Conditions: Squamous Cell Carcinoma of the Head and Neck
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 78
Healthy volunteers: no

Brief summary:
Study of the combination of acalabrutinib (ACP-196) and pembrolizumab in subjects with advanced head and neck squamous cell carcinoma.

Detailed description:

Arms:
arm 1: pembrolizumab arm 2: acalabrutinib in combination with pembrolizumab

Interventions: intervention 1: pembrolizumab intervention 2: Acalabrutinib
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_001.pdf: 
Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
Acerta Pharma 
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Page 1 of 165 
 
PROTOCOL 
TITLE: 
A Phase 2 Proof-of-Concept Study of the Combination of 
ACP-196 and Pembrolizumab in Subjects with Advanced 
Head and Neck Squamous Cell Carcinoma 
PROTOCOL NUMBER: 
ACE-ST-006 
STUDY DRUG: 
Acalabrutinib (ACP-196) and KEYTRUDA® 
(pembrolizumab) 
IND NUMBER: 
124819 
MEDICAL MONITOR: 
 
 
 
 
 
SPONSOR: 
Acerta Pharma BV 
Kloosterstraat 9 
5349 AB Oss 
The Netherlands 
PROTOCOL DATE: 
Version 0.1 – 29 January 2015 
AMENDMENT 1: 
Version 1.0 – 31 March 2015 
AMENDMENT 2: 
Version 2.0 – 23 July 2015 
AMENDMENT 3: 
Version 3.0 – 15 January 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: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
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Summary of Amendment 3 
The primary rationale for amending the protocol is to revise the guidance regarding 
pembrolizumab dose modification for hepatotoxicity to match KEYTRUDA® 
(pembrolizumab) prescribing information, as well as add guidance for acalabrutinib 
(also known as ACP-196) treatment modification in the combination arm for 
hepatotoxicity. 
In addition, as hepatitis B virus (HBV) reactivation has occurred in patients treated 
with Btk inhibitors (Ngoma 2015), including 1 subject on acalabrutinib treatment, 
hepatitis serology testing at screening and monthly HBV polymerase chain reaction 
(PCR) testing are being added to ensure adequate monitoring of patients with a 
history of HBV. 
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 
Changed ACP-196 to acalabrutinib throughout. 
ACP-196 changed to 
acalabrutinib to reflect 
international 
nonproprietary name. 
Title Page:   
 
On 01 January 2016, Sponsor address changed to 
Acerta Pharma BV, Kloosterstraat 9, 5349 AB Oss, 
The Netherlands 
 
. 
Administrative change. 
 
Acerta Pharma medical 
monitor change. 
Protocol Approval Page:  Changed Acerta approver to 
 
Acerta Pharma process 
change. 
Synopsis  
Updated to reflect 
changes made 
throughout the protocol. 
Section 1.5.1 Mechanism of Action 
 
Section updated to provide new data from recent 
publication (Covey 2015) and also reduced in length as 
this section now references the Investigator’s Brochure 
for greater detail. 
 
Removed Table 1-1 Potency of ACP-196 and Ibrutinib 
on Group of 3F-Cys Kinases and associated text. 
Added the following text: 
 
For additional details, refer to the Acalabrutinib 
Investigator Brochure.   
Replaced table and 
associated text with a 
reference to the 
Acalabrutinib Investigator 
Brochure.   


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
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Section 1.7 Clinical Experience – Acalabrutinib 
Removed Table 1-2 ACP-196 Clinical Studies as of 
January 2015. 
 
Added the following text: 
For more detailed information on the clinical 
experience for acalabrutinib please refer to the 
Investigator Brochure.   
Obsolete summary of 
clinical study status was 
removed.   
Section 1.8  KEYTRUDA (Pembrolizumab) 
 
Added the following text: 
Pembrolizumab has also been granted approval in 
the United States for the treatment of patients with 
metastatic non-small cell lung cancer (NSCLC) 
whose tumors express PD-L1 as determined by an 
FDA-approved test and who have disease 
progression on or after platinum-containing 
chemotherapy.   
Updated text to reflect 
currently approved 
indications in the 
KEYTRUDA US 
prescribing information. 
Section 3.0 Study Design 
Revised text as follows (bold is new text): 
Treatment Acalabrutinib treatment can continue for 
subjects who are tolerating therapy and have not 
developed progressive disease.   
 
 
Subjects who have confirmed progressive disease on 
the combination of pembrolizumab and ACP-196 
acalabrutinib will discontinue study treatment come 
off study while those with confirmed progressive 
disease in the pembrolizumab monotherapy arm will 
continue on pembrolizumab with the addition of 
acalabrutinib until a second disease progression or 
intolerance of therapy.   
 
Section 3.6 Duration of Therapy 
Revised text as follows (bold is new text): 
 
Subjects may continue to receive study acalabrutinib 
treatment until disease progression or an intolerable 
AE.   
  
Clarified that acalabrutinib 
treatment can continue 
for subjects who are 
tolerating treatment and 
have not progressed. 
 
Revised text to clarify 
subjects with confirmed 
progressive disease on 
the combination of 
pembrolizumab and 
acalabrutinib will be 
discontinued from study 
treatment but will not be 
discontinued from the 
study; these subjects will 
continue to be followed 
for overall survival. 
 
Section 3.0 Study Design 
Revised text as follows (bold is new text): 
 
Subjects who have confirmed progressive disease on 
the combination of pembrolizumab and ACP-196 
acalabrutinib will discontinue study treatment come 
off study while those with confirmed progressive 
disease in the pembrolizumab monotherapy arm will 
continue on pembrolizumab with the addition of ACP-
196 acalabrutinib until a second disease progression 
or intolerance of therapy.   
Revised text to clarify 
subjects with confirmed 
progressive disease on 
the combination of 
pembrolizumab and 
acalabrutinib will be 
discontinued from study 
treatment but will not be 
discontinued from the 
study; these subjects will 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
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continue to be followed 
for overall survival. 
 
Section 3.0 Study Design and footnote “d” of 
Appendix 4 Schedule of Assessments 
Added the following text: 
 
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. 
Clarified that subjects 
who discontinue study 
drug and have not 
progressed will continue 
to be followed for tumor 
assessment. 
Section 3.1.2 Pharmacodynamic, Pharmacokinetic and 
Biomarker Parameters 
Added PK parameter: 
 
Vz/F:  Oral volume of distribution 
 
Added Vz/F as a PK 
parameter for consistency 
with other acalabrutinib 
protocols. 
Section 3.2 Rationale for Study Design and Dosing 
Regimen 
 
The language on dose justification for pembrolizumab 
(200 mg every 3 weeks) was revised to reflect updated 
text from Merck Sharp & Dohme Corp. 
Updated text was 
provided by Merck Sharp 
& Dohme Corp. 
Section 3.3.1.  Inclusion Criteria 
 
Revised the inclusion criterion as follows (bold is new 
text): 
 
6. Women who are sexually active and can bear 
children must agree to use acceptable forms of 
contraception (defined in Section 3.10.4) during the 
study and for 90 days after the last dose of 
acalabrutinib or 120 days after the last dose of 
pembrolizumab, whichever is longer.  Note:  subjects 
receiving pembrolizumab must be willing to use 2 
forms of contraception while receiving pembrolizumab 
treatment through 120 days after the last dose of 
pembrolizumabAcceptable forms of contraception 
are defined in Section 3.10.5. 
Updated text on 
acceptable contraception 
for use with 
pembrolizumab was 
provided by Merck Sharp 
& Dohme Corp. and used 
to revise Section 3.10.5.  
This inclusion criterion 
was revised to be 
consistent with the 
updated language in 
Section 3.10.5. 
Section 3.3.2 Exclusion Criteria 
Revised text as follows (bold is new text): 
 
1. Prior malignancy (other than HNSCC), 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 
or which will not limit survival to < 2 years. Note: these 
cases must be discussed with the Acerta Pharma 
Medical Monitor. 
Clarifying edits. 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
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Section 3.3.2 Exclusion Criteria 
Revised exclusion criterion as follows (bold is new 
text): 
 
9. Receiving ongoing immunosuppressive therapy, 
including systemic or enteric corticosteroids except for 
non-systemically absorbed treatments (such as inhaled 
or topical steroid therapy for asthma, chronic 
obstructive pulmonary disease, or allergic rhinitis) 
within 7 days before the first dose of 
pembrolizumab.   
Revised exclusion 
criterion to include within 
7 days before the first 
dose of pembrolizumab 
as requested by Merck 
Sharp & Dohme Corp. 
Section 3.3.2 Exclusion Criteria 
Revised text as follows (bold is new text): 
 
16. Requires or receiving anticoagulation with warfarin 
or equivalent vitamin K antagonists (eg, 
phenprocoumon) within 728 days of first dose of study 
drug. 
Revised text to decrease 
the duration of the 
washout period for these 
excluded prior 
medications.  Given the 
pharmacokinetics of 
warfarin, a 7-day washout 
period is sufficient. 
Section 3.3.2 Exclusion Criteria 
Revised exclusion criterion as follows (bold is new 
text): 
 
26. Concurrent participation Is currently participating 
in another therapeutica clinical trial and receiving 
study therapy or has participated in a study of an 
investigational agent and received study therapy or 
used an investigational device within 4 weeks of 
the first dose of treatment. 
Revised this exclusion 
criterion as requested by 
Merck Sharp & Dohme 
Corp. 
Section 3.3.2 Exclusion Criteria 
Added the following exclusion criterion: 
 
29. Serologic status reflecting active hepatitis B or 
C 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. 
As HBV reactivation has 
occurred in 1 subject on 
acalabrutinib treatment 
this exclusion criterion is 
being added to ensure 
adequate screening of 
patients with a history of 
HBV. 
Section 3.3.4 Enrollment and Randomization 
Procedures 
 
Revised text as follows (bold is new text): 
 
The enrollment date will be the date that the sponsor 
confirms enrollment form is faxed/emailed to the 
Sponsor.   The sponsor will aim to fax/email a 
completed Enrollment Confirmation Form to the 
study center within 24 hours. 
Clarifying edits. 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
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An Enrollment Confirmation Form will be completed 
and faxed/emailed to the study center by the Sponsor 
within 24 hours.   
Section 3.4.3 Administration of Study Drug 
The following change was made: 
 
Investigators are prohibited from supplying 
acalabrutinib to any subjects not properly enrolled in 
this study or to any physicians or scientists except 
those designated as subinvestigators on FDA Form 
1572. 
 
Detailed information on timing of infusion of 
pembrolizumab was added. 
This detailed information 
is covered in greater 
detail in clinical trial 
agreements with sites. 
 
 
Updated text on 
pembrolizumab infusions 
was provided by Merck 
Sharp & Dohme Corp. 
Table 3-3 Dose Modification Guidelines for Drug 
related Adverse Events 
“Note” revised (bold is new text): 
 
Note:  Permanently discontinue for any severe or 
Grade 3 (Grade 2 for pneumonitis) drug-related AE 
that recurs or any life-threatening event. 
Revised “Note” to match 
recent language from 
Merck Sharp & Dohme 
Corp. 
Section 3.8.2 Supportive Care Guidelines for 
Pembrolizumab 
 
Added the following: 
 
Note:  If after the evaluation the event is determined 
not to be related, the investigator does not need to 
follow the treatment guidance (as outlined below).  
 
Revised guidance for treatment-emergent adverse 
events as follows (bold is new text): 
 
Hepatic: 
• 
For Grade 2 events, monitor liver function tests 
more frequently until returned to baseline 
values (consider weekly) treatment with 
pembrolizumab should be withheld.  Treat 
with IV or oral corticosteroids.  Administer 
corticosteroids (initial dose of 0.5 to 
1 mg/kg/day prednisone or equivalent) 
(Appendix 5).  When LFT laboratory values 
resolve to baseline or return to Grade ≤ 1, 
then taper the corticosteroids over no fewer 
than 4 weeks while continuing to monitor 
LFTs at least weekly.  Further treatment with 
pembrolizumab can be considered after the 
LFT laboratory values have returned to 
Grade ≤ 1 or to baseline either during the 
steroid taper or after stopping 
corticosteroids. 
Revised guidance 
regarding pembrolizumab 
dose modification for 
hepatotoxicity to match 
KEYTRUDA prescribing 
information.  Also revised 
diarrhea/colitis language 
as provided by Merck 
Sharp & Dohme Corp. 
 
Added guidance for 
acalabrutinib treatment 
modification in the 
combination arm for 
hepatotoxicity. 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
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• 
For Grade 3-4 events, permanently 
discontinue pembrolizumab treat with 
intravenous corticosteroids for 24 to 48 hours. 
When symptoms improve to Grade 1 or less, a 
steroid taper should be started and continued 
over no less than 4 weeks. Treat with 
corticosteroids (initial dose 1 to 2 mg/kg/day 
prednisone or equivalent) (Appendix 5) until 
LFT laboratory values resolve to baseline or 
return to Grade ≤ 1, and then taper the 
corticosteroids over no fewer than 4 weeks 
while continuing to monitor LFTs at least 
weekly. 
 
Diarrhea/colitis 
• 
For Grade 2 diarrhea/colitis that persists 
greater than 3 days, administer oral 
corticosteroids. 
• 
For Grade 3 or 4 diarrhea/colitis that persists 
> 1 week, treat with intravenous steroids 
followed by high dose oral steroids. 
 
Section 3.8 Dosing Delays and Modifications 
Added the following text: 
 
For treatment-emergent hepatotoxicity in the 
combination arm only:  Important guidelines for 
treatment-emergent hepatotoxicity are provided in 
Section 3.8.2 for pembrolizumab.  In the 
combination arm, treatment with acalabrutinib 
should be withheld for Grade 3 or 4 hepatitis.  For 
Grade 4 events, acalabrutinib may be restarted 
only after discussion with the medical monitor.  
For Grade 3 events, treatment with acalabrutinib 
can be considered after the LFT laboratory values 
have returned to Grade ≤ 1 or to baseline. 
 
 
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 
acalabrutinib.  Therefore, subjects who are 
hepatitis B core antibody (anti-HBc) positive (or 
have a known history of HBV) should be monitored 
monthly with a quantitative PCR test for HBV DNA.  
Monthly monitoring should continue until 
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. 
 
Subsequent sections 
renumbered accordingly. 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
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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 acalabrutinib in subjects who 
develop HBV reactivation.  
 
Section 3.10.3 Drug-drug interactions 
Revised text as follows (bold is new text): 
 
If a subject requires a strong CYP3A4 inhibitor while 
on study, monitor the subject closely for potential drug-
related toxicities.  
Clarifying edit 
Section 3.10.3 Drug-drug Interactions  
Revised text on ACE-HV-004 to indicate that the study 
is now complete. 
Revised text on ACE-HV-
004 to indicate that the 
study is now complete. 
Section 3.10.3 Drug-drug Interactions 
Revised text as follows: 
 
However, if a subject must take a proton-pump inhibitor 
(for example, for an ulcer that develops on study), 
please discuss with the medical monitor. 
Given the safety and 
efficacy of acalabrutinib 
observed in patients both 
with and without proton-
pump inhibitor treatment, 
if an investigator decides 
to treat a patient with a 
proton-pump inhibitor 
while on study, it is not 
necessary to discuss this 
with the medical monitor. 
Section 3.10.5 Reproductive Toxicity 
 
Section revised to provide definition of women of 
nonchildbearing potential as well as acceptable 
methods of birth control based on recently provided 
text from Merck Sharp & Dohme Corp. 
Revised per request from 
Merck Sharp & Dohme 
Corp. 
Section 3.10.6 Overdose Instructions 
Revised text as follows (bold is new text): 
 
For any subject experiencing an ACP-196 
acalabrutinib or pembrolizumab overdose 
(administration of a dose ≥ 1.5 time the intended dose 
level in the clinical study protocol 1000 mg of ACP-196 
acalabrutinib or ≥ 1000 mg [5 times the dose] of 
pembrolizumab at once) 
Rats treated with 
acalabrutinib at dose 
levels approximating 15-
25 times the daily clinical 
dose (200 mg) 
experienced some signs 
of toxicity after repeated 
dosing.  Therefore, if a 
subject ingests a dose of 
1000 mg or greater 
(5 times the daily clinical 
dose), additional clinical 
monitoring is 
recommended. 
Section 3.11 Treatment After Initial Radiologic 
Progression 
 
Clarifying edits. 


Product: Acalabrutinib (ACP-196) 
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Revised Table 3-5 Imaging and Treatment After 1st 
Radiologic Evidence of Disease Progression to clarify 
that no additional tumor imaging is required when 
repeat tumor imaging confirms PD. 
 
Revised text as follows (bold is new text): 
 
In determining whether or not the tumor burden has 
increased or decreased, site study team should 
consider all target lesions as well as non-target lesions 
(if needed, the tip sheet provided in the study 
binder can be used as a reference to assess 
lesionsplease refer to the Procedure Manual provided 
separately from this protocol). 
Section 3.12 Withdrawal of Subjects From Study 
Treatment [previously Stopping Rules] 
 
Added text: 
 
• 
Study treatment should be discontinued in 
the event of a toxicity lasting > 28 
consecutive days, unless reviewed and 
approved by the medical monitor.   
 
Revised text as follows (bold is new text): 
 
• 
Any subject who has confirmed objective 
evidence of cancer progression while receiving 
ACP-196 acalabrutinib and pembrolizumab 
should be withdrawn from the discontinue 
study treatment.   
Clarifying edits. 
Added Section 3.13 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 
 
Added section specifying 
reasons for study exit, to 
clarify the distinction 
between study exit and 
withdrawal of subjects 
from study treatment. 
Section 4.0 Study Activities and Assessments 
Added the following text: 
 
This study will primarily use central laboratory 
testing for safety laboratory evaluations.  Samples 
from sites’ local laboratories will be used if central 
laboratory testing is unavailable. 
 
Clarified that central 
laboratory testing will be 
primarily used for safety 
laboratory evaluations.   
Section 4.1.4 Concomitant Medications and Therapy 
Revised text as follows (bold is new text): 
 
Revised this text for 
clarity and consistency 
with the screening period. 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
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Document all concomitant medications and procedures 
from within 2821 days before the start of study drug 
administration through 30 days after the last dose of 
study drug. 
Section 4.1.9 Urine or Serum Pregnancy Test and 
footnote “h” in Appendix 4 Schedule of Assessments 
 
Revised text as follows (bold is new text): 
Women of childbearing potential must have a 
negative urine or serum pregnancy testing within 
72 hours prior to receiving the first dose of study 
medication.  If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test 
is required.  If positive, pregnancy must be ruled out 
by ultrasound. 
This additional text was 
requested by Merck 
Sharp & Dohme Corp. 
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 hepatitis C (HCV) 
antibody.  In addition, any subjects testing positive 
for any hepatitis serology, must have PCR testing 
(see Appendix 4 and exclusion criterion #29).  
Testing will be done by a local or central 
laboratory.   
 
Refer to Section 3.10.1 and Appendix 4 regarding 
monitoring of subjects who are anti HBc positive 
or have a known history of HBV. 
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. 
 
Subsequent sections 
renumbered accordingly. 
Section 4.3 Safety Follow-up Visit and Appendix 4 
Schedule of Assessments 
Corrected the safety follow-up visit from 30 days 
(± 7 days) to 30 (+ 7) days 
Clarifying edits. 
Section 5.4.4 Analysis of Efficacy Parameters 
 
Duration of Response and Progression-free Survival 
Revised text as shown (bold is new text): 
Data from surviving, non-progressing subjects will be 
censored and detailed censoring rules will be 
specified in the statistical analysis plan (SAP) at 
the date of the last evaluable tumor assessment that is 
on or before the start date of the new antitumor 
therapy. Data from subjects who have disease 
progression or die after ≥ 2 consecutive missing tumor 
assessments will be censored at the last time prior to 
the missing assessments that lack of disease 
progression was objectively documented. 
Detailed censoring rules 
will be provided in the 
statistical analysis plan. 
 
Clarified the start date in 
the definitions of PFS and 
OS. 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
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Revised text as shown (bold is new text): 
 
Progression-free survival is defined as the interval from 
the date of first dose of study drug start of therapy to 
the earlier of the first documentation of objective 
disease progression or death from any cause. 
 
OS is defined as the time from date of enrollment first 
dose of study drug until date of death due to any 
cause. 
Section 5.5 Futility and Toxicity Monitoring, Table 5-1 
Stopping Boundaries for Toxicity Monitoring and Table 
5-2 Operating Characteristics of the Design 
 
Updated stopping boundaries for toxicity monitoring 
based on corrected calculation.  
 
Error in the original 
calculation was corrected. 
Section 5.5 Futility and Toxicity Monitoring 
Revised text as shown (bold is new text): 
 
The futility and toxicity monitoring will be analyzed in 
the combination arm (Arm 2) only as data become 
available. 
… 
The above futility and toxicity monitoring rules will be 
implemented once the first 10 subjects have been 
evaluated in the combination arm and will use safety 
data as they become available.   
Clarifying edits. 
Section 6.2.1 Adverse Event Reporting Period 
Revised text as shown (bold is new text): 
 
If a fatal AE occurs beyond Fatal AEs occurring 
within 30 days after the last dose of ACP 196 
acalabrutinib and/or pembrolizumab AND it is 
assessed by the investigator as related to ACP-196 
acalabrutinib and/or pembrolizumab, it must be 
reported as an SAE. 
Clarifying edits. 
Section 6.2.3 Pregnancy 
Revised text as shown (bold is new text): 
 
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 ACP-196 
acalabrutinib, or 120 days after the last dose of 
pembrolizumab, or 30 days after the last dose of 
either treatment if the subject initiates new 
anticancer therapy (whichever is earlier longer) will 
Revised text to match 
recent language from 
Merck Sharp & Dohme 
Corp. 


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be reported, followed to conclusion, and the outcome 
reported. 
Section 6.2.4 Expedited Reporting Requirements for 
Serious Adverse Events 
Revised text as follows (bold is new text): 
 
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’s 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) SAE 
to all investigators.  Each investigator must then notify 
his or her IRB/IEC of the SUSAR SAE. 
 
Changed Safety fax number to +1 866 467 0304 or +1 
650 935 4996 
Revised text as a 
correction. 
 
Updated Safety fax 
number. 
Section 6.2.5 Reporting Events of Clinical Interest 
Revised text (bold text is new): 
 
Serious adverse events that classify Selected non-
serious and serious adverse events are also known 
as Events of Clinical Interest (ECI) and must be 
recorded as such on the Adverse Event case report 
forms/worksheets and reported to the Sponsor. 
For the time period beginning when the consent 
form is signed until treatment 
allocation/randomization, any ECI, or follow up to 
an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes 
the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, 
including but not limited to washout or 
discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
 
For the time period beginning at treatment 
allocation/randomization through 30 days following 
cessation of treatment, any ECI, or follow up to an 
ECI, whether or not related to study drug must be 
reported within 24 hours to the Sponsor either by 
electronic media or paper as described in Section 
6.2.4. 
 
Revised per request from 
Merck Sharp & Dohme 
Corp. 
Section 7.4 Case Report Forms 
Revised text as follows (bold is new text): 
 
The investigator will ensure that the eCRFs are 
accurate, complete, legible, and completed promptly 
within 5 days of each subject’s visit (unless required 
earlier for SAE reporting).   
Language made 
consistent with the clinical 
trial agreements. 
 


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Section 7.11 General Investigator Responsibilities 
Revised text as follows (bold is new text): 
 
10. 
eCRF pages are completed promptly within 5 
days of each subject’s visit (unless required earlier for 
SAE reporting). 
Section 7.6 Investigational Study Drug Accountability 
Revised text as follows: 
 
ACP-196 Acalabrutinib capsules must be kept in a 
locked limited access cabinet or space room. The 
study drug must not be used outside the context of the 
protocol. Under no circumstances should the 
investigator or other site personnel supply ACP 196 
capsules to other investigators, subjects, or clinics or 
allow supplies to be used other than as directed by this 
protocol without prior authorization from Acerta 
Pharma. 
Clarifying edits.   
 
This is language is being 
removed from the 
protocol because it is 
covered under individual 
clinical trial agreements. 
Section 7.9 Publication of Study Results 
Revised publication guidelines to the following: 
 
Authorship, in general, will follow the recommendations 
of the International Committee of Medical Journal 
Editors (International Committee of Medical Journal 
Editors 2014).   
Updated to reflect Acerta 
Pharma’s current 
publication policy. 
Section 8.0 References 
Reference list updated. 
Updated to reflect 
changes made 
throughout the protocol.   
Appendix 4 Schedule of Assessments 
 
The following change was made to footnote “o” (bold 
is new text) 
o. Provide tissue sections from either an archived or 
newly obtained tumor sample (most recent biopsy) 
for biomarker analysis and whenever progression 
is confirmed.  Note:  The biopsy at progression 
is optional. 
 
 
 
 
 
 
Added hepatitis serology testing at screening, and HBV 
PCR testing monthly. 
 
Added the following footnotes in Appendix 4: 
 
t. Hepatitis serology must include hepatitis B 
surface antigen (HBsAg), hepatitis B surface 
antibody (HBsAb), hepatitis B core antibody (anti-
 
Change to footnote “o” 
was a clarifying edit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
As HBV reactivation has 
occurred in 1 subject on 
acalabrutinib treatment 
hepatitis serology testing 
at screening and monthly 
HBV PCR testing are 
being added to ensure 


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HBc), and hepatitis C (HCV) antibody.  In addition, 
any subjects testing positive for any hepatitis 
serology, must have PCR testing (see exclusion 
criterion #29).   
 
u. Subjects who are anti-HBc positive (or have a 
known history of HBV) 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. 
adequate screening and 
monitoring of patients 
with a history of HBV. 
 


