel/gemcitabine but who are still receiving ACP-196, hematology assessment is to occur only on Day 1 of 
each cycle for Cycles 3+. 
i. 
Serum chemistry: albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), bone-specific 
alkaline phosphatase, C-reactive protein, CA 19-9, calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, 
sodium, total bilirubin, total protein, and uric acid.  Cycle 1 Day 1 serum chemistry does not need to be repeated if screening serum chemistry was within 7 days. 
j. 
Prothrombin time and partial thromboplastin time. 
k. 
Urinalysis: pH, ketones, specific gravity, bilirubin, blood, and glucose.   
l. 
T/B/NK/monocyte cell count (ie, CD3, CD4, CD8, CD14, CD19, CD16/56).   
m. For the first 20 subjects enrolled in Arm 1:  Blood samples will be drawn at 0 (predose), 0.5, 1, 2, and 4 hours after ACP-196 administration on the visits indicated.  The 
predose sample can be taken up to 30 minutes before dosing.  The window for other timepoints is ± 5 minutes.  Refer to the protocol for more detailed information. 
n. 
Cycle 1 Day -1 dosing of ACP-196, assessments, and PK sample collection in Arm 1 only applies to the first 6 subjects enrolled to this treatment arm. 
o. 
Provide tissue sections from either an archived or newly obtained tumor sample (most recent biopsy) for biomarker analysis, if allowed by regional authorities. 
p. 
The indicated samples at this timepoint must be drawn predose. 
q. 
This peripheral blood sample will be collected if treatment termination is due to disease progression. 
r. 
A pretreatment computed tomography (CT) scan with contrast (unless contraindicated) is required of the chest, abdomen, and pelvis and any other disease sites (eg, neck) 
within 30 days before the first dose of study drug.  CT scans will be done for tumor assessments on Cycle 3 Day 1 and then on Day 1 of every other cycle (± 7 days) or 
more frequently at the investigator’s discretion.  Magnetic resonance imaging (MRI) may be used for subjects allergic to CT contrast media.   
s. 
The pregnancy test can be performed any day from -3 days prior to Cycle 1 Day 1 or on the same day as Cycle 1 Day 1. 
t. 
Per protocol, the first 6 subjects randomized to Arm 1 (ACP-196 + nab-paclitaxel/gemcitabine) are dosed with ACP-196 first at Cycle 1 Day -1.  For these 6 subjects, 
hematology, serum chemistry/CA 19-9, and coagulation panel must be performed and analyzed within 7 days before this first dose of ACP-196.  Additionally, a urine 


Product: ACP-196 (acalabrutinib) 
Date: 01 February 2016 
Protocol: ACE-ST-004 
 
 
 
Acerta Pharma 
Confidential 
Page 160 of 160 
pregnancy test must be performed and analyzed within 1 day of the Cycle 1 Day -1 first dose of ACP-196.  These 4 labs may be performed either locally, or using the 
central laboratory. 
u. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (anti-HBc), and hepatitis C (HCV) 
antibody.  In addition, any subjects testing positive for any hepatitis serology, must have PCR testing (see exclusion criterion #15). 
v. 
Subjects who are anti-HBc positive (or have a known history of HBV infection) should be monitored monthly with a quantitative PCR test for HBV DNA.  Monthly monitoring 
should continue until 12 months after last dose of study drug(s).  Any subject with a rising viral load (above lower limit of detection) should discontinue study drug(s) and 
have antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B.