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TABLE OF CONTENTS 
1.0 
BACKGROUND INFORMATION ........................................................ 34 
1.1 
HNSCC ................................................................................................ 34 
1.2 
Programmed Death Ligand/Receptor Interactions in HNSCC ............. 34 
1.3 
Bruton Tyrosine Kinase Inhibition in Cancer ........................................ 35 
1.4 
A Case for Combination Btk and Checkpoint Blockade ....................... 40 
1.5 
Acalabrutinib ........................................................................................ 42 
1.5.1 
Mechanism of Action .............................................................. 42 
1.5.2 
Safety Pharmacology ............................................................. 42 
1.5.3 
Drug-drug Interaction Potential .............................................. 43 
1.6 
In Vivo General Toxicology – Acalabrutinib ......................................... 44 
1.7 
Clinical Experience – Acalabrutinib ...................................................... 44 
1.7.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib .. 44 
1.7.2 
Acalabrutinib in CLL ............................................................... 46 
1.8 
KEYTRUDA (Pembrolizumab) ............................................................. 48 
1.9 
Benefit/Risk .......................................................................................... 49 
2.0 
STUDY OBJECTIVES ......................................................................... 49 
2.1 
Primary Objectives ............................................................................... 49 
2.2 
Secondary Objectives .......................................................................... 49 
2.3 
Exploratory Objectives ......................................................................... 50 
3.0 
STUDY DESIGN .................................................................................. 50 
3.1 
Study Parameters ................................................................................ 53 
3.1.1 
Safety Parameters .................................................................. 53 
3.1.2 
Pharmacodynamic, Pharmacokinetic and Biomarker 
Parameters ............................................................................. 53 
3.1.3 
Efficacy Parameters ............................................................... 54 
3.2 
Rationale for Study Design and Dosing Regimen ................................ 54 
3.3 
Selection of Study Population .............................................................. 56 
3.3.1 
Inclusion Criteria..................................................................... 56 
3.3.2 
Exclusion Criteria ................................................................... 57 
3.3.3 
Replacement of Subjects ....................................................... 59 
3.3.4 
Enrollment and Randomization Procedures ........................... 59 
3.4 
Study Drugs ......................................................................................... 60 
3.4.1 
Premedications....................................................................... 60 
3.4.2 
Formulation, Packaging, and Storage .................................... 60 
3.4.3 
Administration of Study Drug .................................................. 60 
3.4.4 
Subject Compliance ............................................................... 61 
3.5 
Study Treatment Schedule .................................................................. 62 


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3.5.1 
Arm 1 – Pembrolizumab Monotherapy ................................... 62 
3.5.2 
Arm 2 – Combination Treatment ............................................ 62 
3.6 
Duration of Therapy ............................................................................. 62 
3.7 
Assessment of Dose-Limiting Toxicity (DLT) ....................................... 63 
3.8 
Dosing Delays and Modifications ......................................................... 63 
3.8.1 
Dose Modifications for Pembrolizumab .................................. 64 
3.8.2 
Supportive Care Guidelines for Pembrolizumab .................... 65 
3.9 
Concomitant Therapy .......................................................................... 69 
3.9.1 
Permitted Concomitant Therapy ............................................. 69 
3.9.2 
Prohibited or Restricted Concomitant Therapy ....................... 69 
3.10 
Precautions .......................................................................................... 69 
3.10.1 Hepatitis B Reactivation ......................................................... 69 
3.10.2 Dietary Restrictions ................................................................ 70 
3.10.3 Drug-drug Interactions ............................................................ 70 
3.10.4 Surgery ................................................................................... 71 
3.10.5 Reproductive Toxicity ............................................................. 71 
3.10.6 Overdose Instructions ............................................................ 73 
3.11 
Treatment After Initial Radiologic Progression ..................................... 74 
3.12 
Withdrawal of Subjects From Study Treatment .................................... 76 
3.13 
Reasons for Study Exit ........................................................................ 77 
3.14 
Data and Safety Monitoring ................................................................. 78 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ....................................... 78 
4.1 
Description of Procedures.................................................................... 78 
4.1.1 
Informed Consent ................................................................... 78 
4.1.2 
Medical History ....................................................................... 78 
4.1.3 
Adverse Events ...................................................................... 79 
4.1.4 
Concomitant Medications and Therapy .................................. 79 
4.1.5 
Confirmation of Eligibility ........................................................ 79 
4.1.6 
ECOG Performance Status .................................................... 79 
4.1.7 
Physical Examination, Vital Signs, Height & Weight ............... 79 
4.1.8 
Electrocardiogram .................................................................. 79 
4.1.9 
Urine or Serum Pregnancy Test ............................................. 80 
4.1.10 Hematology ............................................................................ 80 
4.1.11 Serum Chemistry .................................................................... 80 
4.1.12 Amylase and Lipase ............................................................... 80 
4.1.13 Thyroid Panel ......................................................................... 81 
4.1.14 Hepatitis B and C Testing ....................................................... 81 
4.1.15 Urinalysis ................................................................................ 81 
4.1.16 T/B/NK Cell Count .................................................................. 81 


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4.1.17 Serum Immunoglobulin .......................................................... 81 
4.1.18 Pharmacodynamics/Pharmacokinetics and Biomarker 
Studies ................................................................................... 81 
4.1.19 Tumor Assessments ............................................................... 83 
4.1.20 Early Termination Visit ........................................................... 83 
4.1.21 Study Drug Accountability ...................................................... 83 
4.2 
Investigator’s Assessment of Response to Treatment ......................... 83 
4.2.1 
Determination of Response at Each Timepoint (RECIST) ...... 84 
4.2.2 
Confirmation of Tumor Status and Determination of Best 
Overall Response (RECIST) .................................................. 85 
4.2.3 
Immune-related Response Criteria (irRECIST) ...................... 86 
4.3 
Safety Follow-up Visit .......................................................................... 86 
4.4 
Survival ................................................................................................ 87 
4.5 
Missed Evaluations .............................................................................. 87 
5.0 
STATISTICAL METHODS OF ANALYSIS .......................................... 87 
5.1 
General Considerations ....................................................................... 87 
5.2 
Definition of Analysis Sets ................................................................... 88 
5.3 
Missing Data Handling ......................................................................... 88 
5.4 
Endpoint Data Analysis ........................................................................ 88 
5.4.1 
Safety Endpoint ...................................................................... 88 
5.4.2 
Demographics and Baseline Characteristics .......................... 89 
5.4.3 
Study Treatment Administration and Compliance .................. 89 
5.4.4 
Analysis of Efficacy Parameters ............................................. 89 
5.4.5 
PD, PK or Biomarker Analyses .............................................. 90 
5.5 
Futility and Toxicity Monitoring ............................................................. 90 
6.0 
ASSESSMENT OF SAFETY ............................................................... 92 
6.1 
Definitions ............................................................................................ 93 
6.1.1 
Adverse Events ...................................................................... 93 
6.1.2 
Serious Adverse Event ........................................................... 93 
6.1.3 
Severity .................................................................................. 94 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events 94 
6.2.1 
Adverse Event Reporting Period ............................................ 94 
6.2.2 
Assessment of Adverse Events .............................................. 95 
6.2.3 
Pregnancy .............................................................................. 95 
6.2.4 
Expedited Reporting Requirements for Serious Adverse 
Events .................................................................................... 96 
6.2.5 
Reporting Events of Clinical Interest ...................................... 97 
6.2.6 
Type and Duration of Follow-up of Subjects after Adverse 
Events .................................................................................... 97 


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7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .. 98 
7.1 
Institutional Review Board and Independent Ethics Committee........... 98 
7.2 
Informed Consent and Protected Subject Health Information 
Authorization ........................................................................................ 98 
7.3 
Subject Screening Log ......................................................................... 99 
7.4 
Case Report Forms ............................................................................. 99 
7.5 
Study Monitoring Requirements ........................................................... 99 
7.6 
Investigational Study Drug Accountability .......................................... 100 
7.7 
Record Retention ............................................................................... 101 
7.8 
Protocol Amendments ....................................................................... 102 
7.9 
Publication of Study Results .............................................................. 102 
7.10 
Clinical Trial Insurance ...................................................................... 102 
7.11 
General Investigator Responsibilities ................................................. 102 
8.0 
REFERENCES .................................................................................. 104 
9.0 
APPENDICES ................................................................................... 107 
 
 
 


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IN–TEXT TABLES 
 
Table 1-1.  Btk Occupancy in Peripheral Blood of Subjects from ACE-CL-001 ..........47 
Table 1-2.  Preliminary Day 8 PK Results from ACE-CL-001 (December 2014) ........48 
Table 1-3.  Best Response by Cohort from ACE-CL-001 (December 2014) ..............48 
Table 3-1 Pembrolizumab Product Descriptions ........................................................60 
Table 3-2.  Dose Reduction for Acalabrutinib ............................................................62 
Table 3-3.  Dose Modification Guidelines for Drug-Related Adverse Events .............64 
Table 3-4.  Infusion Reaction Treatment Guidelines ..................................................68 
Table 3-5.  Imaging and Treatment After 1st Radiologic Evidence of Disease 
Progression .......................................................................................................75 
Table 4-1.  Evaluation of Target Lesions (RECIST) ...................................................84 
Table 4-2.  Evaluation of Nontarget Lesions (RECIST) .............................................84 
Table 4-3.  Timepoint Response (RECIST) ...............................................................85 
Table 4-4.  Best Overall Response Assessment and Requirements for Confirmation 
(RECIST) ...........................................................................................................86 
Table 5-1.  Stopping Boundaries for Toxicity Monitoring............................................92 
Table 5-2.  Operating Characteristics of the Design ..................................................92 
 
IN–TEXT FIGURES 
 
Figure 1-1.  Efficacy of Acalabrutinib Monotherapy in a Genetic Model of Pancreatic 
Cancer ..............................................................................................................37 
Figure 1-2.  Effects of Acalabrutinib on Tumor-Associated Immunosuppressive Cells 
in a Genetic Model of Pancreatic Cancer ...........................................................37 
Figure 1-3.  Effects of Acalabrutinib on Cytolytic T Cells in a Genetic Model of 
Pancreatic Cancer .............................................................................................38 
Figure 1-4.  Acalabrutinib Impairs ID8 Ovarian Cancer Growth and Decreased 
Immunosuppressive Cellular Subsets in Syngeneic Murine Model ....................39 
Figure 1-5.  Efficacy of Acalabrutinib Monotherapy and Combination Therapy with 
Gemcitabine in an Orthotopic Model of Pancreatic Cancer ................................40 
Figure 1-6.  Acalabrutinib Enhances the Antitumor Effects of α-PD-L1 in the 
Orthotopic CT26 Colon Cancer Model ...............................................................41 
Figure 1-7.  Btk Inhibition Leads to Modulation of Infiltrating Immature Myeloid Cells 
Which Can Limit the Activity of Anti-PD-L1 Antibodies .......................................41 
Figure 3-1.  Study Schema ........................................................................................52 
 
 


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ABBREVIATIONS 
λz 
terminal elimination rate constant 
ACP-196 
acalabrutinib 
AE 
adverse event 
Akt 
protein kinase b 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AV 
atrioventricular 
BCR 
B-cell receptor 
BID 
twice per day (dosing) 
Blk 
B lymphoid kinase 
Bmx 
Bmx tyrosine-protein kinase 
BOR 
best overall response 
Btk 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CIs 
confidence intervals 
CL/F 
oral clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum concentration 
CR 
complete response (remission) 
CRF 
case report form 
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 
DCR 
disease control rate 
DKA 
diabetic ketoacidosis 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ErbB 
receptor tyrosine-protein kinase erbB  
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 


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ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
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 
HNSCC 
head and neck squamous cell carcinoma 
HNSTD 
highest non-severely toxic dose 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
IEC 
independent ethics committee 
Ig 
immunoglobulin 
Itk 
interleukin-2-inducible T-cell kinase  
IND 
Investigational New Drug 
IRB 
institutional review board 
irCR 
immune-related complete response 
irDCR 
immune-related disease control rate 
irDOR 
immune-related duration of response 
irORR 
immune-related overall response rate 
irPD 
Immune-related progressive disease 
irPFS 
immune-related progression-free survival 
irPR 
immune-related partial response 
irRECIST 
immune-related response criteria 
IV 
intravenous or intravenously  
Jak 
Janus kinase 
LDH 
lactate dehydrogenase 
MDSC 
myeloid-derived suppressor cells 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRP 
multidrug-resistance-associated protein 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
NE 
nonevaluable 
NK 
natural killer (cells) 
NOAEL 
no observed adverse effect level 
NSCLC 
non-small cell lung cancer 


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ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic, pharmacodynamics, or progressive disease 
PD-1 
programmed death-1 (receptor) 
PD-L1 
programmed death ligand-1 
PD-L2 
programmed death ligand-2 
PFS 
progression-free survival 
P-gp 
p-glycoprotein 1 (transporter) 
PI3K 
phosphatidylinositol-3 kinase 
PK 
pharmacokinetic or pharmacokinetics 
PO 
per os (orally) 
PR 
partial response (remission) 
Q3W 
every 3 weeks 
QD 
once per day (dosing) 
QM 
every month 
QTc 
corrected QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT 
radiation therapy 
SAE 
serious adverse event 
SD 
stable disease or standard deviation  
SUSAR 
suspected unexpected serious adverse reaction 
Syk 
spleen tyrosine kinase 
t½ 
terminal elimination half-life 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TAM 
tumor-associated macrophage 
Tec 
tyrosine-protein kinase 
Tmax 
time to maximum concentration 
Treg 
regulatory T cells 
TSH 
thyroid-stimulating hormone (thyrotropin) 
TXK 
Txk tyrosine-protein kinase 
ULN 
upper limit of normal 
Vz/F 
oral volume of distribution 
WHODRUG 
World Health Organization Drug Dictionary 
 


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STUDY SYNOPSIS  
Protocol Number: 
ACE-ST-006 
Study Drugs: 
Acalabrutinib (also known as ACP-196) 
KEYTRUDA® (pembrolizumab) 
Protocol Title: 
A Phase 2 Proof-of-Concept Study of the Combination of ACP-196 
and Pembrolizumab in Subjects with Advanced Head and Neck 
Squamous Cell Carcinoma 
Phase: 
Phase 2 
Comparator: 
KEYTRUDA® (pembrolizumab) 
Study Centers: 
Up to 20 centers in the United States will participate on this 
protocol. 
Background and 
Rationale for Study 
Head and neck squamous cell carcinoma (HNSCC) is a common 
cancer with increasing incidence.  Historically, 50% to 60% of 
patients with locoregionally advanced head and neck cancer 
treated with radiation therapy (RT), surgery, or both develop 
locoregional recurrence within 2 years. In addition, 20% to 30% of 
those patients develop distant metastases. For unresectable head 
and neck cancer, the 5-year survival rate with RT alone is < 25%.  
Several negative regulatory checkpoint molecules function to 
check overstimulation of immune responses and contribute to the 
maintenance of immune tolerance to self-antigens. These 
molecules include the programmed death-1 (PD-1) receptor and its 
ligands (PD-L1 and PD-L2).  PD-L1 confers inhibitory signals to 
activated T cells through binding to the PD-1 receptor. Over half of 
solid tumors (including HNSCC, lung cancer, melanoma, renal cell 
carcinoma, pancreatic cancer, ovarian cancer, and others) express 
PD-L1 in the tumor microenvironment which results in immune 
tolerance and impaired immune response against the tumor. 
Additionally, PD-L1 expression in the tumor microenvironment has 
been shown to be a poor prognostic factor in several cancers. 
Targeting immune infiltrates and disrupting PD-1 ligand-receptor 
interactions may impair stromal support and enhance immune cell 
destruction of tumors that could offer therapeutic benefits to 
patients with HNSCC. Indeed, pembrolizumab, a monoclonal 
antibody directed at PD-1, was shown recently to have a 
20% response rate in patients with advanced unresectable 
HNSCC (Chow 2014).  
Myeloid derived suppressor cells (MDSCs) are important in 
promoting tumor growth and metastases by inducing 
epithelial-mesenchymal transition, allowing tumor invasion, and 
promoting angiogenesis (Condamine 2014).  Therefore, MDSCs 
can be a mechanism of resistance to anti-PD-1 therapy. When 
used in combination with checkpoint inhibitors, agents that inhibit 


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MDSCs can improve outcomes in murine models of metastatic 
disease (Kim 2014). 
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 acalabrutinib, an orally 
bioavailable, small molecule inhibitor of Bruton tyrosine kinase 
(Btk).  A Phase 1 study of acalabrutinib in 31 subjects with 
relapsed/refractory chronic lymphocytic leukemia showed an 
overall response rate of 94%.  acalabrutinib monotherapy has 
shown robust antitumor activity in murine solid tumor models.  The 
antitumor effect observed with acalabrutinib correlates with 
biomarkers of response similar to those reported for other 
immunomodulating agents such as inhibitors of cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4), PD-1 and PD-L1.  
To determine whether there is potential synergy between Btk 
inhibition and PD-1 blockade, Acerta has conducted a nonclinical 
study of acalabrutinib in combination with an anti-PD-L1 antibody 
in an orthotopic colon cancer murine model.  Treatment with anti-
PD-L1 as a single agent reduced tumor growth, but tumor 
regression was not observed.  However, combined anti-PD-L1 and 
acalabrutinib treatment showed a further reduction in tumor 
growth.  Specifically, 6 of 9 animals displayed tumor regression 
compared with no animals treated with anti-PD-L1 alone 
(Figure 1-6).  These results suggest the combination therapy of Btk 
inhibition and checkpoint blockade leads to greater benefit 
compared with checkpoint blockade alone. 
This proof-of-concept study will assess the clinical potential of a 
targeted dual inhibition approach by evaluating the safety, 
pharmacodynamics (PD), pharmacokinetics (PK) and efficacy of 
acalabrutinib and pembrolizumab in subjects with advanced 
HNSCC. 
Study Design: 
This clinical trial is a Phase 2, multicenter, open-label, randomized 
study evaluating pembrolizumab monotherapy and the 
combination of acalabrutinib and pembrolizumab in subjects who 
have recurrent, metastatic or unresectable HNSCC.  
Subjects meeting the eligibility criteria for the study will be 
randomized 1:1 to one of the following arms: 
Arm 1:  Pembrolizumab 200 mg administered as an intravenous 
(IV) infusion every 3 weeks (Q3W) 
Arm 2:  Acalabrutinib 100 mg administered orally (PO) twice per 
day (BID) plus pembrolizumab 200 mg IV Q3W 
Although acalabrutinib has not demonstrated any dose-limiting 
toxicity (DLT) to date, the safety of acalabrutinib in combination 


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with pembrolizumab in this patient population needs to be 
assessed.  Thus, standard DLT criteria will be applied to Arm 2 of 
the study.  Therefore an interim safety analysis will occur once 
 have been successfully randomized to the combination 
arm (Arm 2) and have been treated a minimum of 4 weeks.  
Enrollment will be paused while the interim safety analysis occurs. 
If a DLT rate < 33% is observed in Arm 2 (ie, DLT review is 
cleared), then randomization will continue to evaluate the objective 
response rates of pembrolizumab monotherapy and the 
combination of pembrolizumab and acalabrutinib (ie, up to 
 
subjects per arm).  If a DLT rate of ≥ 33% is observed in Arm 2, 
then enrollment (1:1) will continue until an additional 
 are 
randomized to Arm 2, but with a reduced dose level for 
acalabrutinib (Level -1).  If the DLT review is cleared in those 
additional 
 in Arm 2, then continued enrollment will occur 
at Level -1 for the combination arm.  If a DLT rate of ≥ 33% is 
observed in Arm 2 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 
combination arm.  If the DLT review is not cleared, enrollment will 
be halted in Arm 2.  In addition, analyses for futility and toxicity will 
also be done as outlined in Section 5.5. 
Acalabrutinib treatment can continue for subjects who are 
tolerating therapy and have not developed disease progression.  
Pembrolizumab treatment is for 24 months from the date of first 
dose for subjects who are tolerating therapy and not progressing.  
Subjects who have confirmed progressive disease on the 
combination of pembrolizumab and acalabrutinib will discontinue 
study treatment while those with confirmed progressive disease in 
the pembrolizumab monotherapy arm will continue on 
pembrolizumab with the addition of acalabrutinib until a second 
disease progression is observed.  The immune-related response 
criteria (irRECIST; Appendix 7) will be used to determine 
progression on this study. 
Pembrolizumab treatment may end for subjects with confirmed 
complete response (CR) once treatment has been administered for 
at least 24 weeks and 2 doses of pembrolizumab have been 
administered after confirmation of CR.   
Refer to Appendix 4 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 
study drug-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 


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3. Other Grade ≥ 3 toxicities (Note:  transient Grade 3-4 
laboratory abnormalities that are not clinically significant will 
not be considered DLTs) 
4. Dosing delay due to toxicity for > 21 consecutive days. 
Study Objectives: 
Primary Objectives: 
• 
To characterize the safety and tolerability of acalabrutinib in 
combination with pembrolizumab in subjects with recurrent, 
metastatic or unresectable HNSCC 
• 
To determine the overall response rate (ORR) of 
pembrolizumab monotherapy and the combination of 
acalabrutinib and pembrolizumab in subjects with recurrent, 
metastatic or unresectable HNSCC 
Secondary Objectives: 
• 
To determine progression-free survival (PFS) in subjects 
treated with pembrolizumab monotherapy and the combination 
of acalabrutinib and pembrolizumab 
• 
To evaluate the overall survival (OS) in subjects treated with 
pembrolizumab monotherapy and the combination of 
acalabrutinib and pembrolizumab 
Exploratory Objectives: 
• 
Determine the effects of acalabrutinib plus pembrolizumab on 
peripheral blood T cells and myeloid-derived suppressor cells 
(MDSCs) 
• 
Determine the PK of acalabrutinib alone and in combination 
with pembrolizumab 
• 
Determine if any characteristics of peripheral blood T cells 
and/or MDSCs correlate with immune-mediated toxicities 
• 
Determine if any characteristics of peripheral blood T cells 
and/or MDSCs correlate with response to acalabrutinib and 
pembrolizumab  
• 
Determine if any baseline tumor characteristics correlate with 
response to acalabrutinib and pembrolizumab 
• 
To evaluate the efficacy of adding acalabrutinib to 
pembrolizumab in subjects who progress on pembrolizumab 
monotherapy 
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. 


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Pharmacodynamic, 
Pharmacokinetic and 
Biomarker 
Parameters: 
The occupancy of Btk by acalabrutinib will be measured in 
peripheral blood mononuclear cells (PBMCs) with the aid of a 
biotin-tagged acalabrutinib analogue probe.  The effect of 
acalabrutinib and pembrolizumab on B cells, T cells, and MDSCs 
will also be evaluated.  Tumor tissue, when available, will be 
evaluated for PD-L1 expression.  Acalabrutinib will be measured in 
blood plasma. 
Efficacy Endpoints: 
• 
ORR, defined as partial response (PR) and CR, based on 
modified RECIST 1.1 criteria (Appendix 6) 
• 
Disease control rate (DCR), defined as CR, PR, and stable 
disease (SD) based on modified RECIST 1.1 criteria 
• 
Duration of response (DOR) 
• 
PFS 
• 
OS 
 
 
 
 
 
 
 
 
 
   
 
 
Sample Size: 
 
 
 
 
 
 
Inclusion Criteria: 
1. Men and women ≥ 18 years of age. 
2. Histologically or cytologically confirmed recurrent, metastatic or 
unresectable HNSCC of the oral cavity, oropharynx, 
hypopharynx, and larynx that that has either progressed during 
or after platinum-based chemotherapy administered for 
metastatic disease or has recurred during or within 6 months 
after the completion of platinum-based neoadjuvant or adjuvant 
therapy. 
3. Presence of radiographically measurable disease as defined 
by RECIST 1.1. 


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4. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1. 
5. Completion of all therapy (including surgery, radiotherapy, 
chemotherapy, immunotherapy, or investigational therapy) for 
the treatment of cancer ≥ 2 weeks before the start of study 
therapy and recovered (ie, Grade ≤ 1 or baseline) from AEs 
associated with prior cancer therapy.  Note:  Subjects with 
Grade ≤ 2 neuropathy or Grade ≤ 2 alopecia are an exception 
to the latter criterion and may qualify for the study. 
6. Women who are sexually active and can bear children must 
agree to use acceptable forms of contraception during the 
study and for 90 days after the last dose of acalabrutinib or 
120 days after the last dose of pembrolizumab, whichever is 
longer.  Note:  Acceptable forms of contraception are defined in 
Section 3.10.5. 
7. Men who are sexually active and can beget children must 
agree to use acceptable forms of contraception during the 
study and for 90 days after the last dose of acalabrutinib or 
120 days after the last dose of pembrolizumab, whichever is 
longer. 
8. Men must agree to refrain from sperm donation during the 
study and for 90 days after the last dose of acalabrutinib or 
120 days after the last dose of pembrolizumab, whichever is 
longer. 
9. Able to provide tissue for biomarker analysis from either an 
archived tissue sample or a newly obtained core or excisional 
biopsy of a tumor lesion not previously irradiated.  “Newly 
obtained” is within 30 days of first dose of study drug. 
10. Willing and able to participate in all required evaluations and 
procedures in this study protocol including swallowing 
capsules. 
11. 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 patient privacy regulations). 
Exclusion Criteria: 
1. Prior malignancy (other than HNSCC), except for adequately 
treated basal cell or squamous cell skin cancer, in situ cancer, 
or other cancer from which the subject has been disease free 
for ≥ 2 years.  
2. Known central nervous system metastases and/or 
carcinomatous meningitis.  Brain metastases are allowed if 
they had been previously treated (either surgically resected or 
by radiation therapy) and had remained stable by repeat 
imaging at least 4 weeks after treatment before enrolling on 
this protocol.    
3. A life-threatening illness, medical condition (including 
psychiatric conditions) or organ system dysfunction which, in 
the investigator’s opinion, could compromise the subject’s 


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safety, interfere with the absorption or metabolism of 
acalabrutinib, or put the study outcomes at undue risk. 
4. Significant cardiovascular disease such as uncontrolled or 
symptomatic arrhythmias, congestive heart failure, or 
myocardial infarction within 6 months of starting study drug, 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. 
5. 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. 
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. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti- CTLA-4 antibody (including ipilimumab 
nivolumab, pembrolizumab, MPDL3280A or any other antibody 
or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways). 
8. Prior complications from radiation, such as history of radiation 
pneumonitis that, in the opinion of the investigator, may have 
risk of increasing toxicity with acalabrutinib and/or anti-PD1 
therapy. 
9. Receiving ongoing immunosuppressive therapy, including 
systemic or enteric corticosteroids except for except for non-
systemically absorbed treatments (such as inhaled or topical 
steroid therapy for asthma, chronic obstructive pulmonary 
disease, or allergic rhinitis) within 7 days before the first dose 
of pembrolizumab.  
10. Active autoimmune disease that has required systemic 
treatment in past 2 years (ie, with use of disease modifying 
agents, corticosteroids or immunosuppressive drugs). Note:  
replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment. 
11. Has history of interstitial lung disease or evidence of active 
non-infectious pneumonitis. 
12. Has history of severe allergic, anaphylactic, or other 
hypersensitivity reactions to chimeric or humanized antibodies 
or fusion proteins. 
13. History of bleeding diathesis (eg, hemophilia or von Willebrand 
disease). 
14. Requires treatment with a strong cytochrome P450 3A 
(CYP3A) inhibitor/inducer. 


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15. Requires treatment with proton-pump inhibitors (eg, 
omeprazole, esomeprazole, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole). 
16. Requires or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonists (eg, phenprocoumon) within 7 
days of first dose of study drug. 
17. Known history of human immunodeficiency virus (HIV) or 
active infection with hepatitis C virus (HCV), or hepatitis B virus 
(HBV), or any active infection requiring systemic therapy.  
18. History of stroke or intracranial hemorrhage within 6 months 
before the first dose of study drug. 
19. Major surgical procedure within 28 days of first dose of study 
drug. Note:  If a subject had major surgery, they must have 
recovered adequately from any toxicity and/or complications 
from the intervention before the first dose of study drug. 
20. Prior allogeneic bone marrow transplantation or prior solid 
organ transplantation. 
21. Has received a live vaccine within 30 days of planned start of 
study therapy. 
22. Absolute neutrophil count (ANC) < 1.5 x 109/L or platelet count 
< 100 x 109/L or hemoglobin < 8.0 g/dL. 
23. Total bilirubin > 1.5 x institutional upper limit of normal (ULN) or 
aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 3.0 x ULN. 
24. Estimated creatinine clearance of < 30 mL/min, calculated 
using the formula of Cockroft and Gault 
25. Breastfeeding or pregnant or expecting to conceive or father 
children within the projected duration of the trial, starting with 
the screening visit through 120 days after the last dose of trial 
treatment. 
26. Is currently participating in a clinical trial and receiving study 
therapy or has participated in a study of an investigational 
agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment. 
27. Immediate family members of the Sponsor personnel or site 
staff directly involved with the conduct of this protocol are 
excluded from participating on this study. 
28. Presence of a gastrointestinal ulcer diagnosed by endoscopy 
within 3 months prior to screening. 
29. Serologic status reflecting active hepatitis B or C 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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Dose Regimen/Route 
of Administration: 
Acalabrutinib is provided as hard gelatin capsules for oral 
administration. 
KEYTRUDA® (pembrolizumab) is provided as a 100 mg/4 mL 
(25 mg/mL) solution in a single-use vial or as a lyophilized powder 
for reconstitution (50 mg/vial).  It is administered as an IV infusion 
over 30 minutes. 
Arm 1: 
Pembrolizumab 200 mg Q3W 
Arm 2:  
Dose Level 
Acalabrutinib 
Pembrolizumab 
Starting Dose 
100 mg BID PO 
200 mg Q3W IV 
Level -1 
100 mg QD PO 
200 mg Q3W IV 
Level -2 
50 mg BID PO 
200 mg Q3W IV 
Abbreviations: BID = twice per day; IV = intravenous, PO = oral; Q3W = every 3 weeks; 
QD = once per day 
Concomitant 
Medications: 
The concomitant use of strong inhibitors/inducers of CYP3A with 
acalabrutinib should be avoided when possible.  The effect of 
agents that reduce gastric acidity (eg, proton-pump inhibitors, H2-
receptor antagonists or antacids) on acalabrutinib 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 acalabrutinib.  Use of any proton-
pump inhibitors (eg, eg, omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole) while taking 
acalabrutinib is not recommended due to a potential decrease in 
acalabrutinib exposure.   
Statistical Methods: 
Descriptive statistics (including means, standard deviation [SD], 
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 interim safety 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). 
 
 


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1.0 
BACKGROUND INFORMATION 
1.1 
HNSCC 
HNSCC is the sixth most common cancer worldwide; approximately 600,000 new 
cases are diagnosed per year worldwide (International Agency for Research on 
Cancer 2012; Machiels 2014).  While early stage disease may be treated with a single 
modality such as surgery or RT, most patients (60%) present with Stage III/IV poor 
prognosis disease (Seiwert 2007).  These patients are generally treated with a 
combination of RT, surgery, and cytotoxic or targeted chemotherapy.  Despite this 
aggressive multimodal treatment, most patients will relapse.  The survival rates for all 
patients with HNSCC are approximately 40% to 60% at 5 years (Grégoire 2010).  
While the addition of cetuximab, an immunoglobulin G1 (IgG1) monoclonal antibody 
targeting the epidermal growth factor receptor (EGFR), improves OS when combined 
with RT or chemotherapy (median OS is 10.1 months for the combination of cisplatin 
or carboplatin with 5-fluorouracil and cetuximab), few patients will benefit from 
anti-EGFR monoclonal antibodies, and the objective response rate in monotherapy is 
between 6% and 13% (Bonner 2010, Machiels 2011, Vermorken 2008a, 
Vermorken 2008b).  Based on recent developments in HNSCC molecular biology, 
new compounds are currently being investigated including immune checkpoint 
inhibitors (Schmitz 2014). 
1.2 
PROGRAMMED DEATH LIGAND/RECEPTOR INTERACTIONS IN 
HNSCC 
Several negative regulatory checkpoint molecules function to check overstimulation of 
immune responses and contribute to the maintenance of immune tolerance to self-
antigens (McDermott 2013).  These molecules include CTLA-4 as well as the PD-1 
receptor and its ligands (PD-L1 and PD-L2). CTLA-4 acts as a signal dampener that 
acts largely within the lymph nodes to regulate the magnitude of early activation of 
naive and memory T cells. By contrast, PD-1 is induced on T cells after activation in 
response to inflammatory signals and limits T-cell function at sites of infection or 
tumor in peripheral tissues.  As the T-cell response increases, these negative 
regulatory molecules are induced, limiting the magnitude and duration of the response 
to prevent healthy tissue damage.  Tumors are capable of exploiting the homeostatic 
mechanisms regulated by these checkpoint molecules, thus limiting immune 
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Over half of solid tumors (including HNSCC, lung cancer, melanoma, renal cell 
carcinoma, pancreatic cancer, ovarian cancer, and others) express PD-L1 in the 
tumor microenvironment which results in immune tolerance and impaired immune 
response against the tumor (Zou 2008).  Additionally, PD-L1 expression in the tumor 
microenvironment has been shown to be a poor prognostic factor in several cancers 
(Pardoll 2012).  In a clinical study of the anti-PD-1 monoclonal antibody, 
pembrolizumab, in subjects with advanced unresectable HNSCC (N=60), a 20% ORR 
was observed with response lasting up to 41 weeks (Chow 2014).  Pembrolizumab 
was well tolerated with few serious drug-related AEs (Seiwert 2014). 
1.3 
BRUTON TYROSINE KINASE INHIBITION IN CANCER 
Bruton tyrosine kinase (Btk) is a non-receptor enzyme in the tyrosine-protein kinase 
(Tec) 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, 
Lannutti personal communication).  These data suggest inhibition of Btk may impair 
the invasive 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 
tumor-associated macrophages (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 myeloid derived 
suppressor cells (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, subjects with progressive 
disease had proportionally higher circulating MDSC levels and a high myeloid gene 
signature (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 
acalabrutinib was evaluated in mice with advanced pancreatic cancer arising as the 
result of genetic modifications of oncogenes KRAS and p53, and the pancreatic 
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 acalabrutinib 
administered PO at a dosage of 15 mg/kg BID (N=6).  As shown in Figure 1-1, 
treatment with single-agent acalabrutinib substantially slowed pancreatic cancer 
growth and increased animal survival.  


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Figure 1-1.  Efficacy of Acalabrutinib Monotherapy in a Genetic Model of 
Pancreatic Cancer 
 
Abbreviation:  ACP-196 = acalabrutinib. 
Analysis of tumor tissues showed that immunosuppressive TAMs 
(CD11b+Ly6ClowF4/80+Csf1r+), MDSCs (Gr1+Ly6CHi), and regulatory T cells (Treg) 
(CD4+CD25+FoxP3+) were significantly reduced with acalabrutinib 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 Acalabrutinib on Tumor-Associated 
Immunosuppressive Cells in a Genetic Model of Pancreatic Cancer 
 
Abbreviations: ACP-196 = acalabrutinib; MDSC=myeloid-derived suppressor cell; TAM=tumor-
associated macrophage; Treg=regulatory T cell. 


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Figure 1-3.  Effects of Acalabrutinib on Cytolytic T Cells in a Genetic Model of 
Pancreatic Cancer 
 
Abbreviation:  ACP-196 = acalabrutinib. 
Similar single-agent activity was also observed with acalabrutinib (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 acalabrutinib 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. 


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Figure 1-4.  Acalabrutinib Impairs ID8 Ovarian Cancer Growth and Decreased 
Immunosuppressive Cellular Subsets in Syngeneic Murine Model 
 
Abbreviations: ACP-196 = acalabrutinib; MDSC = myeloid-derived suppressor cell. 
Lastly, the activity of acalabrutinib was confirmed in an orthotopic mouse model 
evaluating both single-agent and combination efficacy.  In this study, 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 that had developed 
pancreatic tumors.  Animals were treated with vehicle (N=6); acalabrutinib 15 mg/kg 
BID PO (N=6); gemcitabine 50 mg/kg IV administered every 4 days for 3 injections 
(N=6); or acalabrutinib 15 mg/kg BID PO 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 1-5); relative 
to the vehicle treatment, acalabrutinib monotherapy resulted in a 2-fold reduction in 
tumor growth, results which compared favorably with gemcitabine alone.  The 
combination of acalabrutinib and gemcitabine resulted in a further reduction in tumor 
growth when compared to each single agent. 


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Figure 1-5.  Efficacy of Acalabrutinib Monotherapy and Combination Therapy 
with Gemcitabine in an Orthotopic Model of Pancreatic Cancer 
 
Abbreviations: ACP-196 = acalabrutinib; Gem = gemcitabine. 
In summary, acalabrutinib alone and in combination with gemcitabine produced 
robust antitumor effects in established solid tumor models.  The antitumor effect 
observed with acalabrutinib correlates with biomarkers of response similar to those 
reported for other immunomodulating agents such as inhibitors of CTLA-4, PD-1 and 
PD-L1.   
1.4 
A CASE FOR COMBINATION BTK AND CHECKPOINT BLOCKADE 
To determine whether there is potential synergy between Btk inhibition and PD-1 
blockade, Acerta has conducted a nonclinical study of acalabrutinib in combination 
with an anti-PD-L1 antibody in an orthotopic colon cancer murine model.  Mice were 
inoculated with syngeneic CT26 colorectal cancer cells on Day 0; anti-PD-L1 (150 μg 
on Day 6, 9, 12, 15) and acalabrutinib (15 mg/kg BID) treatment was begun on Day 6, 
when the tumor was well established.  Treatment with anti-PD-L1 as a single agent 
reduced tumor growth, but tumor regression was not observed (Figure 1-1).  
However, combined anti-PD-L1 and acalabrutinib treatment showed substantially 
improved antitumor activity (anti-PD-L1, 820 mm3 vs anti-PD-L1/acalabrutinib, 411 
mm3).  Most strikingly, 6 of 9 animals displayed tumor regression (Figure 1-6).  These 
results suggest the combination therapy of Btk inhibition and checkpoint blockade 
leads to greater benefit compared with checkpoint blockade alone. 


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Figure 1-6.  Acalabrutinib Enhances the Antitumor Effects of α-PD-L1 in the 
Orthotopic CT26 Colon Cancer Model 
 
Abbreviation:  ACP-196 = acalabrutinib. 
In the tumor microenvironment, we observed a significant reduction in the number of 
MDSCs within the tumor in mice treated with the anti-PD-L1/acalabrutinib combination 
when compared with anti-PD-L1 treatment alone (Figure 1-7).  The decrease of 
MDSCs is directly related to Btk inhibition.  This effect has been observed in 
monotherapy studies of acalabrutinib in murine pancreatic and ovarian cancer models 
(as described in Section 1.3).  Together, these data implicate tumor-associated 
MDSCs in preventing the full benefit of immune checkpoint blockade and offer a 
translatable, therapeutic option by targeting the MDSCs population with acalabrutinib 
to improve the efficacy of checkpoint blockade. 
Figure 1-7.  Btk Inhibition Leads to Modulation of Infiltrating Immature Myeloid 
Cells Which Can Limit the Activity of Anti-PD-L1 Antibodies 
 
Abbreviation:  ACP-196 = acalabrutinib. 


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This proof-of-concept study will assess the clinical potential of combined Btk inhibition 
and checkpoint blockade by evaluating the safety, PD, and efficacy of acalabrutinib 
and pembrolizumab in subjects with advanced HNSCC. 
Summaries of preclinical and clinical studies for acalabrutinib are provided below.  For 
more detailed information please refer to the investigator brochure for acalabrutinib.  
For detailed information on pembrolizumab refer to the KEYTRUDA package insert 
provided in Appendix 5. 
1.5 
ACALABRUTINIB 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol. 
The compound has 1 stereogenic center and acalabrutinib is the S-enantiomer.  
Acalabrutinib is orally bioavailable in animals and is suitable for formulating in 
capsules.  For clinical testing, acalabrutinib has been manufactured and formulated 
according to current Good Manufacturing Practices (cGMP). 
Acalabrutinib is an investigational product and has not been approved for marketing in 
any country.   
1.5.1 
Mechanism of Action 
Acalabrutinib was specifically designed to be a more potent and selective inhibitor of 
Btk to avoid off-target side effects as seen with ibrutinib.  When profiled against 395 
human kinases, acalabrutinib is more selective than ibrutinib (Covey 2015).  For 
additional details, refer to the Acalabrutinib Investigator Brochure.   
1.5.2 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib 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, acalabrutinib shows 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 acalabrutinib on human ether-à-go-go-related gene (hERG) 
channel activity was investigated in vitro in human embryonic kidney cells stably 
transfected with hERG.  Acalabrutinib inhibited hERG channel activity by 25% at 


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10 μM, suggesting a low clinical risk that acalabrutinib would induce clinical QT 
prolongation as predicted by this assay. 
Acalabrutinib 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 
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 acalabrutinib 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 acalabrutinib is unlikely to cause serious off-target effects or 
adverse effects on critical organ systems. 
1.5.3 
Drug-drug Interaction Potential 
The in vitro studies suggest CYP-mediated metabolism of acalabrutinib appears to be 
catalyzed predominantly by CYP3A4/5.  However, in elimination studies in preclinical 
species, the metabolic fate of acalabrutinib is dominated by direct conjugation of 
acalabrutinib 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-gp inhibitor, itraconazole, on the plasma 
levels of acalabrutinib was evaluated.  The mean plasma acalabrutinib maximum 
concentration (Cmax) and area under the curve (AUC) of the last quantifiable 
concentration (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 
acalabrutinib is a substrate for P-gp.   
Acalabrutinib 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 acalabrutinib is not anticipated to 
alter the pharmacokinetics (PK) of other therapeutic agents that are substrates for 
MDR1, OATP1B1, OATP1B3, OAT1, OAT3 and OCT2.   
Please refer to Section 3.10.2 for guidance on drugs that may cause drug-drug 
interactions. 


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1.6 
IN VIVO GENERAL TOXICOLOGY – ACALABRUTINIB 
The systemic toxicity of acalabrutinib has been investigated in 6 repeat-dose general 
toxicology studies, 3 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. 
The no observed 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 (HNSTD).  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 predominantly 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. 
1.7 
CLINICAL EXPERIENCE – ACALABRUTINIB 
For more detailed information on the clinical experience for acalabrutinib please refer 
to the Investigator Brochure.   
1.7.1 
Pharmacokinetics and Pharmacodynamics of Acalabrutinib 
ACE-HV-001 was a PK/PD, 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/PD of acalabrutinib at various dose levels and regimens.  The 
starting dose for acalabrutinib was 2.5 mg BID.  This study has been completed and 


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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 acalabrutinib 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 
evaluated, all had observed systemic concentrations of acalabrutinib.  Acalabrutinib 
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, AUC0-24 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 the oral volume of distribution values (Vz/F: 233 to 612 L) 
appeared to be independent of the dose administered. 
Acalabrutinib was not detected in the urine of subjects receiving the 2.5- or 5.0-mg 
BID doses of acalabrutinib.  Acalabrutinib 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 acalabrutinib (75 mg) after a single oral 
administration was evaluated in 6 men and 6 women.  Median time to acalabrutinib 
Tmax values were increased in the fed state (2.5 hours) relative to the fasted state 
(0.5 hour).  The mean plasma acalabrutinib Cmax fed values decreased to 27.3% of 
the Cmax values observed in the fasted state.  In contrast, the relative AUC exposure 
of acalabrutinib remained mostly unchanged in both states. This decrease in 
exposure is not clinically significant; therefore, acalabrutinib can be taken without 
regard to meals. 
In Part 3, the effect of itraconazole on the PK of acalabrutinib (50 mg) after a single 
oral administration was evaluated in 17 subjects.  No difference in acalabrutinib Tmax 
values was observed in the presence or absence of itraconazole. 
Mean acalabrutinib exposures (as assessed by Cmax, AUC0-last, AUC0-24, and AUC0-inf) 
increased in the presence of itraconazole.  The mean plasma acalabrutinib Cmax 
values increased 3.7-fold in the presence of itraconazole.  The mean plasma 


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AUC0-last, AUC0-24, 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 PD of acalabrutinib 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 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 acalabrutinib 
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%). 
1.7.2 
Acalabrutinib in CLL 
ACE-CL-001 (NCT02029443), an ongoing Phase 1/2 study in subjects with 
relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) or 
Richter’s syndrome, has a sequential, dose-escalation design.  As of 22 January 
2015, 125 subjects have received acalabrutinib 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, acalabrutinib has been well tolerated at all dose levels evaluated.  No DLTs 
have occurred at any dose level.  No study-drug related SAEs 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 PD data show that Btk occupancy with acalabrutinib, in peripheral blood 
cells, is > 95% at 4 hours after dosing but decreases to < 95% at 24 hours, while with 
BID dosing full Btk occupancy (≥ 95%) is maintained over 24 hours (Table 1-1).  
These data suggest that synthesis of de novo Btk may occur within 24 hours. 


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Table 1-1.  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; Std. dev = standard deviation; 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 1-2). 


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Table 1-2.  Preliminary Day 8 PK Results from ACE-CL-001 (December 2014) 
Cohort 
Mean Cmax ± Std. dev. 
(ng/mL) 
Mean AUC0-6h ± Std. dev. 
(ng•h/mL) 
100 mg QD (N=8) 
529 ± 286 
637 ± 197 
175 mg QD (N=7) 
800 ± 692 
1240 ± 789 
250 mg QD (N=7) 
1350 ± 933 
1520 ± 959 
400 mg QD (N=6) 
932 ± 576 
2170 ± 1180 
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. 
Abbreviations:  AUC = area under the curve; *BID = twice per day (Cmax and AUC0-6h of first dose); Cmax = 
maximum concentration; Std. dev. = 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 1-3). 
Table 1-3.  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) Cycles 
 
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) 
Abbreviations:  BID = twice per day; PR = partial response; PR+L = partial response with lymphocytosis; 
SD = stable disease; PD = progressive disease; QD = once per day. 
 
1.8 
KEYTRUDA (PEMBROLIZUMAB) 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2.  Pembrolizumab is approved for treatment of patients 
with unresectable or metastatic melanoma and disease progression following 
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.  Pembrolizumab 
has also been granted approval in the United States for the treatment of patients with 
metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as 
determined by an FDA-approved test and who have disease progression on or after 
platinum-containing chemotherapy.  For complete information on pembrolizumab refer 


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to the KEYTRUDA package insert (Appendix 5) or to the Pembrolizumab Investigator 
Brochure.  Serious adverse reactions associated with pembrolizumab are described 
in the package insert (Appendix 5) and also in Section 3.8.1 of this protocol. 
1.9 
BENEFIT/RISK 
Acalabrutinib is a potent, orally available small-molecule inhibitor of Btk.  A PK/PD 
study has been completed with acalabrutinib in healthy volunteers (ACE-HV-001; 
Section 1.7.1).  The safety results showed no safety risk was identified in healthy 
subjects receiving 1 or 2 days of acalabrutinib ≤ 100 mg.  In the Phase 1/2 study of 
acalabrutinib in subjects with CLL, no DLTs have been identified and no SAEs related 
to study drug have occurred 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 acalabrutinib is well tolerated and has robust activity as a single agent in 
the treatment of subjects with CLL including those with 17p del.   
The nonclinical and toxicology results of acalabrutinib suggest it may have an 
improved therapeutic window relative to ibrutinib; it may be more readily combined 
with other agents for the treatment of cancer.  Based on the currently known toxicity 
profiles of acalabrutinib and pembrolizumab overlapping toxicities are not anticipated.  
Preliminary results in preclinical cancer models suggests a synergistic antitumor 
effect of Btk inhibition in combination with PD-1 blockade, which support evaluating 
the combination in clinical trials. 
2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
• 
To characterize the safety profile of acalabrutinib and pembrolizumab in 
subjects with recurrent, metastatic or unresectable HNSCC 
• 
To determine the ORR of pembrolizumab monotherapy and the combination 
of acalabrutinib and pembrolizumab in subjects with recurrent, metastatic or 
unresectable HNSCC 
2.2 
SECONDARY OBJECTIVES 
• 
To determine PFS in subjects treated with pembrolizumab monotherapy and 
the combination of acalabrutinib and pembrolizumab 
• 
To evaluate the OS in subjects treated with pembrolizumab monotherapy and 
the combination of acalabrutinib and pembrolizumab 


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2.3 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
3.0 
STUDY DESIGN 
This clinical trial is a Phase 2, multicenter, open-label, randomized study evaluating 
pembrolizumab monotherapy and the combination of acalabrutinib and 
pembrolizumab in subjects who have recurrent, metastatic or unresectable HNSCC 
and limited treatment options.  
Subjects meeting the eligibility criteria for the study will be randomized 1:1 to one of 
the following arms: 
Arm 1:  Pembrolizumab 200 mg administered as an IV infusion Q3W 
Arm 2:  Acalabrutinib 100 mg administered PO BID plus pembrolizumab 200 mg IV 
Q3W 
Although acalabrutinib has not demonstrated any DLT to date, the safety of 
acalabrutinib in combination with pembrolizumab in this patient population needs to 
be assessed.  Thus, standard DLT criteria will be applied to Arm 2 of the study.  
Therefore an interim safety analysis will occur once
 have been 
successfully randomized to the combination arm (Arm 2) and have been treated a 
minimum of 4 weeks.  Enrollment will be paused while the interim safety analysis 
occurs.  If a DLT rate of < 33% is observed in Arm 2 (ie, DLT review is cleared), then 
randomization will continue to evaluate the objective response rates of 
pembrolizumab monotherapy and the combination of pembrolizumab and 
acalabrutinib (ie, up to 
 per arm).  If a DLT rate of 
 is observed 
in Arm 2, then enrollment (1:1) will continue until an additional 
 are 
randomized to Arm 2, but with a reduced dose level for acalabrutinib (Level -1).  If the 


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DLT review is cleared in those additional 
 in Arm 2 then continued 
enrollment will occur at Level -1 for the combination arm.  If a DLT rate of ≥ 33% is 
observed in Arm 2 at Level -1, then an additional 
 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 combination arm.  If the DLT review is not cleared, 
enrollment will be halted in Arm 2.  In addition, analyses for futility and toxicity will also 
be done as outlined in Section 5.5. 
Acalabrutinib treatment can continue for subjects who are tolerating therapy and have 
not developed progressive disease.  Pembrolizumab treatment is for 24 months from 
the date of first dose for subjects who are tolerating therapy and not progressing.  
Subjects who have confirmed progressive disease on the combination of 
pembrolizumab and acalabrutinib will discontinue study treatment while those with 
confirmed progressive disease in the pembrolizumab monotherapy arm will continue 
on pembrolizumab with the addition of acalabrutinib until a second disease 
progression or intolerance of therapy.  Disease progression will be determined based 
on irRECIST guidelines (Appendix 7 and detailed in Section 3.11). 
Pembrolizumab treatment may end for subjects with confirmed CR once treatment 
has been administered for at least 24 weeks and 2 doses of pembrolizumab have 
been administered after confirmation of CR.  Treatment on this protocol can continue 
for a minimum of 12 months after the last subject is randomized. 
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 and hematology.  PD and PK testing will be 
performed during the first few months of treatment.  Radiologic tumor assessments 
will be completed at baseline and at ~6-week intervals during the trial.  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. 
Refer to Appendix 4 for a comprehensive list of study assessments and their timing.  
The study schema is provided below (Figure 3-1). 


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Figure 3-1.  Study Schema 
 
Abbreviations:  ACP-196 = acalabrutinib; BID = twice per day; DLT = dose-limiting toxicity; HNSCC = 
head and neck squamous cell carcinoma; IV = intravenous; Q3W = every 3 weeks. 
* Acalabrutinib and pembrolizumab administration begin on the same day except for the first 6 subjects 
enrolled due to pharmacokinetic sampling.  In the first 6 subjects, acalabrutinib will be administered on 
Day 1 of Week 1.  On Day 2 of Week 1, the first pembrolizumab infusion will occur.  When both are 


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administered on the same day, acalabrutinib is administered first followed by the pembrolizumab 
infusion.   
3.1 
STUDY PARAMETERS 
3.1.1 
Safety Parameters 
The safety of acalabrutinib and pembrolizumab 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; DLTs or AEs 
leading to discontinuation of study treatment.  
3.1.2 
Pharmacodynamic, Pharmacokinetic and Biomarker 
Parameters 
The occupancy of Btk by acalabrutinib will be measured in PBMCs with the aid of a 
biotin-tagged acalabrutinib analogue probe.  The effect of acalabrutinib and 
pembrolizumab on B cells, T cells and MDSCs will also be evaluated.  Tumor tissue, 
when available, will be evaluated for PD-L1 expression.  Additional exploratory 
correlative studies of tumor tissue, when available, may include characterization of 
tumor subtypes by immunohistochemistry, gene expression or mutation analysis. 
The following PK parameters will be calculated, whenever possible, from plasma 
concentrations of acalabrutinib: 
• 
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. 
• 
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 


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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 6). 
Efficacy endpoints will include: 
• 
ORR 
• 
DCR  
• 
DOR 
• 
PFS 
• 
OS 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
3.2 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
As described in Section 1.7.2, acalabrutinib 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 acalabrutinib. All tested dose levels have been well tolerated: 
• 
No MTD has been reached. 
• 
No DLT has occurred at any dose level. 
• 
No study-drug related AE has led to discontinuation from the study.   
• 
No study-drug related SAEs have occurred. 


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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 1-2).  PD 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 1-1).   
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.  The 
dose recently approved in the United States and several other countries for treatment 
of melanoma subjects is 2 mg/kg Q3W.  Information on the rationale for selecting 
200 mg Q3W is summarized below. 
KEYNOTE-001 was an open-label Phase 1 study conducted to evaluate the safety, 
tolerability, PK and PD, and anti-tumor activity of pembrolizumab when administered 
as monotherapy.  The dose escalation portion of this trial evaluated 3 dose levels, 
1 mg/kg, 3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and dose 
expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with 
advanced solid tumors.  All dose levels were well tolerated and no DLTs were 
observed.  This first-in-human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels.  No 
MTD has been identified.  In addition, 2 randomized cohort evaluations of melanoma 
subjects receiving pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have 
been completed, and 1 randomized cohort evaluating 10 mg/kg Q3W versus 
10 mg/kg Q2W has also been completed.  The clinical efficacy and safety data 
demonstrate a lack of important differences in efficacy or safety profile across doses.  
An integrated body of evidence suggests that 200 mg Q3W is expected to provide 
similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.  Previously, a 
flat pembrolizumab exposure-response relationship for efficacy and safety has been 
found in subjects with melanoma in the range of doses between 2 mg/kg and 
10 mg/kg.  Exposures for 200 mg Q3W are expected to lie within this range and will 
be close to those obtained with 2 mg/kg Q3W dose.   
A population pharmacokinetic (PK) model, which characterized the influence of body 
weight and other patient covariates on exposure, has been developed.  The PK profile 
of pembrolizumab is consistent with that of other humanized monoclonal antibodies, 
which typically have a low clearance and a limited volume of distribution.  The 
distribution of exposures from the 200 mg fixed dose are predicted to considerably 
overlap those obtained with the 2 mg/kg dose and importantly will maintain individual 


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patient exposures within the exposure range established in melanoma as associated 
with maximal clinical response.  Pharmacokinetic properties of pembrolizumab, and 
specifically the weight-dependency in clearance and volume of distribution are 
consistent with no meaningful advantage to weight-based dosing relative to fixed 
dosing. 
In translating to other tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as 
the anti-tumor effect of pembrolizumab is driven through immune system activation 
rather than through a direct interaction with tumor cells, rendering it independent of 
the specific tumor type.  In addition, available PK results in subjects with melanoma, 
NSCLC, and other tumor types support a lack of meaningful difference in 
pharmacokinetic exposures obtained at tested doses among tumor types.  Thus the 
200 mg Q3W fixed-dose regimen is considered an appropriate fixed dose for other 
tumor indications as well.   
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage.  
The existing data suggest 200 mg Q3W as the appropriate dose for pembrolizumab. 
As described in Section 1.4, Acerta Pharma has conducted a nonclinical study to 
evaluate the potential synergy of Btk inhibition with checkpoint blockade and has seen 
encouraging results, which warrant testing the hypothesis in a clinical trial.   
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. Histologically or cytologically confirmed recurrent, metastatic or unresectable 
HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx that has either 
progressed during or after platinum-based chemotherapy administered for 
metastatic disease or has recurred during or within 6 months after the completion 
of platinum-based neoadjuvant or adjuvant therapy. 
3. Presence of radiographically measurable disease as defined by RECIST 1.1 
4. ECOG performance status of 0 or 1. 
5. Completion of all therapy (including surgery, radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of cancer ≥ 2 weeks 


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before the start of study therapy and recovered (ie, Grade ≤ 1 or baseline) from 
AEs associated with prior cancer therapy.  Note:  Subjects with Grade ≤ 2 
neuropathy or Grade ≤ 2 alopecia are an exception to the latter criterion and may 
qualify for the study. 
6. Women who are sexually active and can bear children must agree to use 
acceptable forms of contraception (defined in Section 3.10.4) during the study and 
for 90 days after the last dose of acalabrutinib or 120 days after the last dose of 
pembrolizumab, whichever is longer.  Note:  Acceptable forms of contraception 
are defined in Section 3.10.5. 
7. Men who are sexually active and can beget children must agree to use acceptable 
forms of contraception (defined in Section 3.10.4) during the study and for 
90 days after the last dose of acalabrutinib or 120 days after the last dose of 
pembrolizumab, whichever is longer. 
8. Men must agree to refrain from sperm donation during the study and for 90 days 
after the last dose of acalabrutinib or 120 days after the last dose of 
pembrolizumab, whichever is longer. 
9. Able to provide tissue for biomarker analysis from either an archived tissue 
sample or a newly obtained core or excisional biopsy of a tumor lesion not 
previously irradiated.  “Newly obtained” is within 30 days of first dose of study 
drug. 
10. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing capsules. 
11. 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 patient 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 HNSCC), except for adequately treated basal cell or 
squamous cell skin cancer, in situ cancer, or other cancer from which the subject 
has been disease free for ≥ 2 years.  
2. Known central nervous system metastases and/or carcinomatous meningitis. 
Note:  Imaging studies of the central nervous system are not required as a 
condition of study enrollment.  Brain metastases are allowed if they had been 
previously treated (either surgically resected or by radiation therapy) and had 
remained stable by repeat imaging at least 4 weeks after treatment before 
enrolling on this protocol. 
3. A life-threatening illness, medical condition (including psychiatric conditions) or 
organ system dysfunction which, in the investigator’s opinion, could compromise 
the subject’s safety, interfere with the absorption or metabolism of acalabrutinib, 
or put the study outcomes at undue risk. 
4. Significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
starting study drug, or any Class 3 or 4 cardiac disease as defined by the New 
York Heart Association Functional Classification, or QTc > 480 msec at screening. 
5. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
or resection of the stomach or small bowel, symptomatic inflammatory bowel 


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disease, partial or complete bowel obstruction, or gastric restrictions and bariatric 
surgery, such as gastric bypass. 
6. Prior therapy with any inhibitor of Btk, Akt, Jak, mTOR, PI3K, Syk. 
7. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody (including ipilimumab nivolumab, pembrolizumab, 
MPDL3280A or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways). 
8. Prior complications from radiation, such as history of radiation pneumonitis that, in 
the opinion of the investigator, may have risk of increasing toxicity with 
acalabrutinib and/or anti-PD1 therapy. 
9. Receiving ongoing immunosuppressive therapy, including systemic or enteric 
corticosteroids except for except for non-systemically absorbed treatments (such 
as inhaled or topical steroid therapy for asthma, chronic obstructive pulmonary 
disease, or allergic rhinitis) within 7 days before the first dose of pembrolizumab.  
10. Active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs).  Note:  replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not 
considered a form of systemic treatment. 
11. Has history of interstitial lung disease or evidence of active non-infectious 
pneumonitis.  
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins. 
13. History of bleeding diathesis (eg, hemophilia or von Willebrand disease). 
14. Requires treatment with a strong CYP3A inhibitor/inducer. 
15. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 
16. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. 
17. Known history of HIV or active infection with HCV, or HBV, or any active infection 
requiring systemic therapy.  
18. History of stroke or intracranial hemorrhage within 6 months before the first dose 
of study drug. 
19. Major surgical procedure within 28 days of first dose of study drug.  Note:  If a 
subject had major surgery, they must have recovered adequately from any toxicity 
and/or complications from the intervention before the first dose of study drug. 
20. Prior allogeneic bone marrow transplantation or prior solid organ transplantation. 
21. Has received a live vaccine within 30 days of planned start of study therapy. 
22. ANC < 1.5 x 109/L or platelet count < 100 x 109/L or hemoglobin < 8.0 g/dL. 
23. Total bilirubin > 1.5 x ULN or AST or ALT > 3.0 x ULN. 
24. Estimated creatinine clearance of < 30 mL/min, calculated using the formula of 
Cockroft and Gault. 
25. Breastfeeding or pregnant or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days 
after the last dose of trial treatment. 


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26. Is currently participating in a clinical trial and receiving study therapy or has 
participated in a study of an investigational agent and received study therapy or 
used an investigational device within 4 weeks of the first dose of treatment. 
27. Immediate family members of the Sponsor personnel or site staff directly involved 
with the conduct of this protocol are excluded from participating on this study. 
28. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months 
prior to screening. 
29. Serologic status reflecting active hepatitis B or C 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 hepatitis B surface antigen positive or hepatitis B PCR positive 
and those who are hepatitis C PCR positive will be excluded. 
3.3.3 
Replacement of Subjects 
Subjects will not be replaced on this study except if needed to complete the DLT 
assessment (N=6).  However, subjects who discontinue from the study due to a DLT 
during the DLT assessment period will not be replaced.   
3.3.4 
Enrollment and Randomization 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. 
The Enrollment Confirmation Form will contain treatment-arm allocation.  The 
treatment assignment is based on the randomization list generated by the Sponsor 
before study enrollment begins. 
Treatment must begin within the screening window (Section 4.1) and after the site has 
received the treatment-arm allocation from the sponsor.   


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3.4 
STUDY DRUGS 
3.4.1 
Premedications 
No specific premedications or supporting medications are required in conjunction with 
acalabrutinib or pembrolizumab administration.  
3.4.2 
Formulation, Packaging, and Storage 
Acalabrutinib 
Acalabrutinib is manufactured according to current cGMP regulations and will be 
provided to the investigational site by Acerta Pharma or designee.  Acalabrutinib 
should be stored according to the instructions on the label that is affixed to the 
package of the drug product.  Acalabrutinib 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 Acalabrutinib Investigator’s 
Brochure for additional information regarding the drug products to be used in this trial. 
Pembrolizumab 
Commercially available pembrolizumab (KEYTRUDA) will be provided by the Sponsor 
for use on this study (Table 3-1).  Pembrolizumab (100 mg/4 mL) is provided as 
25-mg/mL solution in single-use vials or as a lyophilized powder for reconstitution 
(50 mg/vial). 
Table 3-1 Pembrolizumab Product Descriptions 
Product Name & Potency 
Dosage Form 
MK-3475 50 mg 
Lyophilized Powder for Injection 
MK-3475 100 mg/ 4mL 
Solution for Injection 
Information on the formulation, packaging and storage of pembrolizumab is provided 
in the package insert (Appendix 5). 
3.4.3 
Administration of Study Drug  
Investigators are prohibited from supplying acalabrutinib to any subjects not properly 
enrolled in this study.  The investigator must ensure that subjects receive 
acalabrutinib or pembrolizumab only from personnel who fully understand the 
procedures for administering the drugs. 


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Acalabrutinib 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 inhibition of CYP3A).  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. 
Refer to Section 3.10.2 for guidance on concomitant dosing of acalabrutinib with 
agents that affect gastric pH. 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV 
infusion.  Sites should make every effort to target infusion timing to be as close to 
30 minutes as possible.  However, given the variability of infusion pumps from site to 
site, a window between -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes -5 min/+10 min).  Detailed information on preparation of pembrolizumab 
for infusion is provided in Appendix 5.  
When acalabrutinib and pembrolizumab are administered on the same day, 
acalabrutinib should be administered first, followed by pembrolizumab.  When PK 
sampling is done, the pembrolizumab infusion should begin within 10 minutes of 
ingesting acalabrutinib. 
3.4.4 
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 acalabrutinib 
treatments 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.   
Pembrolizumab infusions will be administered only at the clinics per the study 
schedule.  
Subject compliance with acalabrutinib dosing will be assessed at every visit.  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 


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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 – Pembrolizumab Monotherapy 
Pembrolizumab 200 mg will be administered every 3 weeks by IV infusion.  
3.5.2 
Arm 2 – Combination Treatment 
The dose of acalabrutinib is 100 mg BID PO.  The doses may be modified for DLTs 
as summarized in Table 3-2.  
Pembrolizumab 200 mg will be administered every 3 weeks by IV infusion for a 
maximum of 24 months from the date of first dose.   
Acalabrutinib and pembrolizumab dosing will begin on the same day on Week 1 
except for the first 6 subjects enrolled due to PK sampling.  The first 6 subjects 
enrolled will receive acalabrutinib on Day 1 of Week 1.  Then on Day 2 of Week 1 the 
first pembrolizumab infusion will be administered. 
Table 3-2.  Dose Reduction for Acalabrutinib 
Dose Level 
Acalabrutinib 
Pembrolizumab 
Starting Dose 
100 mg BID PO 
200 mg Q3W IV 
Level -1 
100 mg QD PO 
200 mg Q3W IV 
Level -2 
50 mg BID PO 
200 mg Q3W IV 
Abbreviations: BID = twice per day; IV = intravenous, PO = oral; Q3W = every 3 weeks; QD = once per 
day. 
3.6 
DURATION OF THERAPY 
Subjects may continue to receive acalabrutinib treatment until disease progression or 
an intolerable AE.  Pembrolizumab treatment is for 24 months from the date of first 
dose for subjects who are tolerating therapy and not progressing.  Pembrolizumab 
treatment may end for subjects with confirmed CR once treatment has been 
administered for at least 24 weeks and 2 doses of pembrolizumab have been 
administered after confirmation of CR. 
Treatment on this protocol can continue for a minimum of 12 months after the last 
subject is randomized to the study. 


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3.7 
ASSESSMENT OF DOSE-LIMITING TOXICITY (DLT) 
As outlined in Section 3.0, DLT review will be applied to Arm 2 as the combination of 
acalabrutinib plus pembrolizumab has not been evaluated before, therefore an interim 
safety analysis will occur once 6 subjects have been successfully randomized to the 
combination arm (Arm 2) and have been treated a minimum of 4 weeks.  Enrollment 
will be paused while the interim safety analysis occurs. 
A DLT will be defined as the occurrence of any of the following study drug-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 that 
are not clinically significant will not be considered DLTs) 
4. Dosing delay due to toxicity for > 21 consecutive days. 
3.8 
DOSING DELAYS AND MODIFICATIONS 
Subjects should be followed closely for AEs or laboratory abnormalities that might 
indicate acalabrutinib- or pembrolizumab-related toxicity.  If a subject experiences a 
treatment-related DLT or other intolerable AE during the course of therapy, then 
acalabrutinib, pembrolizumab, or both drugs should be held, as necessary, until the 
AE resolves or stabilizes to an acceptable degree (ie, Grade ≤ 1).  As appropriate, 
certain laboratory abnormalities may warrant more frequent monitoring (eg, once per 
week) until abnormalities have recovered to Grade ≤ 1.  Dose reductions for 
acalabrutinib are provided in Table 3-2.  If acalabrutinib 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 acalabrutinib 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 acalabrutinib is 100 mg BID 
for this protocol. 
For treatment-emergent hepatotoxicity in the combination arm only:  Important 
guidelines for treatment-emergent hepatotoxicity are provided in Section 3.8.2 for 
pembrolizumab.  In the combination arm, treatment with acalabrutinib should be 


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withheld for Grade 3 or 4 hepatitis.  For Grade 4 events, acalabrutinib may be 
restarted only after discussion with the medical monitor.  For Grade 3 events, 
treatment with acalabrutinib can be considered after the LFT laboratory values have 
returned to Grade ≤ 1 or to baseline. 
Note:  temporary withholding of acalabrutinib 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. 
3.8.1 
Dose Modifications for Pembrolizumab 
Adverse events (nonserious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology.  These adverse events may occur shortly 
after the first dose or several months after the last dose of treatment.  Pembrolizumab 
must be withheld for drug-related toxicities and severe or life-threatening AEs as per 
Table 3-3 below.  See Section 3.8.2 for supportive care guidelines, including use of 
corticosteroids. 
Table 3-3.  Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 
0-1. 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks 
of last dose. 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for 
new onset Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia associated 
with evidence of beta cell 
failure. 
Resume pembrolizumab when patients are 
clinically and metabolically stable. 
Hypophysitis 
2-4 
Toxicity resolves to Grade 
0-1. Therapy with 
pembrolizumab can be 
continued while endocrine 
replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
Hyperthyroidism  
3 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Hypothyroidism 
 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted. 
Infusion Reaction 
2b 
Toxicity resolves to Grade 
0-1 
Permanently discontinue if toxicity develops 
despite adequate premedication. 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks 
of last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note:  Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that 
recurs or any life-threatening event. 
 
a. For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater 
than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b. If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original 
infusion rate   (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject 
should be premedicated for the next scheduled dose; Refer to Table 3-4  – Infusion Treatment Guidelines for further 
management details. 
c. Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has 
been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
3.8.2 
Supportive Care Guidelines for Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary 
by the treating investigator.  Suggested supportive care measures for the 
management of adverse events with potential immunologic etiology are outlined 
below.  Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.  Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased.  For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care.  The treatment guidelines are intended to be 
applied when the investigator determines the events to be related to pembrolizumab.  


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Note:  If after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below).  Refer to 
Section 3.8.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
• 
Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids.  When 
symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.  
For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) 
or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I 
diabetes mellitus and for Grade 3-4 hyperglycemia associated 
with metabolic acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, 
urine ketones, glycosylated hemoglobin, and C-peptide.  
• 
Hypophysitis: 
o For Grade 2 events, treat with corticosteroids.  When symptoms 
improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 


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o For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids.  When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 
4 weeks.  Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment.  Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs 
and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (eg, 
propranolol) are suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids.  When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 
4 weeks.  Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
• 
Hepatic: 
o For Grade 2 events, treatment with pembrolizumab should be 
withheld.  Administer corticosteroids (initial dose of 0.5 to 1 mg/kg/day 
prednisone or equivalent) (Appendix 5).  When LFT laboratory values 
resolve to baseline or return to Grade ≤ 1, then taper the 
corticosteroids over no fewer than 4 weeks while continuing to monitor 
LFTs at least weekly.  Further treatment with pembrolizumab can be 
considered after the LFT laboratory values have returned to Grade ≤ 1 
or to baseline either during the steroid taper or after stopping 
corticosteroids. 
o For Grade 3-4 events, permanently discontinue pembrolizumab.  Treat 
with corticosteroids (initial dose 1 to 2 mg/kg/day prednisone or 
equivalent) (Appendix 5) until LFT laboratory values resolve to 
baseline or return to Grade ≤ 1, and then taper the corticosteroids over 
no fewer than 4 weeks while continuing to monitor LFTs at least 
weekly.  
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
• 
Management of Infusion Reactions: 


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o Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of 
completion of infusion.  
o Table 3-4 shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab. 
Table 3-4.  Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion 
rate (eg, from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should 
be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (eg, renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
 
 


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3.9 
CONCOMITANT THERAPY 
3.9.1 
Permitted Concomitant Therapy 
Antiemetics are permitted if clinically indicated. Standard supportive care medications 
are permitted as per institutional standards.   
3.9.2 
Prohibited or Restricted Concomitant Therapy 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy 
for treating head and neck squamous cell carcinoma are prohibited.   
Warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) are prohibited.   
At study entry, subjects may be using topical or inhaled corticosteroids as therapy for 
comorbid conditions, but use of corticosteroids as therapy for cancer is not permitted.  
During study participation, subjects may also receive systemic or enteric 
corticosteroids at any required dosage as needed for treatment emergent 
immune-mediated adverse reactions associated with pembrolizumab therapy (see 
Section 3.8), but use of corticosteroids (at dosages equivalent to prednisone 
> 20 mg/day for longer than 2 weeks) as therapy for cancer is not permitted.  
Use of calcium carbonate-containing drugs or supplements and short-acting 
H2-receptor antagonists should be avoided for at least 2 hours before or after 
acalabrutinib administration (see Section 3.10.2). 
Live vaccines within 30 days before the first dose of trial treatment and while 
participating in the trial are prohibited.  Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine.  Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed.  However, intranasal influenza 
vaccines (eg, Flu - Mist®) are live attenuated vaccines and are not allowed. 
3.10 PRECAUTIONS 
3.10.1 
Hepatitis B Reactivation 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated 
with acalabrutinib.  Therefore, subjects who are hepatitis B core antibody (anti-HBc) 
positive (or have a known history of HBV) 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 


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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 acalabrutinib in subjects who 
develop HBV reactivation.   
3.10.2 
Dietary Restrictions 
Acalabrutinib can be taken with or without food.  Because acalabrutinib may be 
metabolized by CYP3A (Section 1.7.1), 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). 
Otherwise subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
3.10.3 
Drug-drug Interactions 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated.  However, as discussed in Section 1.5.3, concomitant 
administration of acalabrutinib with a strong CYP3A inhibitor increased exposure by 
approximately 5-fold.  Consequently, the concomitant use of strong inhibitors/inducers 
of CYP3A (see Appendix 2) should be avoided when possible.   
Based on these considerations, subjects who require therapy with drugs listed in 
Appendix 2 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, monitor the 
subject closely for potential drug-related toxicities.   
The effect of agents that reduce gastric acidity (eg, proton-pump inhibitors, 
H2-receptor antagonists or antacids) on acalabrutinib 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 acalabrutinib.  Use of omeprazole or 
esomeprazole or any other proton-pump inhibitors (eg, lansoprazole, rabeprazole, or 


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pantoprazole) while taking acalabrutinib is not recommended due to a potential 
decrease in acalabrutinib exposure.   
No formal PK drug interaction studies have been conducted with pembrolizumab. 
3.10.4 
Surgery 
Susceptibility to bleeding has been observed with the first generation Btk inhibitor, 
ibrutinib [IMBRUVICA package insert].  As a precaution, it is suggested that 
acalabrutinib be held for 3 days before and after any major surgical procedure. 
3.10.5 
Reproductive Toxicity 
Acalabrutinib 
Note for subjects receiving only acalabrutinib, the information below applies. 
Pilot reproductive toxicity studies have been performed that evaluate the effects of 
acalabrutinib on embryofetal development.  Definitive studies of acalabrutinib on 
embryofetal development are pending.  Women who are sexually active and can bear 
children (see definition below) must agree to use acceptable forms of contraception 
during the study and for 90 days after the last dose of acalabrutinib as defined below. 
Pembrolizumab 
Note for subjects receiving acalabrutinib plus pembrolizumabthe information below 
applies. 
Pembrolizumab may have adverse effects on a fetus in utero.   
Women will be considered of non-reproductive potential if they are either: 
1) postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy 
or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  


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(3) has a congenital or acquired condition that prevents childbearing. 
Men and women of reproductive potential must agree to avoid impregnating a partner 
or becoming pregnant, respectively, while receiving study drug and for 120 days after 
the last dose of study drug by complying with one of the following:   
1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual 
activity.   
Acceptable methods of contraception are‡: 
  
Single method (1 of the following is acceptable): 
• 
IUD 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of 2 of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (eg, calendar, ovulation, sympto-thermal, and post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  


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‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.   
Men must refrain from sperm donation during the study and for 90 days after the last 
dose of acalabrutinib or 120 days after the last dose of pembrolizumab, whichever is 
longer. 
Subjects should be informed that taking the study medication may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study.  To 
participate in the study subjects of childbearing potential must adhere to the 
contraception requirement (described above) from the day of study medication 
initiation (or 14 days prior to the initiation of study medication for oral contraception) 
throughout the study period up to 120 days after the last dose of trial therapy.  If there 
is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
Subjects should promptly notify the investigator if they, or their partner, become 
pregnant during this period.  If a female subject becomes pregnant during the 
treatment period, she must discontinue acalabrutinib and pembrolizumab 
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 acalabrutinib or pembrolizumab overdose (ie, 
administration of a dose ≥ 1000 mg of acalabrutinib or ≥ 1000 mg of pembrolizumab 
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 the overdose ingestion 
of acalabrutinib is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered. 
The medical monitor must be contacted if a study drug overdose occurs (Section 
6.2.5).  


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3.11 TREATMENT AFTER INITIAL RADIOLOGIC PROGRESSION 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics 
seen with treatment of pembrolizumab.  Immunotherapeutic agents such as 
pembrolizumab may produce antitumor effects by potentiating endogenous cancer-
specific immune responses.  The response patterns seen with such an approach may 
extend beyond the typical time course of responses seen with cytotoxic agents and 
can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  Standard RECIST may not provide an accurate response 
assessment of immunotherapeutic agents such as pembrolizumab.  Therefore, 
RECIST 1.1 will be used with the following adaptations: 
• 
If radiologic imaging verifies initial disease progression, tumor assessment 
should be repeated ≥4 weeks later to confirm disease progression with the 
option of continuing treatment per below.   
• 
If repeat imaging shows < 20% tumor burden compared to nadir, stable or 
improved previous new lesion (if identified as cause for initial disease 
progression), and stable/improved non-target disease (if identified as cause 
for initial disease progression), treatment may be continued / resumed.   
• 
If repeat imaging confirms disease progression due to any of the scenarios list 
below, subjects will be discontinued from study therapy (except subjects who 
cross over to receive acalabrutinib in addition to pembrolizumab).   
In determining whether or not the tumor burden has increased or decreased, site 
study team should consider all target lesions as well as non-target lesions (if needed, 
the tip sheet provided in the study binder can be used as a reference to assess 
lesions). 
Scenarios where disease progression is confirmed at repeat imaging: 
• 
Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared 
to nadir 
• 
Non-target disease resulting in initial disease progression is worse (qualitative) 
• 
New lesion resulting in initial disease progression is worse (qualitative) 
• 
Additional new lesion(s) since last evaluation 


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In subjects who have initial evidence of radiological disease progression, it is at the 
discretion of the treating physician whether to continue a subject on study treatment 
until repeat imaging is obtained.  This clinical judgment decision should be based on 
the subject’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data.  Subjects may receive study treatment while waiting 
for confirmation of disease progression if they are clinically stable as defined by the 
following criteria: 
• 
Absence of signs and symptoms indicating disease progression 
• 
No decline in ECOG performance status 
• 
Absence of rapid progression of disease 
• 
Absence of progressive tumor at critical anatomical sites (eg, cord 
compression) requiring urgent alternative medical intervention 
When feasible, subjects should not be discontinued until progression is confirmed.  
This allowance to continue treatment despite initial radiologic progression takes into 
account the observation that some subjects can have a transient tumor flare in the 
first few months after the start of immunotherapy, but with subsequent disease 
response.  Subjects that are deemed clinically unstable are not required to have 
repeat imaging for confirmation of progressive disease.  The decision to continue 
study treatment after the first evidence of disease progression is at the Investigator’s 
discretion based on the clinical status of the subject as described in Table 3-5 below.   
Table 3-5.  Imaging and Treatment After 1st Radiologic Evidence of Disease 
Progression 
Clinically Stable 
Clinically Unstable 
Tumor Imaging 
Treatment 
Tumor Imaging 
Treatment 
First radiologic 
evidence of PD 
Repeat imaging at 
> 4 weeks at site 
to confirm PD 
May continue study 
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site 
Repeat tumor imaging 
at > 4 
weeks to confirm PD 
per physician 
discretion only 
Discontinue treatment 
Repeat tumor 
imaging 
confirms 
PD 
No additional tumor 
imaging required 
 
Discontinue treatment 
No additional tumor 
imaging 
required 
N/A 


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Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease. 
 
In determining whether or not the tumor burden has increased or decreased, study 
site investigators should consider all target lesions as well as non-target lesions (if 
needed, the tip sheet provided in the study binder can be used as a reference to 
assess lesions).  Subjects that are deemed clinically unstable are not required to have 
repeat tumor imaging for confirmation.  If radiologic progression is confirmed by 
subsequent scan then the subject will be discontinued from trial treatment (or if on 
pembrolizumab alone arm may be eligible for cross over to receive acalabrutinib in 
addition to pembrolizumab).  If radiologic progression is not confirmed, then the 
subject should resume or continue assigned treatment and have their next tumor 
imaging according to the protocol schedule.   
NOTE:  If a subject has confirmed radiographic progression (ie, 2 scans at least 
4 weeks apart demonstrating progressive disease) per irRECIST, but the subject is 
achieving a clinically meaningful benefit, an exception to continue treatment may be 
considered following consultation with the Sponsor. 
irRECIST data will be collected in the clinical database. 
3.12 WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
Any subject has the right to withdraw from the study at any time. 
• 
Study treatment should be discontinued in the event of a toxicity lasting > 
28 consecutive days, unless reviewed and approved by the medical monitor.   
• 
Any subject who has confirmed objective evidence of cancer progression 
while receiving acalabrutinib and pembrolizumab should be discontinue study 
treatment.  Note:  Study subjects receiving immunotherapies can experience 
transient immunotherapy-related increases in lesion size 
(“pseudoprogression”) preceding tumor regression (Hodi 2010).  If there is 
uncertainty regarding whether there is true cancer progression, the subject 
may continue study treatment and remain under close observation (eg, 
Repeat tumor 
imaging shows 
SD, PR or CR 
Continue regularly 
scheduled 
tumor imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue regularly 
scheduled tumor 
imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
Investigator’s 
discretion 


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evaluated at 4-week intervals) pending confirmation of progression 
(Section 3.11). 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 should be done 
to determine 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 
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 case report form (CRF).   
3.13 REASONS FOR STUDY EXIT 
Reasons for study exit are: 
• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor to terminate the study 


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• 
Subject lost to follow-up 
• 
Death 
3.14 DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the sponsor’s Pharmacovigilance 
Committee procedures.  AEs and SAEs will be reviewed internally on an ongoing 
basis to identify safety concerns.  Monthly conference calls with the investigators and 
applicable site staff will be conducted to discuss study progress, obtain investigator 
feedback and exchange, and discuss "significant safety events" (ie, AEs leading to 
dose reductions, related SAEs, and deaths).  In addition, for the interim safety 
analysis, a mandatory safety teleconference will occur before the expansion phase of 
the protocol can open.  
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The Schedule of Assessments is provided in Appendix 4.  Descriptions of the 
scheduled evaluations are outlined below and complete information on study drug 
and dosing is provided in Section 3.4. 
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.  This study will primarily use central laboratory testing 
for safety laboratory evaluations.  Samples from sites’ local laboratories will be used if 
central laboratory testing is unavailable. 
4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the ICF approved by the IRB/IEC, 
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 


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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 28 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 28 days of the 
first dose of study drug. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 1. 
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 the 
screening ECG.  Before first dose of study drug on Day 1, Week 1, 3 ECGs will be 
done at least 1 minute apart.  These ECGs and the screening ECG will be considered 
the baseline ECGs.  If an unscheduled ECG is done at any time, then an electrolyte 


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panel (ie, calcium, magnesium, and potassium) must be done to coincide with the 
ECG testing. 
Single on-treatment ECGs will be done at any time during the following visits: 
• 
Week 2 
• 
Week 4 
• 
Week 7 
• 
Early termination and/or safety follow-up visit 
4.1.9 
Urine or Serum Pregnancy Test 
Pregnancy tests will be required only for women of childbearing potential.  Women of 
childbearing potential must have a negative urine or serum pregnancy testing within 
72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test is required.  
Testing will be done by a local or central laboratory as listed on the investigator’s 
Form FDA 1572. 
4.1.10 
Hematology 
Hematology studies must include complete blood count (CBC) with differential and 
platelet and reticulocyte counts.  Testing will be done by a local or 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, calcium, chloride, 
creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate, 
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 
local or 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 performed at the study center’s local 
laboratory or other clinical laboratory listed on the investigator’s form FDA 1572. 


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4.1.13 
Thyroid Panel 
The thyroid panel will include total triiodothyronine (T3), free thyroxine (T4), and 
thyroid stimulating hormone (TSH).  Testing will be done by a local or 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 hepatitis C (HCV) antibody.  In addition, 
any subjects testing positive for any hepatitis serology, must have PCR testing (see 
Appendix 4 and exclusion criterion #29).  Testing will be done by a local or central 
laboratory.   
Refer to Section 3.10.1 and Appendix 4 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 local or central laboratory as listed on the investigator’s 
Form FDA 1572.  
4.1.16 
T/B/NK Cell Count 
Flow cytometry testing will include CD3+, CD4+, CD8+, CD19+, and CD16/56+ cells.  
Testing will be done by a local or central laboratory as listed on the investigator’s 
Form FDA 1572. 
4.1.17 
Serum Immunoglobulin  
Testing for IgG, IgM, and IgA will be done by a local or central laboratory as listed on 
the investigator’s Form FDA 1572. 
4.1.18 
Pharmacodynamics/Pharmacokinetics and Biomarker 
Studies 
Blood samples will be used for PD testing (including, but not limited to, Btk 
occupancy, B-cell activation, MDSCs, and T-cell activation), cytokine analysis, and for 
further characterization of circulating tumor cells, lymphocyte and myeloid cell 
subsets.  
Tissue sections from archival tumor biopsies and/or any newly obtained biopsies 
performed during the study will be used for exploratory biomarker studies (including, 


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but not limited to, expression of PD-L1, characterization of disease subtype, and 
evaluations of MDSCs and activated CD8+ cells).  Additional exploratory studies may 
include, but are not necessarily limited to, characterization of Btk pathway activation 
status, identification disease subtype, specific genetic markers with prognostic 
significance and evaluation of tumor microenvironment components and cell cycle 
proteins in malignant cells.  De-identified pathology reports from the most recent 
diagnostic work-up, including immunohistochemistry and cytogenetic analyses of 
tumor tissue, will be requested by the sponsor. 
Refer to the laboratory manual for instructions on collection and shipment of the PD 
and biomarker samples.  All testing will be done by the sponsor or designee. Leftover 
blood and tumor samples may also be used for genomic analyses to study 
mechanisms of action. 
Blood sampling for PK analysis of acalabrutinib will be done on all subjects in the 
combination arm only and intensive PK will be on the first 6 subjects enrolled in the 
combination arm.  For these first 6 subjects, acalabrutinib will be administered alone 
on Day 1/Week 1.  Then on Day 2/Week 1 the first pembrolizumab infusion will be 
administered. When PK sampling is done at Week 3 and Week 7, the pembrolizumab 
infusion should begin within 10 minutes of ingesting acalabrutinib.  The PK sampling 
timepoints for these 6 subjects is as follows: 
Visit 
PK Sample Timepoints Relative to 
Acalabrutinib Administration 
Day 1, Week 1 
predose and 0.5, 1, 2, and 4 hours  
Day 2, Week 1 
predose 
Week 3 
predose and 0.5, 1, 2, and 4 hours postdose 
Week 7 
predose and 0.5, 1, 2, and 4 hours postdose 
For all other subjects enrolled in the combination arm, PK sampling will be done pre- 
and 1 hour postdose on Week 3.   
The predose sample can be taken up to 30 minutes before dosing.  The window for all 
other timepoints is ± 5 minutes.  Leftover plasma from PK analysis may be 
repurposed for exploratory acalabrutinib plasma metabolite analysis.  Testing will be 
done by a central lab.  Refer to the laboratory manual for instructions on collection 
and shipment of PK samples. 


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4.1.19 
Tumor Assessments 
A pretreatment computerized tomography (CT) scan with contrast (unless 
contraindicated) is required of the chest, abdomen, pelvis, head and neck (and any 
other disease area) within 30 days before the first dose of study drug.  
On-treatment CT scans with contrast (unless contraindicated) of the neck, chest and 
abdomen (and any other known or suspected sites of disease) will be done for tumor 
assessments at Week 7, 13, 19 (± 7 days) then every 3 months (± 10 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 6 for more details on RECIST 1.1).  Response will also 
be assessed by irRECIST (refer to Appendix 7 for more details). 
De-identified copies of all radiology results may be requested by the sponsor.   
4.1.20 
Early Termination Visit 
An early termination visit is required for safety assessments as outlined in the 
Schedule of Assessments (Appendix 4).  The early termination visit is not required for 
subjects who discontinue from the study within 10 days of a scheduled study visit. 
4.1.21 
Study Drug Accountability 
See Section 7.6. 
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. 


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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).   
Abbreviations: CR = complete response, PD = progressive disease, PR = partial response,  
SD = stable disease 
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. Refer to Section 3.11 
for more detailed information. 
 
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 timepoints specified in the Schedule of Assessments (Appendix 4). 
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).   
Abbreviations: CR = complete response, PD = progressive disease 
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.  
b. 
Refer to RECIST 1.1 criteria for detailed explanation of “unequivocal progression”. Refer to 
Section 3.11 for more detailed information. 
 
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.  


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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:  CR = complete response, PD = progressive disease, PR = partial response, SD = stable 
disease, NE = nonevaluable 
a. 
If a CR is truly met at first timepoint, then any disease seen at a subsequent timepoint, 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 timepoint.  Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
 
4.2.3 
Immune-related Response Criteria (irRECIST) 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics 
seen with treatment of pembrolizumab.  Immunotherapeutic agents such as 
pembrolizumab may produce antitumor effects by potentiating endogenous cancer-
specific immune responses.  The response patterns seen with such an approach may 
extend beyond the typical time course of responses seen with cytotoxic agents and 
can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  Standard RECIST may not provide an accurate response 
assessment of immunotherapeutic agents such as pembrolizumab.  Therefore, 
RECIST 1.1 will be used with the adaptations described for irRECIST (Appendix 7). 
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 


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(see Section 6.2.6) and to document the occurrence of any new events; unless, the 
subject receives a new anticancer therapy within this timeframe.  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 4) 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.  
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  
5.1 
GENERAL CONSIDERATIONS 
Descriptive statistics (including means, Std dev, and medians for continuous variables 
and proportions and CIs for discrete variables) will be used to summarize data as 
appropriate.  
For the interim safety 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 MTD.  The trial employs the standard National Cancer 
Institute definition of MTD (dose associated with DLT in ≤ 17% of subjects).  Provided 
the DLT review period is cleared in the combination arm and this arm is not stopped 
early for futility or toxicity (Section 5.5), then up to 
 will be added 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 40% in pembrolizumab/acalabrutinib arm and 18% in 
pembrolizumab arm.  
 each arm.  PASS version 11 was 
employed to conduct the sample size calculation. 


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5.2 
DEFINITION OF ANALYSIS SETS 
The following definitions will be used for the efficacy and safety analysis sets. 
Safety analysis set:  All enrolled subjects who receive ≥ 1 dose of study drug. 
Per-protocol (PP) analysis set:  All enrolled subjects who receive ≥ 1 dose of study 
drug, have sufficient baseline measurements, and undergo ≥ 1 assessment for the 
endpoint of interest (eg, response and PD parameters) after treatment. 
The safety analysis set will be used for evaluating the safety and efficacy parameters 
in this study (with the exception of assessment of duration of response).  The PP 
analysis sets will be analyzed for efficacy and PD parameters in this study. 
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 and events of clinical 
interest will be reported in each treatment group by Medical Dictionary for Regulatory 
Activities (MedDRA) System Organ Class and Preferred Term.  Summaries will also 
be presented by the severity of the AE (per Common Terminology Criteria for Adverse 
Events [CTCAE], v4.03) and by relationship to study drug (eg, either acalabrutinib, 
pembrolizumab, 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.   


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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 Drug Dictionary 
(WHODRUG). 
5.4.3 
Study Treatment Administration and Compliance 
Descriptive information will be provided regarding the number of acalabrutinib and 
pembrolizumab 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, acalabrutinib and pembrolizumab compliance will be described in 
terms of the proportion of study drug actually taken. 
5.4.4 
Analysis of Efficacy Parameters 
Disease Control and 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.  DCR will be defined 
as the proportion of subjects who achieve a SD, PR or CR.  ORR will be defined as 
the proportion of subjects who achieve a response (PR or CR see Section 4.2).  
DCR and ORR will be calculated and the corresponding 2-sided 95% CI will be 
derived.  
In addition to evaluation of DCR and ORR by RECIST 1.1 criteria (Eisenhauer 2009), 
these endpoints will also be evaluated by irRECIST criteria (Appendix 7), though the 
ORR by RECIST will be considered the primary endpoint. 
Duration of Response 
The DOR is 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 


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subjects will be censored and detailed censoring rules will be specified in the 
statistical analysis plan (SAP).  
In addition to evaluation of DOR by RECIST 1.1 criteria (Eisenhauer 2009), DOR will 
also be evaluated by irRECIST criteria (Appendix 7). 
Progression-free Survival 
PFS 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.  
In addition to evaluation of PFS by RECIST 1.1 criteria (Eisenhauer 2009), PFS will 
also be evaluated by irRECIST criteria (Appendix 7). 
Overall Survival 
OS is defined as the time from date of the 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.  The analysis methods 
for overall survival will be similar to those described for PFS.  
5.4.5 
PD, PK 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. 
5.5 
FUTILITY AND TOXICITY MONITORING 
The futility and toxicity monitoring will be analyzed in the combination arm (Arm 2) 
only as data become available.  Futility will be monitored by irDCR, which is defined 
as irCR, irPR, and irSD by irRECIST (Appendix 7).  irDCR of at least 20% is clinically 
meaningful in this population.  The response outcome within the 12 weeks will be 
used in the primary analysis.  A Bayesian method (Thall 1995) will be used for futility 
and toxicity monitoring for the combination arm.  The stopping rules are: 
Pr(θE< 0.2 |data)>0.95 


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Or 
Pr(TE > 0.3 | data)  > 0.90 
Enrollment in the combination arm will be stopped early if there is > 95% probability 
that the irDCR is < 20% or there is > 90% probability that the toxicity rate is higher 
than 30% in that arm.  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 (0.2, 0.8), and TE denotes the marginal toxicity rate, assuming that TE 
has a prior distribution of beta (a, b), where a and b represent toxicity and no toxicity 
(0.3, 0.7).  The definition of toxicity 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 
 have been evaluated in the combination arm and will use safety data as 
they become available.  The corresponding stopping boundaries for the futility 
monitoring are: enrollment will be stopped early due to futility if (number of subjects 
with irDCR/number subjects evaluated) ≤ 0/(10-15), 1/(16-23), 2/(24-30) and 3/(31-
37).  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 Toxicity Monitoring  
                  
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  
35-36  
15-36  
37 
Always stop due to maximum 
sample size 
 
Table 5-2.  Operating Characteristics of the Design 
irDCR 
Toxicity rate 
Probability of early stop 
Average # of subjects 
treated  
0.2 
0.1 
0.23  
32.1  
0.2 
0.3 
0.41  
28.2  
0.2 
0.5 
0.95  
14.8  
0.3 
0.1 
0.05  
35.9  
0.3 
0.3 
0.28  
31.3  
0.3 
0.5 
0.94  
15.5  
 
6.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording DLTs, 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 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 HNSCC 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. 
Abnormal laboratory values should not be reported as AEs; however, any clinically 
significant laboratory abnormalities (ie, those that require medical intervention or 
discontinuation or adjustment of study drug) will be reported as AEs. 
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 inpatient 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). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to 
a mother exposed to the investigational product. 


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• 
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 Complaint 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 unless a subject received a new 
anticancer therapy before the safety follow-up visit.  An exception to this reporting 
period is any AE occurring due to a protocol-defined screening procedure.  If a fatal 
AE occurs beyond 30 days after the last dose of acalabrutinib and/or pembrolizumab 
AND it is assessed by the investigator as related to acalabrutinib and/or 
pembrolizumab, 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 
timepoints 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 diagnostic term, 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 
relationship 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 
drugs?’  Answer Yes or No.  
See Appendix 3 for more detail on assessing relationship. 
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 acalabrutinib, 120 days after the last dose of pembrolizumab, or 
30 days after the last dose of either treatment if the subject initiates new anticancer 
therapy (whichever is earlier) 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 


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considered AEs.  Any SAEs associated with pregnancy (eg, congenital 
abnormalities/birth defects/spontaneous miscarriage or any other serious events) 
must be reported as such using the SAE report form. 
Subjects should be instructed to immediately notify the investigator of any 
pregnancies.  Any female subjects 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. 
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 using the protocol-specific electronic data 
capture system.  If electronic SAE reporting is not available, paper SAE/Product 
Complaint forms must 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). 
Whenever possible, SAEs should be reported by diagnosis term not as a constellation 
of symptoms.  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’s Brochure (ie, an unexpected event).  In this case, Acerta Pharma Drug 
Safety/Designee will forward a formal notification describing the suspected 
unexpected adverse reaction (SUSAR) to all investigators.  Each investigator must 
then notify his or her IRB/IEC of the SUSAR. 
Drug Safety Contact Information 
Fax: 
 


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Email: 
 
6.2.5 
Reporting Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be reported to the Sponsor. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject 
must be reported within 24 hours to the Sponsor if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, placebo treatment 
or a procedure. 
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not 
related to study drug must be reported within 24 hours to the Sponsor either by 
electronic media or paper as described in Section 6.2.4. 
Events of Clinical Interest for this trial include: 
1. An overdose of study drug (overdose is defined in Section 3.10.6) that is not 
associated with clinical symptoms or abnormal laboratory results.  
2. An elevated AST or ALT lab value that is ≥ 3 times the ULN and an elevated total 
bilirubin value that is ≥ 2 times ULN and, at the same time, an alkaline phosphatase 
value that is < 2X the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The guidance for 
assessment and follow up of these criteria can be found in the study binder provided 
separately from this protocol. 
6.2.6 
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. 


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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 
• 
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’s 
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 GCP guidelines 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 (Statement of Investigator) 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 


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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 with individual local and national patient 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 
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 


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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 
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 
Acalabrutinib capsules must be kept in a locked limited access cabinet or space. The 
study drug must not be used outside the context of the protocol. 
Study drug accountability records 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-006) 
2. 
subject identification number 
3. 
lot number(s) of acalabrutinib dispensed for that subject 


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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 
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 


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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 
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 


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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. 
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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9.0 
APPENDICES 
 
 
 
 
 
 


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Appendix 1. ECOG 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, MM, Creech, RH, Tormey, DC, Horton, J, Davis, TE, McFadden, ET, Carbone, PP: 
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 2.  Known Strong in Vivo Inhibitors or Inducers of CYP3A 
 
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 
 
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 
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. 
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for 
CYP3A 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 for CYP3A is defined as an inducer that results in ≥ 80% decrease in the AUC of a 
substrate for CYP3A. 
f. 
In vivo inducer of P-glycoprotein.   
 
 
 
 


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Appendix 3.  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 4.  Schedule of Assessments 
 
Treatment Phase (Weeks)b 
Safety 
Follow Visitc 
Follow-up 
Phased 
Study Weeks 
Screeninga 
1 
2 
3 
4 
5s 
6 
7 
8 
≥10 
(Q3W) 
ET 
+30 days 
after last 
dose 
Q12W 
Study Window 
-28 days 
± 3 days 
± 3 days 
+ 3 days 
+ 7 days 
± 10 days 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
PEe/Vital signsf/Weight 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 
ECOG status 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
ECGg 
x 
x 
x 
 
x 
 
 
x 
 
 
x 
x 
 
Lab assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
x 
xq 
 
 
x 
 
 
x 
 
x 
x 
x 
 
 
Hematologyi 
x 
xq 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 
 
Serum chemistryj 
x 
xq 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 
 
Serum lipase/amylase 
x 
xq 
 
 
x 
x 
 
x 
 
x 
x 
x 
 
 
Thyroid panelk 
x 
xq 
 
 
 
 
 
x 
 
Q6W 
x 
x 
 
 
Hepatitis serologyt 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRu 
 
 
 
 
x 
 
 
 
x 
QM 
 
 
QM 
 
Urinalysisl 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
T/B/NK cell countm 
 
xq 
 
 
 
 
 
xq 
 
Week 10 then 
Q3M 
 
 
 
 
Serum Ign 
 
xq 
 
 
 
 
 
xq 
 
Week 10 then 
Q3M 
 
 
 
 
Pharmacokineticsr 
 
x 
 
x 
 
 
 
x 
 
 
 
 
 
 
PD/Biomarkers 
Tumor 
sampleo 
xq 
xq 
xq 
xq 
 
 
xq 
 
Week 10 and 13 
onlyq 
Tumor 
sampleo 
 
 
Acalabrutinib 100 mg BID 
/pembrolizumab 200 mg 
Q3W 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Study drug compliance 
 
x 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
Tumor assessmentp 
x 
 
 
 
 
 
 
x 
 
Week 13 and 19 
then every 
12 weeks 
 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 
Adverse events 
 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
x 
x 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
 
Acerta Pharma 
Confidential 
Page 112 of 165 
Abbreviations: BID = twice per day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ET = early termination; HBV = hepatitis B virus; Ig = 
immunoglobulin; NK = natural killer; PCR = polymerase chain reaction; PE = physical examination; PD = pharmacodynamic; Q3M = every 3 months; Q12W = every 12 
weeks; Q3W = every 3 weeks; Q6W = every 6 weeks; QM = every month. 
Note:  Visits to the sites are not required on Week 6 and 8, but subjects will continue to take acalabrutinib 100 mg BID during those weeks. 
Footnotes for ACE-ST-006 Schedule of Study Activities: 
a.  Screening tests should be performed within 28 days before the first administration of study drug, unless otherwise indicated. 
b. 
Pembrolizumab treatment may be stopped earlier for confirmed complete response (CR) as described in the protocol. 
c. 
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. 
d. 
Subjects who discontinue study therapy will be followed for 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 be followed for tumor assessment until disease 
progression or initiation of any other anticancer therapies, whichever comes first. 
e. 
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.   
f. 
Vital signs (blood pressure, pulse, respiratory rate and temperature) will be assessed after the subject has rested in the sitting position.   
g. 
Subjects should be in supine position and resting for ≥ 10 minutes before study-related ECGs.  On Day 1, Week 1 predose ECGs will be done in triplicate ≥ 1 minute apart.  
At all other visits the single ECGs will be done at any time during the visit. 
h. 
Women of childbearing potential must have a negative urine or serum pregnancy testing within 72 hours prior to receiving the first dose of study medication.  If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test is required. 
i. 
Hematology includes complete blood count with differential and platelet and reticulocyte counts. Week 1 hematology does not need to be repeated if screening hematology 
was done within 7 days. 
j. 
Serum chemistry: albumin, alkaline phosphatase, alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), bone-specific 
alkaline phosphatase, calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate, potassium, sodium, total bilirubin, total protein, and uric 
acid. Week 1 serum chemistry does not need to be repeated if screening serum chemistry was within 7 days. 
k. 
Thyroid panel:  total triiodothyronine (T3), free thyroxine (T4), and thyroid stimulating hormone (TSH).  Week 1 thyroid panel does not need to be repeated if screening 
thyroid panel was within 7 days. 
l. 
Urinalysis: pH, ketones, specific gravity, bilirubin, blood, and glucose.  
m. T/B/NK cell count (ie, CD3, CD4, CD8, CD19, CD16/56).   
n. 
Serum immunoglobulin: IgG, IgM, IgA.   
o. 
Provide tissue sections from either an archived or newly obtained tumor sample (most recent biopsy) for biomarker analysis and whenever progression is confirmed.  Note:  
The biopsy at progression is optional. 
p. 
A pretreatment computed tomography (CT) scan with contrast (unless contraindicated) is required of the chest, abdomen, pelvis, head and neck and any other disease sites 
within 30 days before the first dose of study drug. CT scans will be done for tumor assessments at Week 7, 13, 19 (±7 days) and then every 12 weeks (± 10 days) or more 
frequently at the investigator’s discretion.  
q. 
The indicated samples at this timepoint must be drawn predose. 
r. 
Only subjects in Arm 2 will have PK sampling.  The first 6 subjects in Arm 2 will have PK samples drawn at Week 1 (Day 1 and Day 2), Week 3 and Week 7.  All other 
subjects in Arm 2 will only have PK samples drawn at Week 3.  Refer to Section 4.1.17 for complete instructions on the PK sampling timepoints. 
s. 
The Week 5 visit is only required for subjects who will contribute to the DLT assessment. 
t. 
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 #29).   
u. 
Subjects who are anti-HBc positive (or have a known history of HBV) 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. 
 
 


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
 
Acerta Pharma 
Confidential 
Page 113 of 165 
Appendix 5.  KEYTRUDA Package Insert 
 
 
 
 


KEYTRUDA- pembrolizumab injection, powder, lyophilized, for solution  
KEYTRUDA- pembrolizumab injection, solution  
Merck Sharp & Dohme Corp.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use KEYTRUDA safely and effectively. See full
prescribing information for KEYTRUDA. 
KEYTRUDA  (pembrolizumab) for injection, for intravenous use 
KEYTRUDA  (pembrolizumab) injection, for intravenous use 
Initial U.S. Approval: 2014
RECENT MAJOR CHANGES
Indications and Usage (1.2)
10/2015
Dosage and Administration (2.1, 2.3)
10/2015
Dosage and Administration (2.4)
01/2015
Warnings and Precautions (5.1, 5.2, 5.4, 5.6)
10/2015
Warnings and Precautions (5.4, 5.6, 5.7)
06/2015
INDICATIONS AND USAGE
KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of:
patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600
mutation positive, a BRAF inhibitor. (1.1)
patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who have
disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor
aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving
KEYTRUDA. (1.2)
These indications are approved under accelerated approval based on tumor response rate and durability of response. An
improvement in survival or disease-related symptoms has not yet been established. Continued approval for these
indications may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1.1, 1.2)
DOSAGE AND ADMINISTRATION
Administer 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks. (2.2)
Dilute prior to intravenous infusion. (2.4)
DOSAGE FORMS AND STRENGTHS
For injection: 50 mg lyophilized powder in single-use vial for reconstitution (3)
Injection: 100 mg/4 mL (25 mg/mL) solution in a single-use vial (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Immune-mediated Pneumonitis: Withhold for moderate, and permanently discontinue for severe, life-threatening or
recurrent moderate pneumonitis. (5.1)
Immune-mediated Colitis: Withhold for moderate or severe, and permanently discontinue for life-threatening colitis.
(5.2)
Immune-mediated Hepatitis: Monitor for changes in hepatic function. Based on severity of liver enzyme elevations,
withhold or discontinue. (5.3)
Immune-mediated Endocrinopathies (5.4):
Hypophysitis: Withhold for moderate and withhold or permanently discontinue for severe or life-threatening
hypophysitis.
Thyroid disorders: Monitor for changes in thyroid function. Withhold or permanently discontinue for severe or life-
threatening hyperthyroidism.
Type 1 diabetes mellitus: Monitor for hyperglycemia. Withhold KEYTRUDA in cases of severe hyperglycemia.
Immune-mediated nephritis: Monitor for changes in renal function. Withhold for moderate, and permanently
discontinue for severe or life-threatening nephritis. (5.5)
Infusion-related reactions: Stop infusion and permanently discontinue KEYTRUDA for severe or life-threatening
®
®


infusion reactions. (5.7)
Embryofetal toxicity: KEYTRUDA can cause fetal harm. Advise females of reproductive potential of the potential risk to
a fetus. (5.8)
ADVERSE REACTIONS
Most common adverse reactions (reported in ≥20% of patients) with:
melanoma included fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.
(6.1)
NSCLC included fatigue, decreased appetite, dyspnea and cough. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck &
Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Lactation: Discontinue nursing or discontinue KEYTRUDA. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Melanoma
1.2 Non-Small Cell Lung Cancer
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
2.2 Recommended Dosing
2.3 Dose Modifications
2.4 Preparation and Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Immune-Mediated Pneumonitis
5.2 Immune-Mediated Colitis
5.3 Immune-Mediated Hepatitis
5.4 Immune-Mediated Endocrinopathies
5.5 Immune-Mediated Nephritis and Renal Dysfunction
5.6 Other Immune-Mediated Adverse Reactions
5.7 Infusion-Related Reactions
5.8 Embryofetal Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic 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
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Melanoma
14.2 Non-Small Cell Lung Cancer
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Melanoma
KEYTRUDA  (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic
melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a
BRAF inhibitor [see Clinical Studies (14.1)].
This indication is approved under accelerated approval based on tumor response rate and durability of
response. An improvement in survival or disease-related symptoms has not yet been established.
Continued approval for this indication may be contingent upon verification and description of clinical
benefit in the confirmatory trials.
1.2 Non-Small Cell Lung Cancer
KEYTRUDA is indicated for the treatment of patients with metastatic non-small cell lung cancer
(NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease
progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor
aberrations should have disease progression on FDA-approved therapy for these aberrations prior to
receiving KEYTRUDA [see Clinical Studies (14.2)].
This indication is approved under accelerated approval based on tumor response rate and durability of
response. An improvement in survival or disease-related symptoms has not yet been established.
Continued approval for this indication may be contingent upon verification and description of clinical
benefit in the confirmatory trials.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients for second line or greater treatment of metastatic NSCLC with KEYTRUDA based on
the presence of positive PD-L1 expression [see Clinical Studies (14.2)]. Information on FDA-approved
tests for the detection of PD-L1 expression in NSCLC is available at:
http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dosing
The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30
Sections or subsections omitted from the full prescribing information are not listed.
®


minutes every 3 weeks until disease progression or unacceptable toxicity.
2.3 Dose Modifications
Withhold KEYTRUDA for any of the following:
Grade 2 pneumonitis [see Warnings and Precautions (5.1)]
Grade 2 or 3 colitis [see Warnings and Precautions (5.2)]
Grade 3 or 4 endocrinopathies [see Warnings and Precautions (5.4)]
Grade 2 nephritis [see Warnings and Precautions (5.5)]
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times
upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN
Any other severe or Grade 3 treatment-related adverse reaction [see Warnings and Precautions (5.6)]
Resume KEYTRUDA in patients whose adverse reactions recover to Grade 0-1.
Permanently discontinue KEYTRUDA for any of the following:
Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone
replacement therapy)
Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity [see Warnings and
Precautions (5.1)]
Grade 3 or 4 nephritis [see Warnings and Precautions (5.5)]
AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN
For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or
ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week
Grade 3 or 4 infusion-related reactions [see Warnings and Precautions (5.7)]
Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within
12 weeks
Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone
replacement therapy) that do not recover to Grade 0-1 within 12 weeks after last dose of
KEYTRUDA
Any severe or Grade 3 treatment-related adverse reaction that recurs [see Warnings and Precautions
(5.6)]
2.4 Preparation and Administration
Reconstitution of KEYTRUDA for Injection (Lyophilized Powder)
Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial and
not directly on the lyophilized powder (resulting concentration 25 mg/mL).
Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.
Preparation for Intravenous Infusion
Visually inspect the solution for particulate matter and discoloration prior to administration. The
solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible
particles are observed.
Dilute KEYTRUDA injection (solution) or reconstituted lyophilized powder prior to intravenous
administration.
Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an intravenous (IV)
bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted
solution by gentle inversion. The final concentration of the diluted solution should be between 1
mg/mL to 10 mg/mL.
Discard any unused portion left in the vial.
Storage of Reconstituted and Diluted Solutions


The product does not contain a preservative.
Store the reconstituted and diluted solution from the KEYTRUDA 50 mg vial either:
At room temperature for no more than 6 hours from the time of reconstitution. This includes room
temperature storage of reconstituted vials, storage of the infusion solution in the IV bag, and the
duration of infusion.
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of
reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to
administration.
Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either:
At room temperature for no more than 6 hours from the time of dilution. This includes room
temperature storage of the infusion solution in the IV bag, and the duration of infusion.
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of
dilution. If refrigerated, allow the diluted solution to come to room temperature prior to
administration.
Do not freeze.
Administration
Administer infusion solution intravenously over 30 minutes through an intravenous line containing a
sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
Do not co-administer other drugs through the same infusion line.
3 DOSAGE FORMS AND STRENGTHS
For injection: 50 mg lyophilized powder in a single-use vial for reconstitution
Injection: 100 mg/4 mL (25 mg/mL) solution in a single-use vial
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Immune-Mediated Pneumonitis
Pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Monitor patients for
signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic
imaging and administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent
followed by a taper) for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for moderate (Grade
2) pneumonitis, and permanently discontinue KEYTRUDA for severe (Grade 3) or life-threatening
(Grade 4) or recurrent moderate (Grade 2) pneumonitis [see Dosage and Administration (2.3) and Adverse
Reactions (6.1)].
Melanoma
Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%)
and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to development
of pneumonitis was 5 months (range 0.3 weeks to 9.9 months). The median duration was 4.9 months
(range 1 week to 14.4 months). Five of eight patients with Grade 2 and the one patient with Grade 3
pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to
40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of
high-dose corticosteroid treatment was 63.4 mg/day of prednisone or equivalent with a median duration
of treatment of 3 days (range 1 to 34) followed by a corticosteroid taper. Pneumonitis led to


discontinuation of KEYTRUDA in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the
nine patients with Grade 2-3 pneumonitis.
NSCLC
Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4
(0.4%), or 5 (0.2%) pneumonitis in patients, receiving KEYTRUDA in Trial 1. The median time to
development of pneumonitis was 1.7 months (range 0.6 weeks to 12.9 months). In patients receiving
KEYTRUDA 10 mg/kg every 2 weeks, the median time to development of pneumonitis was shorter (1.5
months) compared with patients receiving 10 mg/kg every 3 weeks (3.5 months). Sixteen of the 19
patients (84%) received corticosteroids, with 14 of the 19 (74%) requiring high-dose systemic
corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day). The median starting
dose of high-dose corticosteroid treatment for these fourteen patients was 60 mg/day with a median
duration of treatment of 8 days (range 1 day to 4.2 months). The median duration of pneumonitis was 1.2
months (range 0.7 weeks to 12.4 months). Pneumonitis occurred more frequently in patients with a
history of asthma/chronic obstructive pulmonary disease (5.4%) than in patients without a history of
these diseases (3.1%). Pneumonitis occurred more frequently in patients with a history of prior thoracic
radiation (6.0%) than in patients who did not receive prior thoracic radiation (2.6%). Pneumonitis led to
discontinuation of KEYTRUDA in 12 (2.2%) patients. Pneumonitis completely resolved in 9 patients.
Pneumonitis was reported as ongoing in 9 patients and one patient with ongoing pneumonitis died within
30 days of the last dose of pembrolizumab.
5.2 Immune-Mediated Colitis
Colitis occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis.
Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a
taper) for Grade 2 or greater colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade
3) colitis, and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis [see Dosage
and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases
in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to
onset of colitis was 6.5 months (range 2.3 to 9.8). The median duration was 2.6 months (range 0.6 weeks
to 3.6 months). All three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids
(greater than or equal to 40 mg prednisone or equivalent per day) with a median initial dose of 70
mg/day of prednisone or equivalent; the median duration of initial treatment was 7 days (range 4 to 41),
followed by a corticosteroid taper. One patient (0.2%) required permanent discontinuation of
KEYTRUDA due to colitis. All four patients with colitis experienced complete resolution of the event.
NSCLC
Colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients
receiving KEYTRUDA in Trial 1. The median time to onset of colitis was 1.6 months (range 4 weeks to
2.2 months) and the median duration was 16 days (range 1.0 weeks to 1.3 months).Two patients were
started on high-dose corticosteroids (≥40 mg/day of prednisone or equivalent) and two patients were
started on low dose corticosteroids. One patient (0.2%) discontinued KEYTRUDA due to colitis.
Three patients with colitis experienced complete resolution of the event.
5.3 Immune-Mediated Hepatitis
Hepatitis occurred in patients receiving KEYTRUDA. Monitor patients for changes in liver function.
Administer corticosteroids (initial dose of 0.5 to 1 mg/kg/day [for Grade 2 hepatitis] and 1 to 2
mg/kg/day [for Grade 3 or greater hepatitis] prednisone or equivalent followed by a taper) and, based on
severity of liver enzyme elevations, withhold or discontinue KEYTRUDA [see Dosage and
Administration (2.3) and Adverse Reactions (6.1)].


Melanoma
Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4
case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The time to onset was 22 days for the case
of Grade 4 hepatitis which lasted 1.1 months. The patient with Grade 4 hepatitis permanently
discontinued KEYTRUDA and was treated with high-dose (greater than or equal to 40 mg prednisone
or equivalent per day) systemic corticosteroids followed by a corticosteroid taper. Both patients with
hepatitis experienced complete resolution of the event.
5.4 Immune-Mediated Endocrinopathies
Hypophysitis
Hypophysitis occurred in patients receiving KEYTRUDA. Monitor for signs and symptoms of
hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and
hormone replacement as clinically indicated. Withhold KEYTRUDA for moderate (Grade 2)
hypophysitis and withhold or discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade
4) hypophysitis [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 4 case
(0.2% each), in patients receiving KEYTRUDA in Trial 1. The time to onset was 1.7 months for the
patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 hypophysitis. Both
patients were treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per day)
corticosteroids followed by a corticosteroid taper and remained on a physiologic replacement dose.
NSCLC
In Trial 1, hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. The time
to onset was 3.7 months. The patient was treated with systemic corticosteroids and physiologic
hormone replacement therapy. The patient did not discontinue KEYTRUDA due to hypophysitis.
Thyroid Disorders
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid
function (at the start of treatment, periodically during treatment, and as indicated based on clinical
evaluation) and for clinical signs and symptoms of thyroid disorders.
Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides
and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for severe (Grade 3) or life-
threatening (Grade 4) hyperthyroidism [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1
(0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. The median time to onset was 1.5
months (range 0.5 to 2.1). The median duration was 2.8 months (range 0.9 to 6.1). One of two patients
with Grade 2 and the one patient with Grade 3 hyperthyroidism required initial treatment with high-dose
corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a
corticosteroid taper. One patient (0.2%) required permanent discontinuation of KEYTRUDA due to
hyperthyroidism. All five patients with hyperthyroidism experienced complete resolution of the event.
Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient,
receiving KEYTRUDA in Trial 1. The median time to onset of hypothyroidism was 3.5 months (range
0.7 weeks to 19 months). All but two of the patients with hypothyroidism were treated with long-term
thyroid hormone replacement therapy. The other two patients only required short-term thyroid hormone
replacement therapy. No patient received corticosteroids or discontinued KEYTRUDA for management
of hypothyroidism.
NSCLC


Hyperthyroidism occurred in 10 (1.8%) of 550 patients receiving KEYTRUDA in Trial 1, including
Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. The median time to onset was 1.8 months (range 2 days to
3.4 months), and the median duration was 4.5 months (range 4 weeks to 7.5 months). No patients
discontinued KEYTRUDA due to hyperthyroidism.
Hypothyroidism occurred in 38 (6.9%) of 550 patients receiving KEYTRUDA in Trial 1, including
Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. The median time to onset was 4.2 months (range 2.9 weeks
to 11.2 months), and the median duration was 5.8 months (range 1.6 weeks to 22.8 months). No patients
discontinued KEYTRUDA due to hypothyroidism.
Type 1 Diabetes mellitus
Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving
KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer
insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients
with severe hyperglycemia [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
5.5 Immune-Mediated Nephritis and Renal Dysfunction
Nephritis occurred in patients receiving KEYTRUDA. Monitor patients for changes in renal function.
Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a
taper) for Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2), and permanently
discontinue KEYTRUDA for severe (Grade 3) or life-threatening (Grade 4) nephritis [see Dosage and
Administration (2.3) and Adverse Reactions (6.1)].
Melanoma
Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%)
and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. The time
to onset of autoimmune nephritis was 11.6 months after the first dose of KEYTRUDA (5 months after
the last dose) and lasted 3.2 months; this patient did not have a biopsy. Acute interstitial nephritis was
confirmed by renal biopsy in two patients with Grades 3-4 renal failure. All three patients fully
recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg
prednisone or equivalent per day) followed by a corticosteroid taper.
5.6 Other Immune-Mediated Adverse Reactions
Other clinically important immune-mediated adverse reactions can occur.
For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or
exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and
administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and
continue to taper over at least 1 month. Resume KEYTRUDA when the immune-mediated adverse
reaction remains at Grade 1 or less following steroid taper. Permanently discontinue KEYTRUDA for
any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening
immune-mediated adverse reaction [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].
Across clinical studies with KEYTRUDA, the following clinically significant, immune-mediated
adverse reactions have occurred: bullous pemphigoid and Guillain-Barré syndrome.
Melanoma
The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of
patients treated with KEYTRUDA in Trial 1: exfoliative dermatitis, uveitis, arthritis, myositis,
pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain
parenchyma.
NSCLC
The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of


550 patients with NSCLC treated with KEYTRUDA in Trial 1: rash, vasculitis, hemolytic anemia, serum
sickness and myasthenia gravis.
5.7 Infusion-Related Reactions
Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients
receiving KEYTRUDA across the clinical development program employing various doses and
schedules and enrolling patients with various solid tumors. Monitor patients for signs and symptoms of
infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension,
hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions,
stop infusion and permanently discontinue KEYTRUDA [see Dosage and Administration (2.3)].
5.8 Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant
woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through
induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the
patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
Advise females of reproductive potential to use highly effective contraception during treatment with
KEYTRUDA and for 4 months after the last dose of KEYTRUDA [see Use in Specific Populations (8.1,
8.3)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling.
Immune-mediated pneumonitis [see Warnings and Precautions (5.1)].
Immune-mediated colitis [see Warnings and Precautions (5.2)].
Immune-mediated hepatitis [see Warnings and Precautions (5.3)].
Immune-mediated endocrinopathies [see Warnings and Precautions (5.4)].
Immune-mediated nephritis and renal dysfunction [see Warnings and Precautions (5.5)].
Other immune-mediated adverse reactions [see Warnings and Precautions (5.6)].
Infusion-related reactions [see Warnings and Precautions (5.7)].
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 practice.
The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to
KEYTRUDA in an uncontrolled, open-label, multiple cohort trial (Trial 1). In Trial 1, the safety data are
available from 411 patients with unresectable or metastatic melanoma and 550 patients with metastatic
NSCLC who received KEYTRUDA at either 2 mg/kg every 3 weeks (n=61) or 10 mg/kg every 2 or 3
weeks (n=489).
Metastatic Melanoma
Among the 411 patients with metastatic melanoma enrolled in Trial 1, the median duration of exposure to
KEYTRUDA was 6.2 months (range 1 day to 24.6 months) with a median of 10 doses (range 1 to 51).
The study population characteristics were: median age of 61 years (range 18 to 94), 39% age 65 years
or older, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated
LDH, 54% with prior exposure to ipilimumab, and 47% with two or more prior systemic therapies for
advanced or metastatic disease.
KEYTRUDA was discontinued for adverse reactions in 9% of the 411 patients. Adverse reactions,
reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal
failure, and pain. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The


most frequent serious adverse drug reactions reported in 2% or more of patients in Trial 1 were renal
failure, dyspnea, pneumonia, and cellulitis.
Table 1 presents adverse reactions identified from analyses of 89 patients with unresectable or
metastatic melanoma who received KEYTRUDA 2 mg/kg every three weeks in one cohort of Trial 1.
Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600
mutation positive, a BRAF inhibitor. This cohort of Trial 1 excluded patients with severe immune-
related toxicity related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with
corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day
prednisone or equivalent dose) for greater than 12 weeks; a medical condition that required systemic
corticosteroids or other immunosuppressive medication; a history of pneumonitis or interstitial lung
disease; or any active infection requiring therapy, including HIV or hepatitis B or C. Of the 89 patients
in this cohort, the median age was 59 years (range 18 to 88), 33% were age 65 years or older, 53%
were male, 98% were white, 44% had an elevated LDH, 84% had Stage M1c disease, 8% had brain
metastases, and 70% received two or more prior therapies for advanced or metastatic disease. The
median duration of exposure to KEYTRUDA was 6.2 months (range 1 day to 15.3 months) with a median
of nine doses (range 1 to 23). Fifty-one percent of patients were exposed to KEYTRUDA for greater
than 6 months and 21% for greater than 1 year.
KEYTRUDA was discontinued for adverse reactions in 6% of the 89 patients. The most common
adverse reactions (reported in at least 20% of patients) were fatigue, cough, nausea, pruritus, rash,
decreased appetite, constipation, arthralgia, and diarrhea.
Table 1: Adverse Reactions in ≥10% of Patients with Unresectable or Metastatic
Melanoma
KEYTRUDA
2 mg/kg every 3 weeks
N=89
Adverse Reaction
All Grades
(%)
Grade 3  
(%)
General Disorders and Administration Site Conditions
  Fatigue
47
7
  Peripheral Edema
17
1
  Chills
14
0
  Pyrexia
11
0
Gastrointestinal Disorders
  Nausea
30
0
  Constipation
21
0
  Diarrhea
20
0
  Vomiting
16
0
  Abdominal pain
12
0
Respiratory, Thoracic and Mediastinal Disorders
  Cough
30
1
  Dyspnea
18
2
Skin and Subcutaneous Tissue Disorders
  Pruritus
30
0
  Rash
29
0
  Vitiligo
11
0
Metabolism and Nutrition Disorders
  Decreased appetite
26
0
Musculoskeletal and Connective Tissue Disorders
*


*
  Arthralgia
20
0
  Pain in extremity
18
1
  Myalgia
14
1
  Back pain
12
1
Nervous System Disorders
  Headache
16
0
  Dizziness
11
0
Blood and Lymphatic System Disorders
  Anemia
14
5
Psychiatric Disorders
  Insomnia
14
0
Infections and Infestations
  Upper respiratory tract infection
11
1
Other clinically important adverse reactions observed in up to 10% of patients treated with
KEYTRUDA were:
Infections and infestations: sepsis
Table 2: Laboratory Abnormalities Worsened from Baseline in ≥20% of
Patients with Unresectable or Metastatic Melanoma
KEYTRUDA
2 mg/kg every 3 weeks
N=89
*
Laboratory Test
All Grades
%
Grades 3-4
%
Chemistry
  Hyperglycemia
40
2
  Hyponatremia
35
9
  Hypoalbuminemia
34
0
  Hypertriglyceridemia
25
0
  Increased Aspartate
Aminotransferase
24
2
  Hypocalcemia
24
1
Hematology
  Anemia
55
8
NSCLC
Among the 550 patients with metastatic NSCLC enrolled in Trial 1, the median duration of therapy was
2.8 months (range: 1 day to 25.6 months). Patients with NSCLC and autoimmune disease, a medical
condition that required immunosuppression, or who had received more than 30 Gy of thoracic radiation
within the prior 26 weeks were ineligible for Trial 1. The median age of patients was 64 years (range:
28 to 93), 47% were age 65 years or older, 53% were male, 83% were white, and 67% received two or
more prior systemic treatments. Disease characteristics were Stage III (4%), Stage IV (96%), and brain
metastases (11%). Baseline ECOG performance status was 0 (35%) or 1 (65%).
There were no Grade 5 adverse reactions reported. Of the ≥10% adverse reactions, none was
reported as Grade 4.
Grade 4 abnormalities in this table limited to hyperglycemia, increased aspartate
aminotransferase, and anemia (one patient each)
*
*
*


KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions
occurred in 38% of patients receiving KEYTRUDA. The most frequent serious adverse reactions
reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and
pneumonitis. The incidence of adverse reactions, including serious adverse reactions, was similar
between the two 10 mg/kg dosing schedules; therefore, these data were pooled. The majority of
patients treated with KEYTRUDA 2 mg/kg every three weeks had shorter follow-up compared with
patients treated with the 10 mg/kg schedules; therefore, comparisons of adverse reactions between
doses were not appropriate.
Table 3 summarizes adverse reactions that occurred in at least 10% of patients. The most common
adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, dyspnea, and
cough.
Table 3: Adverse Reactions in ≥10% of Patients with NSCLC
KEYTRUDA
2 mg/kg every 3 weeks
or 10 mg/kg every 2 or 3
weeks
N=550
Adverse Reaction
All Grades
(%)
Grade 3  
(%)
*
†
‡
§
General Disorders and Administration Site Conditions
  Fatigue
44
4
  Pyrexia
12
1
  Peripheral Edema
10
0
Metabolism and Nutrition Disorders
  Decreased appetite
25
1
Respiratory, Thoracic and Mediastinal Disorders
  Dyspnea
23
4
  Cough
29
<1
Gastrointestinal Disorders
  Nausea
18
1
  Diarrhea
15
1
  Constipation
15
<1
  Vomiting
12
1
Musculoskeletal and Connective Tissue Disorders
  Arthralgia
15
1
  Back pain
10
2
Blood and Lymphatic System Disorders
  Anemia
12
2
Skin and Subcutaneous Tissue Disorders
  Pruritus
12
0
  Rash
18
<1
Table 4: Laboratory Abnormalities Worsened from Baseline in ≥20% of
*
Of the ≥10% adverse reactions, none was reported as Grade 4 or 5.
Includes the terms fatigue and asthenia
Includes the terms cough, productive cough and hemoptysis
Includes the terms dermatitis, dermatitis acneiform, erythema multiforme, drug eruption, rash,
rash generalized, rash pruritic, rash macular/maculo-papular, papular
†
‡
§


Patients with NSCLC
KEYTRUDA
N=550
Laboratory Test
All Grades
%
Grades 3-4
%
*
Chemistry
  Hyperglycemia
48
3
  Hyponatremia
38
6
  Hypoalbuminemia
32
1
  Increased alkaline
phosphatase
26
1
  Hypertriglyceridemia
23
0
  Increased aspartate
aminotransferase
20
1
  Hypercholesterolemia
20
1
Hematology
  Anemia
36
2
6.2 Immunogenicity
As with all therapeutic proteins, there is the potential for immunogenicity. Because trough levels of
pembrolizumab interfere with the electrochemiluminescent (ECL) assay results, a subset analysis was
performed in the patients with a concentration of pembrolizumab below the drug tolerance level of the
anti-product antibody assay. In this analysis, none of the 225 patients who were treated with 2 mg/kg
every 3 weeks tested positive for treatment-emergent anti-pembrolizumab antibodies.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay
may be influenced by several factors including assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease. For these reasons, comparison of
incidence of antibodies to KEYTRUDA with the incidences of antibodies to other products may be
misleading.
7 DRUG INTERACTIONS
No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant
woman. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of
pregnancy through induction of maternal immune tolerance to fetal tissue [see Data]. Human IgG4
(immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be
transmitted from the mother to the developing fetus. There are no available human data informing the
risk of embryo-fetal toxicity. Apprise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
Grade 4 abnormalities in this table limited to hyperglycemia (n=4),
hypercholesterolemia (n=3), and anemia (n=1).
*
*
*


clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on
reproduction and fetal development, but an assessment of the effects on reproduction was provided. A
central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune
tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to
disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of
administering KEYTRUDA during pregnancy include increased rates of abortion or stillbirth. As
reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the
offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice.
Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing
immune-mediated disorders or of altering the normal immune response.
8.2 Lactation
Risk Summary
It is not known whether KEYTRUDA is excreted in human milk. No studies have been conducted to
assess the impact of KEYTRUDA on milk production or its presence in breast milk. Because many
drugs are excreted in human milk, instruct women to discontinue nursing during treatment with
KEYTRUDA and for 4 months after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant
woman [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)]. Advise females of
reproductive potential to use effective contraception during treatment with KEYTRUDA and for at least
4 months following the final dose.
8.4 Pediatric Use
Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.
8.5 Geriatric Use
Of the 411 patients with melanoma treated with KEYTRUDA, 39% were 65 years and over. No overall
differences in safety or efficacy were reported between elderly patients and younger patients.
Of the 550 patients with NSCLC treated with KEYTRUDA, 47% were 65 years and over. No overall
differences in safety or efficacy were reported between elderly patients and younger patients.
8.6 Renal Impairment
Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with renal
impairment [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with mild
hepatic impairment [total bilirubin (TB) less than or equal to ULN and AST greater than ULN or TB
greater than 1 to 1.5 times ULN and any AST]. KEYTRUDA has not been studied in patients with
moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN
and any AST) hepatic impairment [see Clinical Pharmacology (12.3)].


10 OVERDOSAGE
There is no information on overdosage with KEYTRUDA.
11 DESCRIPTION
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its
ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate
molecular weight of 149 kDa.
KEYTRUDA for injection is a sterile, preservative-free, white to off-white lyophilized powder in
single-use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of
reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg),
polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to
adjust pH to 5.5.
KEYTRUDA injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly
yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg of
pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is
formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection,
USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell
proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and
signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of
tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its
interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response,
including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity
resulted in decreased tumor growth.
12.3 Pharmacokinetics
The pharmacokinetics of pembrolizumab was studied in 1645 patients who received doses of 1 to 10
mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on population pharmacokinetic analyses in
patients with solid tumors, the geometric mean [% coefficient of variation (CV%)] for clearance,
steady-state volume of distribution, and terminal half-life were 209 mL/day (38%), 7.75 L (20%) and 28
days (41%), respectively.
Steady-state concentrations of pembrolizumab were reached by 18 weeks of repeated dosing with an
every 3-week regimen and the systemic accumulation was approximately 2-fold. The peak concentration
(C
), trough concentration (C
), and area under the plasma concentration versus time curve at steady
state (AUC ) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every
3 weeks.
Specific Populations: The effects of various covariates on the pharmacokinetics of pembrolizumab were
assessed in population pharmacokinetic analyses. The CL of pembrolizumab increased with increasing
body weight; the resulting exposure differences were adequately addressed by the administration of a
weight-based dose. The following factors had no clinically important effect on the CL of
pembrolizumab: age (range 15 to 94 years), gender, renal impairment, mild hepatic impairment, and tumor
burden. The effect of race could not be assessed due to limited data available in non-White patients.
Renal Impairment: The effect of renal impairment on the CL of pembrolizumab was evaluated by
population pharmacokinetic analyses in patients with various solid tumors and mild (eGFR 60 to 89
max
min
ss


mL/min/1.73 m ; n=705), moderate (eGFR 30 to 59 mL/min/1.73 m ; n=159), or severe (eGFR 15 to 29
mL/min/1.73 m ; n=4) renal impairment compared to patients with normal (eGFR greater than or equal to
90 mL/min/1.73 m ; n=756) renal function. No clinically important differences in the CL of
pembrolizumab were found between patients with renal impairment and patients with normal renal
function [see Use in Specific Populations (8.6)].
Hepatic Impairment: The effect of hepatic impairment on the CL of pembrolizumab was evaluated by
population pharmacokinetic analyses in patients with various solid tumors and mild hepatic impairment
(TB less than or equal to ULN and AST greater than ULN or TB between 1 and 1.5 times ULN and any
AST; n=192) compared to patients with normal hepatic function (TB and AST less than or equal to ULN;
n=1407). No clinically important differences in the CL of pembrolizumab were found between patients
with mild hepatic impairment and normal hepatic function. There is insufficient information to determine
whether there are clinically important differences in the CL of pembrolizumab in patients with moderate
or severe hepatic impairment [see Use in Specific Populations (8.7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to test the potential of pembrolizumab for carcinogenicity or
genotoxicity.
Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose
toxicology studies in monkeys, there were no notable effects in the male and female reproductive
organs; however, most animals in these studies were not sexually mature.
13.2 Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-1 signaling resulted in an increased severity of some infections and
enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly
decreased survival compared with wild-type controls, which correlated with increased bacterial
proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown
decreased survival following infection with lymphocytic choriomeningitis virus (LCMV).
Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection
resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT,
which persisted for at least 1 month after discontinuation of pembrolizumab.
14 CLINICAL STUDIES
14.1 Melanoma
The efficacy of KEYTRUDA was investigated in a multicenter, open-label, randomized (1:1), dose-
comparative, activity-estimating cohort of Trial 1. Key eligibility criteria were unresectable or
metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3
mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease
progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with
autoimmune disease; a medical condition that required immunosuppression; and a history of severe
immune-mediated adverse reactions with ipilimumab, defined as any Grade 4 toxicity requiring treatment
with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day
prednisone or equivalent dose) for greater than 12 weeks. Patients were randomized to receive 2 mg/kg
(n=89) or 10 mg/kg (n=84) of KEYTRUDA every 3 weeks until unacceptable toxicity or disease
progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with
a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Assessment of
tumor status was performed every 12 weeks. The major efficacy outcome measures were confirmed
overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
2
2
2
2


as assessed by blinded independent central review and duration of response.
Among the 173 patients enrolled, the median age was 61 years (36% age 65 or older); 60% male; 97%
White; and 66% and 34% with an ECOG performance status 0 and 1, respectively. Disease
characteristics were BRAF V600 mutation (17%), elevated lactate dehydrogenase (39%), M1c (82%),
brain metastases (9%), and two or more prior therapies for advanced or metastatic disease (73%).
The ORR was 24% (95% confidence interval: 15, 34) in the 2 mg/kg arm, consisting of 1 complete
response and 20 partial responses. Among the 21 patients with an objective response, 3 (14%) had
progression of disease 2.8, 2.9, and 8.2 months after initial response. The remaining 18 patients (86%)
had ongoing responses with durations ranging from 1.4+ to 8.5+ months, which included 8 patients with
ongoing responses of 6 months or longer. One additional patient developed two new asymptomatic
lesions at the first tumor assessment concurrent with a 75% decrease in overall tumor burden;
KEYTRUDA was continued and this reduction in tumor burden was durable for 5+ months.
There were objective responses in patients with and without BRAF V600 mutation-positive melanoma.
Similar ORR results were observed in the 10 mg/kg arm.
14.2 Non-Small Cell Lung Cancer
The efficacy of KEYTRUDA was investigated in a sub-group of a cohort of 280 patients enrolled in a
multicenter, open-label multi-cohort, activity-estimating study (Trial 1). The cohort consisted of
patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if
appropriate, targeted therapy for ALK or EGFR mutations and any evidence of PD-L1 expression by a
clinical trial immunohistochemistry assay. Patients with autoimmune disease; a medical condition that
required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the
prior 26 weeks were ineligible.
A prospectively defined sub-group was retrospectively analyzed using an analytically validated test for
PD-L1 expression tumor proportion score (TPS). This retrospectively identified sub-group of 61
patients accounts for 22% of the 280 patients in the cohort. Patients included in this sub-group had a
PD-L1 expression TPS of greater than or equal to 50% tumor cells as determined by the PD-L1 IHC
22C3 pharmDx Kit. Patients received KEYTRUDA 10 mg/kg every 2 (n=27) or 3 (n=34) weeks until
unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required
urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks
with repeat imaging. Assessment of tumor status was performed every 9 weeks. The major efficacy
outcome measures were ORR according to RECIST 1.1 as assessed by blinded independent central
review (IRC) and duration of response.
Among the 61 patients with a TPS greater than or equal to 50%, the baseline characteristics were:
median age 60 years (34% age 65 or older); 61% male; 79% White; and 34% and 64% with an ECOG
performance status 0 and 1, respectively. Disease characteristics were squamous (21%) and non-
squamous (75%); M1 (98%); brain metastases (11%); one (26%), two (30%), or three or more (44%)
prior therapies; and the incidence of genomic aberrations was EGFR (10%) or ALK (0%).
Efficacy results are summarized in Table 5. The ORR and duration of response were similar regardless
of schedule (every 2 weeks or every 3 weeks) and thus the data below are pooled.
Table 5: Efficacy Results
Endpoint
N=61
Overall Response Rate
  ORR %, (95% CI)
41% (29, 54)
    Complete Response
0%
    Partial Response
41%


Among the 25 responding patients, 21 (84%) patients had ongoing responses at the final analysis of
ORR; 11 (44%) patients had ongoing responses of 6 months or longer.
In a separate subgroup of 25 patients with limited follow-up with PD-L1 expression TPS greater than or
equal to 50% receiving KEYTRUDA at a dose of 2 mg/kg every 3 weeks in Trial 1, activity was also
observed.
16 HOW SUPPLIED/STORAGE AND HANDLING
KEYTRUDA for injection (lyophilized powder): carton containing one 50 mg single-use vial (NDC
0006-3029-02).
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F).
KEYTRUDA injection (solution): carton containing one 100 mg/4 mL (25 mg/mL), single-use vial (NDC
0006-3026-02)
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do
not freeze. Do not shake.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid
treatment and interruption or discontinuation of KEYTRUDA, including:
Pneumonitis: Advise patients to contact their healthcare provider immediately for new or
worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].
Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe
abdominal pain [see Warnings and Precautions (5.2)].
Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe
nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.3)].
Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or
unusual headache, extreme weakness, dizziness or fainting, or vision changes [see Warnings and
Precautions (5.4)].
Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider
immediately for signs or symptoms of hyperthyroidism and hypothyroidism [see Warnings and
Precautions (5.4)].
Type 1 Diabetes Mellitus: Advise patients to contact their healthcare provider immediately for
signs or symptoms of type 1 diabetes [see Warnings and Precautions (5.4)].
Nephritis: Advise patients to contact their healthcare provider immediately for signs or
symptoms of nephritis [see Warnings and Precautions (5.5)].
Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-
related reactions [see Warnings and Precautions (5.7)].
Advise patients of the importance of keeping scheduled appointments for blood work or other
laboratory tests [see Warnings and Precautions (5.3, 5.4, 5.5)].
Advise women that KEYTRUDA can cause fetal harm. Instruct women of reproductive potential to
use highly effective contraception during and for 4 months after the last dose of KEYTRUDA [see
Warnings and Precautions (5.8) and Use in Specific Populations (8.1, 8.3)].
Advise nursing mothers not to breastfeed while taking KEYTRUDA and for 4 months after the final
dose [see Use in Specific Populations (8.2)].
Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of
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For KEYTRUDA for injection, at:
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For KEYTRUDA injection, at:
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uspi-mk3475-iv-1510r003
MEDICATION GUIDE
KEYTRUDA  (key-true-duh)
(pembrolizumab)
for injection
KEYTRUDA  (key-true-duh)
(pembrolizumab)
injection
What is the most important information I should know about KEYTRUDA? 
KEYTRUDA is a medicine that may treat your melanoma or lung cancer by working with your immune
system. KEYTRUDA can cause your immune system to attack normal organs and tissues in many areas
of your body and can affect the way they work. These problems can sometimes become serious or life-
threatening and can lead to death.
Call or see your doctor right away if you develop any symptoms of the following problems or
these symptoms get worse:
Lung problems (pneumonitis). Symptoms of pneumonitis may include:
shortness of breath
chest pain
new or worse cough
Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of
colitis may include:
diarrhea or more bowel movements than usual
stools that are black, tarry, sticky, or have blood or mucus
severe stomach-area (abdomen) pain or tenderness
Liver problems (hepatitis). Signs and symptoms of hepatitis may include:
yellowing of your skin or the whites of your eyes
nausea or vomiting
pain on the right side of your stomach area (abdomen)
dark urine
feeling less hungry than usual
bleeding or bruising more easily than normal
Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs
and symptoms that your hormone glands are not working properly may include:
rapid heart beat
weight loss or weight gain
increased sweating
feeling more hungry or thirsty
urinating more often than usual
®
®


hair loss
feeling cold
constipation
your voice gets deeper
muscle aches
dizziness or fainting
headaches that will not go away or unusual headache
Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:
change in the amount or color of your urine.
Problems in other organs. Signs of these problems may include:
rash
changes in eyesight
severe or persistent muscle or joint pains
severe muscle weakness
low red blood cells (anemia)
Infusion (IV) reactions, that can sometimes be severe and life-threatening. Signs and symptoms of
infusion reactions may include:
chills or shaking
shortness of breath or wheezing
itching or rash
flushing
dizziness
fever
feeling like passing out
Getting medical treatment right away may help keep these problems from becoming more
serious. 
Your doctor will check you for these problems during treatment with KEYTRUDA. Your doctor may
treat you with corticosteroid or hormone replacement medicines. Your doctor may also need to delay
or completely stop treatment with KEYTRUDA, if you have severe side effects.
What is KEYTRUDA? 
KEYTRUDA is a prescription medicine used to treat:
a kind of skin cancer called melanoma. KEYTRUDA may be used when your melanoma:
has spread or cannot be removed by surgery (advanced melanoma) and,
after you have tried a medicine call ipilimumab and it did not work or is no longer working and,
if your tumor has an abnormal "BRAF" gene, and you also have tried a different medicine called
a BRAF inhibitor, and it did not work or is no longer working.
a kind of lung cancer called non-small cell lung cancer. KEYTRUDA may be used when your lung
cancer:
has spread and,
tests positive for "PD-L1" and,
you have tried chemotherapy that contains platinum, and it did not work or is no longer working
and,
if your tumor has an abnormal "EGFR" or "ALK" gene, and you have also tried an EGFR or
ALK inhibitor medicine.
It is not known if KEYTRUDA is safe and effective in children less than 18 years of age.
What should I tell my doctor before receiving KEYTRUDA?


Before you receive KEYTRUDA, tell your doctor if you:
have immune system problems such as Crohn's disease, ulcerative colitis, or lupus
have had an organ transplant
have lung or breathing problems
have liver problems
have any other medical problems
are pregnant or plan to become pregnant
KEYTRUDA can harm your unborn baby.
Females who are able to become pregnant should use an effective method of birth control
during and for at least 4 months after the final dose of KEYTRUDA. Talk to your doctor about
birth control methods that you can use during this time.
Tell your doctor right away if you become pregnant during treatment with KEYTRUDA.
are breastfeeding or plan to breastfeed.
It is not known if KEYTRUDA passes into your breast milk.
Do not breastfeed during treatment with KEYTRUDA and for 4 months after your final dose of
KEYTRUDA.
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 of them to show your doctor and pharmacist when you get a
new medicine.
How will I receive KEYTRUDA?
Your doctor will give you KEYTRUDA into your vein through an intravenous (IV) line over 30
minutes.
KEYTRUDA is usually given every 3 weeks.
Your doctor will decide how many treatments you need.
Your doctor will do blood tests to check you for side effects.
If you miss any appointments, call your doctor as soon as possible to reschedule your appointment.
What are the possible side effects of KEYTRUDA?
KEYTRUDA can cause serious side effects. See "What is the most important information I
should know about KEYTRUDA?" 
The most common side effects of KEYTRUDA include:
feeling tired
cough
nausea
itching
rash
decreased appetite
shortness of breath
constipation
joint pain
diarrhea
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of KEYTRUDA. 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 KEYTRUDA 
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you


This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: October 2015
would like more information about KEYTRUDA, talk with your doctor. You can ask your doctor or
nurse for information about KEYTRUDA that is written for healthcare professionals. For more
information, go to www.keytruda.com.
What are the ingredients in KEYTRUDA?
Active ingredient: pembrolizumab
Inactive ingredients: 
KEYTRUDA for injection: L-histidine, polysorbate 80, and sucrose. May contain hydrochloric
acid/sodium hydroxide.
KEYTRUDA injection: L-histidine, polysorbate 80, sucrose, and Water for Injection, USP.
Manufactured by: Merck Sharp & Dohme
Corp., a subsidiary of
MERCK & CO., INC., Whitehouse
Station, NJ 08880, USA
For KEYTRUDA for injection, at:
Schering-Plough (Brinny) Co., County Cork, Ireland
For KEYTRUDA injection, at:
MSD Ireland (Carlow), County Carlow, Ireland
U.S. License No. 0002
For patent information:
www.merck.com/product/patent/home.html
Copyright © 2014-2015 Merck Sharp & Dohme Corp., a
subsidiary of Merck & Co., Inc. 
All rights reserved.
usmg-mk3475-iv-1510r003
PRINCIPAL DISPLAY PANEL - 50 mg Vial Carton
NDC 0006-3029-02
Keytruda  
(pembrolizumab)
for Injection
50 mg / vial
For Intravenous Infusion Only
Dispense the enclosed Medication Guide to each patient.
Sterile lyophilized powder must be reconstituted with Sterile Water for
Injection, USP. Reconstituted solution requires further dilution prior
to administration.
Rx only
Single-use vial. Discard unused portion.
®


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
 
Acerta Pharma 
Confidential 
Page 136 of 165 
Appendix 6. 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
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


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.
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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)
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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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247


Product: Acalabrutinib (ACP-196) 
Date: 15 January 2016 
Protocol: ACE-ST-006 
 
 
 
Acerta Pharma 
Confidential 
Page 157 of 165 
Appendix 7.  irRECIST Guidelines 
 


Adaptation of the  
immune-related response 
criteria: irRECIST
Oliver Bohnsack, PAREXEL 
Katarina Ludajic, PAREXEL 
Axel Hoos, GSK
ESMO 2014 Abstract 4958


RECIST 1.1 has its 
shortcomings for targeted 
immunotherapy in oncology. 
Using RECIST 1.1 in 
immunotherapy trials  
would lead to declaration  
of progressive disease  
(PD) too early, when the 
treatment effect is not yet 
fully evident. RECIST also 
neglects the importance  
of the ‘flare effect’ -  
pseudo-progression  
effect within the so-called 
flare time window. 
Immune related Response 
Criteria (irRC) based on  
WHO criteria were published 
with an aim to provide better 
assessment of the effect  
of immunotherapeutic 
agents. With this poster we 
introduce irRECIST based on 
RECIST 1.1, irRC and Nishino 
et al., 2013 findings. Our aim 
is to define criteria that 
better capture antitumor 
activity and reduce irRC 
criteria ambiguity. 
Consistent implementation 
of irRECIST by both 
investigators and blinded 
independent readers  
will help reduce site: 
central discordance.
AIM
2
Original irRC, Including WHO  
Criteria References
irRECIST  
Modifications and Clarifications
Rationale for Modification
At the baseline tumor assessment, the 
sum of the products of the two largest  
perpendicular diameters (SPD) of all 
index lesions (five lesions per organ, 
up to 10 visceral lesions and five 
cutaneous index lesions) is calculated.
1. 0 Baseline: Measurable Lesion  
Definitions and Target Lesion 
Selection
Follow the definitions from RECIST 1.1. 
Measurable lesions must be 
accurately measured in at least one 
dimension with a minimum size of:
• 10 mm in the longest diameter by 
CT or MRI scan (or no less than 
double the slice thickness) for non-
nodal lesions and ≥15 mm in short 
axis for nodal lesions
• 10 mm caliper measurement by  
clinical exam
• 20 mm by chest X-ray
Up to 5 target lesions may be selected  
at baseline. Lesions will be measured  
unidimensionally. The minimum target 
lesion size at baseline in irRECIST is 
aligned with RECIST 1.1, as outlined in 
Nishino et al., 2013. 
WHO 5.1.2
Unmeasurable Disease
There are many forms of 
unmeasurable disease, and only a few 
are mentioned as examples:
Lymphangitic pulmonary metastases.
Skin involvement in breast cancer.
Abdominal masses that can be 
palpated but not measured.
1.1. Baseline: Non-measurable  
Lesion Definitions  
Follow the definitions from RECIST 1.1 
 Non-target lesions will include:
• Measurable lesions not selected as 
target lesions
• All sites of non-measurable disease, 
such as neoplastic masses that are too 
small to measure because their longest 
uninterrupted diameter is < 10 mm (or 
< two times the axial slice thickness), 
ie. the longest per-pendicular 
diameter is  ≥10 and < 15 mm.
• Other types of lesions that are 
confidently felt to represent 
neoplastic tissue, but are difficult to 
measure in a reproducible manner. 
These include bone metastases, 
leptomeningeal metastases, 
malignant ascites, pleural or 
pericardial effusions, ascites, 
inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic 
lesions, ill-defined abdominal 
masses, skin lesions, etc.
Although irRC does not specifically 
define non-target lesions, irRC is 
derived from WHO criteria and 
indicates accordance with the same 
for the purposes of definitions of  
non-target lesions. Further 
clarifications in alignment with  
RECIST 1.1 are provided.
Not specified.
1.2 Baseline: Target and Non-Target 
Lymph Node Lesion Definitions
Follow the definitions from RECIST 1.1
No change in definition of target  
and non-target lymph nodes from  
RECIST 1.1.
Not specified.
1.3 Baseline: Non-Target  
Lesion Selection
All lesions or sites of disease not  
recorded as target lesions should  
be recorded as non-target lesions  
at baseline. There is no limit to the 
number of non-target lesions that  
can be recorded at baseline.
In alignment with RECIST 1.1, all  
malignant lesions have to be selected 
at baseline. The excess of measurable 
lesions and all true non-measurable 
lesions will be selected as non-target 
lesions at baseline and followed at 
subsequent timepoints.
 Not specified.
1.4 Baseline: Bone Lesions
Follow the definitions from RECIST 1.1.
Regardless of the imaging modality 
blastic bone lesions will not be select-
ed as target lesions. Lytic or mixed 
lytic-blastic lesions with a measurable 
soft tissue component ≥10 mm can be 
selected as target lesions.
Bone lesions are to be handled the 
same as in RECIST 1.1.
Not specified.
1.5 Baseline: Brain Lesions detected 
on brain scans can be considered as 
both target or non-target lesions.
Brain lesions can be selected as target 
or non-target lesions at baseline,  
depending on the protocol definition, 
indication, and study design.


The adaptations from  
irRC and WHO criteria,  
as applicable in 
immunotherapy clinical 
studies, are documented in 
the “irRECIST Modifications 
and Clarifications” column  
in a comparative table 
format within our Blinded 
Independent Central  
Review (BICR) Charter. 
The modifications we 
introduce represent 
adaptations of published 
criteria based on radiology 
practice and clinical trial 
experience, and they provide 
more objective and 
reproducible response 
assessments for 
investigators and for  
the central independent 
image review.
Methods
3
Original irRC, Including WHO  
Criteria References
irRECIST  
Modifications and Clarifications
Rationale for Modification
Not specified.
1.6 Baseline: Cystic and Necrotic 
Lesions as Target Lesions
Lesions that are partially cystic or 
necrotic can be selected as target 
lesions. The longest diameter of such 
a lesion will be added to the Total 
Measured Tumor Burden (TMTB) of  
all target lesions at baseline. If other 
lesions with a non-liquid/non-necrotic 
component are present, those should 
be preferred. 
RECIST 1.1 does not integrate viability 
of tumor tissue into the assessment, 
and that is carried over into irRECIST.
Not specified.
1.7 Baseline: Lesions With Prior  
Local Treatment
During target lesion selection the 
radiologist will consider information 
on the anatomical sites of previous 
intervention (e.g. previous irradiation, 
RF-ablation, TACE, surgery, etc.). 
Lesions undergoing prior intervention 
will not be selected as target lesions 
unless there has been a demon-
stration of progress in the lesion.
In order to minimize site vs. central 
discrepancy information about prior 
intervention needs to be available  
to both the investigators and 
independent reviewers. 
Not specified.
1.8 Baseline: No Disease at Baseline 
If a patient has no measurable and  
no non-measurable disease at  
baseline the radiologist will assign  
‘No Disease’ (irND) as the overall  
tumor assessment for any available 
follow-up timepoints unless new  
measurable lesions are identified and 
contribute to the TMTB.
irND is a valid assessment in studies 
with adjuvant setting where the  
protocol and study design allow to  
include patients with no visible  
disease. This had not been addressed 
at all in any prior immune-response 
related criteria but needs to be  
included to also allow for these  
patients to be assessed accurately.
At each subsequent tumor 
assessment, the SPD of the index 
lesions and of new, measurable 
lesions (≥5×5 mm; up to 5 new  
lesions per organ: 5 new cutaneous 
lesions and 10 visceral lesions) are 
added together to provide the total 
tumor burden:
SPDindex lesions + SPDnew measured lesion
2.0 Follow-up: Recording of  
Target and New Measureable  
Lesion Measurements
The longest diameters of non-nodal 
target and new non-nodal measurable 
lesions, and short axes of nodal target 
and new nodal measurable lesions will 
be recorded. Together they determine 
the Total Measured Tumor Burden 
(TMTB) at follow-up.
In alignment with Nishino et al., 2013,  
unidimensional measurements are 
used. Measurements of all measured 
lesions (baseline-selected target  
lesions and new measurble lesions) 
are combined into TMTB at follow-up.
2.1 Follow-up: Definition of  
Measurable New Lesions
In order to be selected as new mea-
surable lesions (≤ 2 lesions per organ, 
≤ 5 lesions total, per timepoint), new 
lesions must meet criteria as defined 
for baseline target lesion selection  
and meet the same minimum size  
requirements of 10 mm in long  
diameter and minimum 15 mm in 
short axis for new measurable lymph 
nodes. New measurable lesions shall 
be prioritized according to size, and 
the largest lesions shall be selected  
as new measured lesions. 
Proposed selection of up to 5 new 
measurable lesions of at least 10 mm  
each verus 10 new measurable lesions 
as suggested in the irRC criteria is due 
to the following: 5 new measurable 
lesions add up at least 50 mm to the 
TMTB. Since PD is determined by  
at least a 20% increase in TMTB 
compared to nadir, this would mean 
that for irPD assessment the nadir 
TMTB had to be 25 cm, or 10 cm for  
2 lesions in one organ, which is a 
significant tumor burden already for 
any cancer patient. That is why 
measuring up to 5 new lesions in total 
is sufficient and will not obstruct an 
irPD assessment. Measuring more 
than 5 new lesons is not needed.
Larger lesions must be preferred as  
new measurable over smaller lesions, 
because there will be a greater impact  
of the TMTB %-increase by these 
larger lesions for irPD, to support  
a most conservative approach.


4
irRECIST criteria are based 
on irRC criteria adapted for 
unidimensional measure-
ments, as outlined in Nishino 
et al., 2013. To further align 
the criteria with RECIST 1.1 
we outline the approach for 
the assessment of baseline-
selected non-target lesions 
and new non-measurable 
lesions, and discuss the 
impact of those lesions  
on the overall tumor 
response assessment. 
Guidelines for the evaluation 
of patients with non-target 
disease only and patients in 
adjuvant setting is provided.
results
Original irRC, Including WHO  
Criteria References
irRECIST  
Modifications and Clarifications
Rationale for Modification
Non-index lesions at follow-up 
timepoints contribute to defining irCR 
(complete disappearance required).
2.2 Follow-up: Non-Target 
 Lesion Assessment 
The RECIST 1.1 definitions for  
the assessment of non-target  
lesions apply.
The response of non-target lesions 
primarily contributes to the overall 
response assessments of irCR and 
irNon-CR/Non-PD (irNN). Non-target 
lesions do not affect irPR and irSD 
assessments. Only a massive and 
unequivocal worsening of non-target 
lesions alone, even without progress  
in the TMTB is indicative of irPD. 
Non-target lesions have a subordinate 
function. In the event that non-target 
lesions massively progress one cannot 
ignore such worsening and in these 
rare cases irPD based only on  
non-target lesions will be a valid 
assessment option. 
New, non-measurable lesions at 
follow-up timepoints do not define 
progression, they only preclude irCR.
2.3 Follow-up: New Non-Measurable 
Lesions Definition and Assessment
All new lesions not selected as new 
measurable lesions are considered  
new non-measurable lesions and are 
followed qualitatively. Only a massive  
and unequivocal progression of new 
non-measurable lesions leads to an 
overall assessment of irPD for the 
timepoint. Persisting new non-
measurable lesions prevent irCR.
When new non-measurable lesions 
substantially worsen in these rare 
cases irPD based only on new  
non-measurable lesions will be  
an assessment option. 
irRC Overall Tumor Assessments
irCR, complete disappearance of all  
lesions (whether measurable or not,  
and no new lesions) 
•  Confirmation by a repeat, 
consecutive assessment no  
less than 4 weeks from the date  
first documented 
irPR, decrease in tumor burden ≥50% 
relative to baseline
• Confirmed by a consecutive 
assessment at least 4 weeks after 
first documentation 
irSD, not meeting criteria for irCR or 
irPR, in absence of irPD 
irPD, increase in tumor burden ≥25% 
relative to nadir (minimum recorded  
tumor burden)
• Confirmation by a repeat, 
consecutive assessment no  
less than 4 weeks from the date  
first documented
2.4 irRC Overall Tumor Assessments
irCR, complete disappearance of  
all measurable and non-measurable 
lesions. Lymph nodes must decrease 
to < 10 mm in short axis. Confirmation 
of response is not mandatory. 
irPR, decrease of ≥ 30% in TMTB  
relative to baseline, non-target lesions 
are irNN, and no unequivocal progres-
sion of new non-measurable lesions. 
irSD, failure to meet criteria for irCR 
or irPR in the absence of irPD.
irNN, no target disease was identified 
at baseline and at follow-up the  
patient fails to meet criteria for  
irCR or irPD.
irPD, minimum 20% increase and  
minimum 5 mm absolute increase in  
TMTB compared to nadir, or irPD for 
non-target or new non-measurable  
lesions. Confirmation of progression is 
recommended minimum 4 weeks after 
the first irPD assessment. 
irNE, used in exceptional cases where  
insufficient data exists. 
irND, in adjuvant setting when no  
disease is detected.
The irRECIST overall tumor  
assessment is based on TMTB of  
measured target and new lesions, 
non-target lesion assessment and  
new non-measurable lesions. 
The thresholds for irPR and irPD  
assessment are aligned with  
RECIST 1.1, and confirmation of  
response is not required.
An irPD confirmation scan may be  
recommended for patients with a  
minimal TMTB %-increase over  
20% and especially during the flare 
time-window of the first 12 weeks  
of treatment, depending on the  
compound efficacy expectations, to 
account for expected delayed response.


5
irRECIST criteria as outlined here introduce the needed clarifications and adjustments to irRC 
criteria and Nishino et al., 2013 publication to allow for treatment evaluations that better meet both 
investigators’ and patients’ needs and with that better reflect sponsors’ demands for more reliable 
and reproducible study data in targeted immunotherapy in oncology studies. The main adaptation of 
the existing immune-response criteira lies in the assessment of all detected lesions. Unequivocal 
and substantial increase of non-target and new non-measurable lesions prevents irCR and may also 
lead to irPD. Reduction of the tumor burden in patients in an adjuvant setting may lead to irPR and 
such patients may therefore be enrolled in studies with response endpoints.
Clinical relevance of these adaptations needs to be confirmed.
Conclusions


6 
1. TMTB: Baseline-selected target lesions and new measurable 
lesions should NOT be assessed separately. Measurements of 
those lesions should be combined into the Total Measured 
Tumor Burden (TMTB), and one combined assessment provided.
2. New Measurable Lesions: According to irRC a measurable new 
lesion has to be at least 5 mm x 5 mm to be selected as an 
index lesion. For bidimensional measurements this threshold 
was acceptable. In irRECIST, criteria for unidimensional lesion 
measurment apply to both target and new measurable lesions: 
a minimum 10 mm in the longest diameter for non-nodal 
lesions, and a minimum 15 mm in short axis for lymph nodes. 
Smaller lesions contribute to the non-target or new non-
measurable tumor burden, but do not get measured.
3. irPR if no Target Lesions: If new measurable lesions appear  
in patients with no target lesions at baseline, irPD will be 
assessed. That irPD timepoint will be considered a new 
baseline, and all subsequent timepoints will be compared  
to it for response assessment. irPR is possible if the TMTB  
of new measurable lesions decreases by ≥ 30% compared  
to the first irPD documentation. 
4. irPR in Adjuvant Studies: irRECIST can be used in the adjuvant 
setting, in patients with no visible disease on CT/MRI scans. 
The appearance of new measurable lesion(s) automatically 
leads to an increase in TMTB by 100% and leads to irPD. These 
patients can achieve a response if the TMTB decreases at 
follow-up, as a sign of delayed response.  
 
Considering 3 and 4, sponsors may consider enrolling patients 
with no measurable disease and/or patients with no visible disease 
at all in studies with response related endpoints. 
 
 
 
 
5. Non-Target Lesions: In alignment with RECIST 1.1, baseline 
selected non-target lesions can never convert to measurable 
lesions, not even if they increase in size at subsequent 
timepoints and become measurable. Only true new lesions  
can be measured and contribute to the TMTB.
6. Example: A patient has multiple lung metastases, all smaller 
than 10 mm and selected as non-target lesions at baseline.  
If, at a subsequent timepoint some of these non-target lesions 
increase and become > 10 mm, and one new lesion >10 mm 
appears, only the new measurable lesion will contribute to  
the TMTB, and not the baseline selected non-target lesion  
that increased in size. Otherwise such an increase would  
make persisting non-target lesions switch into the new 
measurable lesion category which would be inaccurate,  
as the lesion existed at baseline.
7. irPD Based on Non-Target Lesions: Unlike irRC that neglect 
non-target lesions for the assessment of irPD, in irRECIST a 
substantial and unequivocal increase of non-target lesions is 
indicative of progression. 
8. irPD Based on New Non-Measurable Lesions: According to 
irRC, a patient with multiple new lesions of 9 mm would be 
considered non-PD, whereas a patient with just one new lesion 
of 10 mm may be assessed as irPD if the TMTB of such a 
patient increases ≥ 20% compared to nadir. According to 
irRECIST, the reviewer may assign irPD for the patient with 
multiple new lesions of 9 mm if they are considered to be a 
sign of unequivocal, massive worsening (see 2.3)
9. irPD Confirmation: Progression confirmation no less than  
4 weeks after the initial irPD assessment is recommended 
especially in case of marginal disease growth and if the  
first irPD assessment is within the compound-specific  
tumor flare window.
Summary and Additional Guidance


 7
1) JD Wolchok, A Hoos, O Bohnsack, et.al., Guidelines for the Evaluation of Immune Therapy  
Activity in Solid Tumors: Immune-Related Response Criteria, Clin Cancer Res 2009;15(23) 
December 1, 2009
2) Nishino M et al. Developing a common language for tumor response to immunotherapy:  
immune-related response criteria using unidimensional measurements. Clin Cancer Res. 2013 
Jul 15;19(14):3936-43
3) Therasse P, Arbuck SG, et al.: New Guidelines to Evaluate the Response to Treatment in Solid 
Tumors. Journal of the National Cancer Institute 2000 92(3):205-216]
4) Eisenhauer EA, Therasse P, Bogaerts J, et al.: New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). In: Eur. J. Cancer. 45, Nr. 2, Januar 2009, S. 228–47.
5) Therasse P, Eisenhauer EA, Verweij J: RECIST revisited: a review of validation studies on tumour 
assessment. In: Eur. J. Cancer. 42, Nr. 8, Mai 2006, S. 1031–9.
6) WHO handbook for reporting results of cancer treatment. Geneva (Switzerland): World Health 
Organization Offset Publication No. 48; 1979.
Oliver.Bohnsack@parexel.com
PAREXEL International 
195 West Street 
Waltham, MA 02451 USA 
+ 1 781 487 9900 
www.PAREXEL.com
References
Contact info


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SAP_000.pdf: 


Product: Acalabrutinib 
Statistical Analysis Plan: Solid Tumor Studies                                   
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Confidential 
Page 1 of 24 
 
A Master Statistical Analysis Plan  
for  
Solid Tumor Studies including ST-003, ST-005, ST-006, ST-007, 
and ST-208 
 
 
 
Version:  
Version 1.0 
Date: 
30Jan 2018 
 
Studies Statistician: 
 
 


Product: Acalabrutinib 
Statistical Analysis Plan: Solid Tumor Studies                                   
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Table 1.   A List of Applicable Studies Covered by This SAP 
Protocol 
Number 
Treatment groups 
Indication 
Phase 
Protocol Title 
ACE-ST-003 
Acalabrutinib 
vs 
Acalabrutinib + 
Pembrolizumab 
Pancreatic 
Cancer 
2 
A Phase 2 Proof-of-Concept 
Study of ACP-196 Alone and 
in Combination with 
Pembrolizumab in Subjects 
with Advanced or Metastatic 
Pancreatic Cancer 
ACE-ST-005 
Pembrolizumab 
vs 
Acalabrutinib + 
Pembrolizumab 
Bladder Cancer 
2 
Randomized Phase 2 Trial of 
ACP-196 and Pembrolizumab 
Immunotherapy Dual 
CHECKpoint Inhibition in 
Platinum Resistant Metastatic 
Urothelial Carcinoma 
ACE-ST-006 
Pembrolizumab 
vs 
Acalabrutinib + 
Pembrolizumab 
Head and Neck 
Cancer 
2 
A Phase 2 Proof-of-Concept 
Study of the Combination of 
ACP-196 and Pembrolizumab 
in Subjects with Advanced 
Head and Neck Squamous 
Cell Carcinoma 
ACE-ST-007 
Pembrolizumab 
vs 
Acalabrutinib + 
Pembrolizumab 
Non-small Cell 
Lung Cancer 
2 
A Phase 2 Proof-of Concept 
Study of the Combination of 
ACP-196 and Pembrolizumab 
in Subjects with Advanced 
Non-small Cell Lung 
Carcinoma 
ACE-ST-208 
Acalabrutinib 
vs 
Acalabrutinib + 
Pembrolizumab 
Ovarian Cancer 
2 
A Phase 2 Proof-of-Concept 
Study of ACP-196 Alone and 
in Combination with 
Pembrolizumab in Subjects 
with Recurrent Ovarian Cancer 
 
 


Product: Acalabrutinib 
Statistical Analysis Plan: Solid Tumor Studies                                   
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Page 3 of 24 
TABLE OF CONTENTS 
Table of Contents .............................................................................................................. 3 
Table of Abbreviations ...................................................................................................... 5 
1. 
INTRODUCTION ...................................................................................................... 7 
2. 
OBJECTIVES ........................................................................................................... 7 
 
Primary Objective ............................................................................................ 7
 
Secondary Objective ....................................................................................... 7
 
Exploratory Objectives ..................................................................................... 7
3. 
STUDY OVERVIEW ................................................................................................. 8
Study Design ................................................................................................... 8
 
Sample Size .................................................................................................... 8
4. 
STUDY ENDPOINTS ............................................................................................... 9
 
Safety Endpoints ............................................................................................. 9
 
Efficacy Endpoints ........................................................................................... 9
 
Exploratory Endpoints ..................................................................................... 9
5. 
HYPOTHESES AND MULTIPLICITY ....................................................................... 9 
6. 
ANALYSIS SETS ................................................................................................... 10 
 
Safety Analysis Set ........................................................................................ 10
 
Efficacy Evaluable Analysis Set .................................................................... 10
 
Pharmacokinetic/Pharmacodynamic Analyses Set ....................................... 10
7. 
FINAL ANALYSIS AND CLINICAL STUDY REPORT ............................................ 10 
8. 
STATISTICAL METHODS OF ANALYSIS ............................................................. 10 
 
General Principles ......................................................................................... 10
 
Subject Accountability ................................................................................... 11
 
Important Protocol Deviations ....................................................................... 11
 
Demographic and Baseline Characteristics ................................................... 11
 
Treatment and Medications ........................................................................... 11
8.5.1 
Prior Anticancer Regimens ............................................................... 11 
8.5.2 
Concomitant Medications ................................................................. 11 
8.5.3 
Exposure to Investigational Product ................................................. 12 
 
Safety Analyses ............................................................................................. 12
8.6.1 
Adverse Events ................................................................................ 12 
8.6.2 
Adverse Events of Clinical Interest ................................................... 13 
8.6.3 
Laboratory Test Results ................................................................... 13 
8.6.4 
Vital Signs ........................................................................................ 13 
8.6.5 
ECOG Performance Status .............................................................. 13 


Product: Acalabrutinib 
Statistical Analysis Plan: Solid Tumor Studies                                   
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Efficacy Analyses .......................................................................................... 13
8.7.1 
Best Overall Response, Disease Control Rate and Overall 
Response Rate ................................................................................. 13 
8.7.2 
Duration of Response ....................................................................... 14 
8.7.3 
Progression-free Survival ................................................................. 14
8.7.4 
Overall Survival ................................................................................ 15
8.7.5 
Serum Cancer Antigens CA-19-9 and CA-125 ................................. 15 
8.7.6 
Exploratory Efficacy Endpoints ......................................................... 15
8.7.7 
Other Exploratory Efficacy Endpoints ............................................... 16 
8.7.8 
Pharmacokinetic, Pharmacodynamic and Biomarker 
Analyses ........................................................................................... 16 
 
Sensitivity Analyses ....................................................................................... 16
9. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ..................................... 16 
10. 
LITERATURE CITATIONS / REFERENCES ......................................................... 17 
11. 
APPENDICES ........................................................................................................ 18 
12.1  Definitions ...................................................................................................... 18 
12.2  Imputation Rules for Partial or Missing Dates ............................................... 19 
12.3  Censoring Rules for Progression-free Survival ............................................. 20 
12.4  Censoring Rules for Overall Survival ............................................................. 21 
12.5. Events of Clinical Interest for acalabrutinib ................................................... 22 
12.6. Events of Clinical Interest for a combination of acalabrutinib and 
pembrolizumab .............................................................................................. 24 


Product: Acalabrutinib 
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TABLE OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice per day 
BMI 
Body mass index 
BOR 
best overall response 
CA19-9 
cancer antigen 19-9 (carbohydrate antigen 19-9) 
CI 
confidence interval 
CR 
complete response  
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR  
disease control rate 
DLT  
dose-limiting toxicity 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
HNSCC 
head and neck squamous cell carcinoma 
ICF 
informed consent form 
IPD 
Important Protocol Deviation 
ir 
immune-related 
irRECIST  
immune-related response criteria 
IV 
intravenous or intravenously 
MDSCs 
myeloid-derived suppressor cells 
MedDRA  
Medical Dictionary for Regulatory Activities  
NCI 
National Cancer Institute  
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate  
OS 
overall survival  
PD 
pharmacodynamics  
PD 
progressive disease 
PD-L1 
programmed death ligand-1 
PFS 
progression-free survival  
PK 
pharmacokinetics  
PO 
orally 
PR 
partial response  
Q3W 
every 3 weeks 
RECIST  
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


Product: Acalabrutinib 
Statistical Analysis Plan: Solid Tumor Studies                                   
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Page 6 of 24 
 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization WHO Drug Dictionary 
 


Product: Acalabrutinib 
Statistical Analysis Plan: Solid Tumor Studies                                   
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Page 7 of 24 
1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocols of 
 
including ST-003(pancreatic cancer), ST-005 (bladder cancer), ST-006 (head and neck 
squamous cell carcinoma, HNSCC), ST-007 (non-small cell lung cancer, NSCLC), and 
ST-208 (ovarian cancer).  The scope of this plan includes the final analysis.  Any 
changes to the methods described in this SAP will be documented in each clinical study 
report (CSR). 
 
2. 
OBJECTIVES 
 
Primary Objective 
• 
To characterize the safety profile of acalabrutinib and pembrolizumab in 
subjects with solid tumors in each of the five studies including ST-003 
(pancreatic cancer), ST-005 (bladder cancer), ST-006 (HNSCC), ST-007 
(NSCLC), and ST-208 (ovarian cancer). 
• 
To determine the best overall response rate and overall response rate (ORR) 
of pembrolizumab monotherapy and the combination of acalabrutinib and 
pembrolizumab. This applies to ST-005, ST-006 and ST-007. 
 
 
Secondary Objective 
• 
To evaluate the efficacy (multiple efficacy endpoints including ORR, PFS and 
OS) of acalabrutinib monotherapy and acalabrutinib and pembrolizumab 
combination treatment in subjects with solid tumors using standard response 
criteria. This applies to ST-003 and ST-208. 
• 
To determine progression-free survival (PFS) in subjects treated with 
pembrolizumab monotherapy and the combination of acalabrutinib and 
pembrolizumab. This applies to ST-005, ST-006, and ST-007. 
• 
To evaluate the overall survival (OS) in subjects treated with pembrolizumab 
monotherapy and the combination of acalabrutinib and pembrolizumab. This 
applies to ST-005, ST-006, and ST-007. 
 
 
 
 
 
  


Product: Acalabrutinib 
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• 
 
 
 
 
3. 
STUDY OVERVIEW 
 
Study Design 
These five studies are phase 2, multicenter, open-label, randomized studies evaluating 
acalabrutinib or pembrolizumab monotherapy and the combination of acalabrutinib and 
pembrolizumab in subjects with solid tumors. Subjects meeting the eligibility criteria for 
the study will be randomized 1:1 to one of the following arms: 
Arm 1:  Acalabrutinib 100 mg administered orally (PO) twice per day (BID) (ST-003, ST-
208) or Pembrolizumab 200 mg administered as an intravenous (IV) infusion every 3 
weeks (Q3W) (ST-005, ST-006, ST-007) 
Arm 2:  Acalabrutinib 100 mg PO BID plus Pembrolizumab 200 mg IV Q3W 
Acalabrutinib treatment can continue for subjects who are tolerating therapy and not 
progressing. Pembrolizumab study treatment is for 24 months from the date of first dose 
for subjects who are tolerating therapy and not progressing. Subjects who have 
confirmed progressive disease on the combination of pembrolizumab and acalabrutinib 
will discontinue study treatment. Subjects who have confirmed progressive disease on 
monotherapy arm may start combination until a second disease progression. Disease 
progression will be determined based on irRECIST guidelines. Also pembrolizumab 
treatment can end for subjects with confirmed complete response (CR) if treatment has 
been administered for at least 24 weeks and 2 doses of pembrolizumab have been 
administered after confirmation of CR.  
Refer to Protocol section 3 for more details. 
 
 
Sample Size  
The planned sample sizes per arm for each of the studies are listed below. For sample 
size justification, reference corresponding study protocols: 
Study 
Arm 1: Acalabrutinib 
Arm 1: Pembrolizumab 
Arm 2: Acalabrutinib 
+ Pembrolizumab 
ST-003 
38 
 
38 
ST-005 
 
37 
37 
ST-006 
 
37 
37 


Product: Acalabrutinib 
Statistical Analysis Plan: Solid Tumor Studies                                   
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Page 9 of 24 
ST-007 
 
37 
37 
ST-208 
38 
 
38 
4. 
STUDY ENDPOINTS  
 
Safety Endpoints 
• 
Type, frequency, severity, timing of onset, duration, and relationship to either 
or both study drug of any treatment-emergent adverse events (TEAEs) or 
abnormalities of laboratory tests, serious adverse events (SAEs), AEs leading 
to dose modification, dose delay and discontinuation of any study drug 
 
 
Efficacy Endpoints 
• 
Disease control rate (DCR) defined as stable disease (SD), partial response 
(PR) or CR based on modified RECIST 1.1 criteria. DCR by RECIST will be 
considered the primary endpoint of ST-003 
• 
ORR, defined as PR or CR based on modified RECIST 1.1 criteria. ORR by 
RECIST will be considered the primary endpoint of ST-005, ST-006, ST-007, 
and ST-208 
• 
Duration of response (DOR)  
• 
PFS 
• 
OS 
• 
Change in serum cancer antigen CA-19-9. This applies to ST-003 only 
• 
Change in serum cancer antigen CA-125. This applies to ST-208 only 
 
 
5. 
HYPOTHESES AND MULTIPLICITY 
This series of solid tumor studies are proof of concept studies. No formal hypothesis will 
be tested and no multiplicity adjustments will be made. 


Product: Acalabrutinib 
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6. 
ANALYSIS SETS 
The following definitions will be used for the efficacy and safety analysis populations. 
 
 
Safety Analysis Set 
The safety analysis set includes all subjects who receive at least one dose of any study 
drug (either acalabrutinib or pembrolizumab). The safety analysis set will be used for 
evaluating the safety and efficacy endpoints with the exception of DOR. The analyses of 
DOR will be conducted on the subset of the safety analysis set who achieve CR or PR 
as their best overall response. 
 
 
Efficacy Evaluable Analysis Set  
All subjects in the safety analysis set who have ≥ 1 evaluable response assessment 
after the first dose of study drug (either acalabrutinib or pembrolizumab). Sensitivity 
analyses of efficacy endpoints will be carried out on the efficacy-evaluable population. 
 
 
Pharmacokinetic/Pharmacodynamic Analyses Set 
Pharmacokinetic/Pharmacodynamic evaluable analysis set will be defined by PK/PD 
group. 
7. 
FINAL ANALYSIS AND CLINICAL STUDY REPORT 
Planned final analysis will be conducted once last subject exits study and database is 
locked. The CSR will be written based on the final analysis. 
 
8. 
STATISTICAL METHODS OF ANALYSIS 
 
General Principles 
Descriptive statistics [including means, standard deviations, medians, minimum and 
maximum for continuous variables and frequency, proportions and confidence intervals 
(CIs) for discrete variables] will be used to summarize data as appropriate. 
Calculation of time to event or duration of event endpoints will be based on the study day 
of the event or censoring date rather than visit number or visit label. Missing efficacy or 
safety data will not be imputed unless otherwise specified. 
The following rules will be used for the days to months/years conversion: 
• 
1 month= 30.4375 days; 
• 
1 year= 365.25 days. 


Product: Acalabrutinib 
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All summaries will be presented by treatment group. 
 
Subject Accountability 
The number of subjects enrolled by site will be presented. Subject disposition will be 
summarized for all enrolled subjects including the following information: 
• 
Proportion of subjects who received study drug 
• 
Proportion of subjects with study drug discontinuation and primary reason for 
study drug discontinuation 
• 
Proportion of subjects discontinuing study and reasons for study discontinuation 
• 
Time on study 
 
 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined and managed by the study 
team during the IPD reviews throughout the study before database lock. The final IPD 
list for each study is used to produce the summary of IPDs and the listing of subjects 
with IPDs, respectively.   
 
 
Demographic and Baseline Characteristics 
Summaries of demographic characteristics will be presented for age, age category (< 65, 
≥ 65), gender, race, ethnicity, and geographic region for each study.   
Baseline characteristics will be presented for Eastern Cooperative Oncology Group 
(ECOG) performance status, disease stage, tumor grade where relevant, number of 
prior anticancer therapies for each study. 
 
 
Treatment and Medications 
8.5.1 
Prior Anticancer Regimens  
Summary statistics will be presented for prior anticancer regimens (might include 
multiple therapies) and prior cancer-related surgery for each study. Prior cancer therapy 
categories will be adjudicated by the medical monitor. 
 
8.5.2 
Concomitant Medications 
Concomitant medications will be coded and tabulated according to the World Health 
Organization Drug Dictionary (WHODRUG). 
 


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8.5.3 
Exposure to Investigational Product  
Number of subjects who received at least one dose of acalabrutinib, pembrolizumab or 
both, duration of exposure, average daily dose of acalabrutinib, average dose of 
pembrolizumab per administration cycle, and relative dose intensity will be summarized 
for each investigational product and by treatment group. 
Exposure parameters are defined in more detail in Appendix 12.1. 
 
 
Safety Analyses 
8.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA v20.1 or higher) will be used 
to code all AEs to a system organ class and a preferred term.  The severity of the AE will 
be assessed by National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. Study drug-related AEs are those assessed by 
investigator as related.  
All AE tables will be summarized by original treatment group and crossover group for 
each study. For subjects who crossed-over from monotherapy to a combination therapy 
of acalabrutinib and pembrolizumab, AEs experienced up to crossover date will 
summarized under monotherapy arm, while AEs on or after the cross-over date (1st dose 
date of second study drug added) will be summarized under crossover group.   
TEAEs are defined as those events that occur or worsen on or after the first dose of 
study drug, through the treatment phase, and within 30 days following the last dose of 
acalabrutinib or within 90 days following the last dose of pembrolizumab. 
TEAEs will be summarized by system organ class (SOC) and preferred terms in 
descending order of frequency, by CTCAE toxicity grade. Drug-related TEAEs, serious 
TEAEs, TEAEs leading to treatment discontinuation and removal from study will be 
summarized by SOC and preferred terms as well as by preferred teams only in 
descending order of frequency and by CTCAE toxicity grade.  
Death information is reported in the study exit case report form (CRF) for all deaths. 
Incidences of deaths are to be reported, along with the primary cause of death. 
 
 
 


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8.6.2 
Adverse Events of Clinical Interest 
Events of Clinical Interest identified for acalabrutinib and combination of acalabrutinib 
with pembrolizumab will be summarized for each study. The definitions of these 
categories are part of Appendix 12.5 and 12.6. 
 
8.6.3 
Laboratory Test Results 
Laboratory data up to 30 days after last dose or the safety follow-up visit date, 
whichever is later, will be reported in SI units. Applicable laboratory results will be 
graded according to CTCAE Version 4.03. For each laboratory parameter, the 
baseline laboratory value/grade is defined as the last laboratory value/grade 
collected on or prior to the date of the first dose of study drug. Treatment-emergent 
laboratory abnormalities for selected parameters will be summarized. 
 
8.6.4 
Vital Signs 
Body temperature, heart rate (beats/min), systolic blood pressure (mmHg), diastolic 
blood pressure (mmHg), respiratory rate (breaths/min), and weight will be collected for 
each study as scheduled in protocol Appendix. For each parameter, summary statistics 
(mean, standard deviation, median, and range) will be produced for baseline, maximum,  
and minimum value. 
 
8.6.5 
ECOG Performance Status 
ECOG performance status scores will be summarized for each treatment group using 
shift table.  The shifts in scores from baseline to worst ECOG score on treatment will be 
summarized.   
 
 
Efficacy Analyses  
8.7.1 
Best Overall Response, Disease Control Rate and Overall Response 
Rate 
DCR is defined as the proportion of subjects who achieve a best response of SD, PR or 
CR at any point of the study. The primary endpoint for ST-003 is DCR by RECIST1.1 
criteria by investigators.   
ORR is defined as the proportion of subjects who achieve a best response of PR or CR 
at any point of the study. The primary endpoint for ST-005, ST-006, ST-007, and ST-208 
is ORR by RECIST1.1 criteria by investigators.  


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The primary analysis of DCR and ORR will be conducted using safety analysis set. DCR 
and ORR will be calculated with the corresponding exact binomial 2-sided 95% CI for 
each original treatment arm and separately for subjects who crossed over from a 
monotherapy to a combination therapy. Monotherapy subjects who crossed-over will be 
summarized according to their original treatment assignment up to the point of 
crossover, and then summarized as a crossover subject using their response 
immediately prior to crossover as a new baseline for their combination treatment. A 
sensitivity analysis using efficacy evaluable analysis set will also be presented. 
Descriptive statistics will be provided for best overall response for each treatment group.  
The number and proportion of subjects within each category of response will be 
presented.     
8.7.2 
Duration of Response 
The DOR is 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.  The DOR will only be summarized for subjects in safety analysis set who 
achieved response (CR or PR) at any point of the study. Kaplan-Meier methods will be 
used to estimate event-free curves and corresponding quantiles (including the median).  
For crossover subjects who originally started on monotherapy, the DOR will only be 
summarized/listed if ORR for this group is non-zero. If confirmed response is achieved 
after the crossover, the DOR for a combination therapy will be summarized. 
Data from surviving, non-progressing subjects will be censored at the date of the last 
adequate disease assessment that is on or before the start date of the new antitumor 
therapy. Data from subjects who have disease progression or die after more than one 
missed visit will be censored at the last visit date before the missing assessments which 
lack objective disease assessment. The details of definition of progression events and 
censoring rules are the same as for PFS endpoint and are listed in Appendix 12.3.  
 
8.7.3 
Progression-free Survival 
Progression-free survival is defined as the interval from the start of therapy 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 
quantiles (including the median).   


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For crossover subjects who originally started on monotherapy, the PFS will only be 
summarized/listed if ORR for this group is non-zero. 
Data from surviving, non-progressing subjects will be censored at the date of the last 
adequate disease assessment that is on or before the start date of the new antitumor 
therapy. Data from subjects who have disease progression or die after more than one 
missed visit will be censored at the last visit date prior to the missing assessments which 
lack objective disease assessment. The details of definition of progression events and 
censoring rules for primary and sensitivity analyses of PFS are listed in Appendix 12.3. 
In the primary analysis using safety analysis set, study treatment end date will be used 
as the date of progression for subjects who discontinued study treatment due to disease 
progression or death prior to 1st radiographic assessment. Data for subjects who 
discontinued study treatment prior to 1st radiographic assessment due to reasons other 
than disease progression or death will be censored at their study treatment start date.  
 
8.7.4 
Overall Survival 
Overall survival is defined as the time from treatment start date 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 lost to follow-up for survival 
immediately after randomization will be censored at first dose date (Appendix 12.4). OS 
will be summarized for safety analysis set only and based on original treatment 
assignment. Crossover subjects who originally started on monotherapy and cross over 
to a combination treatment will be summarized as part of the original monotherapy group 
for OS. The analysis methods for OS will be similar to those described for PFS. 
 
8.7.5 
Serum Cancer Antigens CA-19-9 and CA-125 
Changes in CA-19-9 (ST-003) and CA-125 (ST-208) will be evaluated using descriptive 
statistics using safety analysis set.  
 
8.7.6 
Exploratory Efficacy Endpoints 
In addition to evaluation of DCR, ORR, DOR and PFS by RECIST 1.1 criteria 
exploratory endpoints of irDCR, irORR, irDOR and irPFS were planned to be evaluated 
by irRECIST criteria (Appendix 7 or 8 in the protocols). For studies that did not collect 
these immune-related responses no analysis will be performed.   


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8.7.7 
Other Exploratory Efficacy Endpoints 
Time to initial response (PR or better) in months will be calculated and summarized. 
 
 
8.7.8 
Pharmacokinetic, Pharmacodynamic and Biomarker Analyses 
Additional pharmacodynamic, pharmacokinetic and biomarker analyses may be 
performed, as deemed appropriate. A separate analysis plan for these analyses will be 
developed by PK/PD group. 
 
 
Sensitivity Analyses 
Sensitivity analyses will be done using efficacy evaluable analysis set for efficacy 
endpoints of ORR. if the primary and sensitivity analysis of ORR are consistent, we 
won’t perform sensitivity analysis using efficacy evaluable analysis set for DOR, PFS, 
and OS. They are also referenced in corresponding parts of section 9.7. 
 
9. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES  
Exploratory endpoints of irDCR, irORR, irDOR and irPFS were planned to be evaluated 
by irRECIST criteria. For studies that did not collect these endpoints no analysis will be 
performed. These changes will also be documented in the Clinical Study Report. 
Also, one event of clinical interest (ECIs) defined in these protocols (overdose) will not 
be applicable for this final analysis. Instead, an expanded list of ECIs will be summarized 
based on the emerging clinical data for acalabrutinib and recent FDA submission in 
MCL. Overdose, if occurred, will be summarized as part of the important protocol 
deviations. 
 


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10. 
LITERATURE CITATIONS / REFERENCES 
1. Guidance for Industry. Clinical Trail Endpoints for the Approval of Cancer Drugs 
and Biologics. FDA. May 2007. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation
/Guidances/ucm071590.pdf 
2. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, 
USDHHS, NIH, NCI; publish date May 28, 2009 (v4.03: June 14, 2010). 
3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45:228-247. 
4. Bohnsack O, Ludajic K, Hoos A. Adaption of the immune-related response 
criteria: irRECIST. EMSO 2014, Abstract 4958. 
 
 
 
 


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11. 
APPENDICES 
12.1  
Definitions 
Study Day 
The study day will be calculated in reference to the first dose date of study drug. Study 
Day 1 is defined as the first dose date of study drug. For assessments that occur on or 
after the first dose date of study drug, study day is defined as (date of assessment – 
first dose date of study drug + 1). For assessments that occur prior to the first dose 
date of study drug, study day is defined as (date of assessment – first dose date of 
study drug). There is no Study Day 0. 
 
Duration of Exposure 
The duration of exposure to acalabrutinib or pembrolizumab will be calculated in months 
as (last dose date - first dose date + 1) / 30.4375. The gaps in treatment will be included. 
The duration of exposure in days will be used for planned dose calculation. 
 
Total Dose   
Total dose received is a sum of all actual doses taken through the treatment duration 
and will be presented in grams. For scheduled drug administration visits that are skipped 
the actual dose will be 0. 
 
Average Daily Dose (Acalabrutinib)   
Average daily dose is total dose divided by duration of exposure in days. 
 
Average Dose per administration cycle (Pembrolizumab)   
Average dose per administration cycle is total dose divided by number of cycles for 
pembrolizumab study treatment. 
 
Relative Dose Intensity 
Relative dose intensity is the ratio of total dose to the protocol-specified total dose 
through the duration of exposure. 
 
 


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12.2  
Imputation Rules for Partial or Missing Dates 
Imputation of partial dates will be made for AE onset and stop dates, start and 
end dates of concomitant medication, start date of subsequent anticancer 
therapy, date of initial diagnosis and death date. If dates are completely missing, no 
imputation will be made. For any partial date with missing year, no imputation will be 
made. 
The general rule for imputation is: 
• 
If only day is missing, then the 15th of the month will be used. 
• 
If only year is present, then June 30th will be used. 
If such imputation date for initial diagnosis is on or after date of first dose, then date of 
first dose – 1 will be used. If such imputed date for subsequent anticancer therapies 
is before date of last dose, then date of last dose + 1 will be used.  
If the imputed date is for an AE start date and is in the same year and month as but 
before the first dose date, then the first dose date will be used, or if the imputed AE 
start date is after the AE end date, then the AE end date will be used. If the imputed 
date is for an AE start date and is in the same year and month as but after the last dose 
date + 30 days, then the last dose date + 30 days will be used.  
If the imputed date is for an AE end date and is after the death date, then the death date 
will be used, or if the imputed AE end date is before the AE start date, then the AE start 
date will be used. 
Every effort will be made to obtain complete dates for deaths. If both month and day are 
missing for death date or a death date is totally missing, do not impute and censor the 
subject survival time. If death year and month are available but day is missing, the 
following algorithm will be used: 
• 
If mmyyyy for last contact date = mmyyyy for death date, set death date to the 
day after the last contact date. 
• 
If mmyyyy for last contact date < mmyyyy for death date, set death date to the 
first day of the death month. 
• 
If mmyyyy for last contact date > mmyyyy for death date, data error and do not 
impute. 


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12.3  
Censoring Rules for Progression-free Survival 
Situation 
PFS1 
Date of Progression or 
Censoring 
Outcome 
Progression documented on scheduled visit 
Date of scheduled visit  
Progression 
Progression documented between scheduled visits  
Date of unscheduled visit  
Progression 
Treatment discontinuation for undocumented 
progression  
Date of last visit with adequate 
assessment  
Censor 
Death before first PD assessment  
Date of death  
Progression 
Death between adequate assessment visits  
Date of death  
Progression 
Death or progression after only one missed visit 
Date of death  
Progression 
Death or progression after 2 or more missed visits  
Date of last visit with adequate 
assessment  
Censor 
Death or progression after 2 or more missed visits and 
only baseline tumor assessment available 
Date of 1st dose of study drug 
Censor 
No baseline tumor assessments  
Date of 1st dose of study drug  
Censor 
Baseline tumor assessments only and no evidence of 
documented PD, treatment discontinuation due to PD or 
death within no more than one missed visit 
Date of 1st dose of study drug  
Censor 
No progression  
Date of last visit with adequate 
assessment  
Censor 
Treatment discontinuation for toxicity or other reason  
Date of last visit with adequate 
assessment  
Censor 
New anticancer treatment started  
Date of last visit with adequate 
assessment  
Censor 
 


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12.4  
Censoring Rules for Overall Survival 
Situation
Date Death or Censoring
Outcome
Death at any timepoint 
Date of death 
Death 
Lost to follow-up immediately after 1st 
dose of study drug 
Date of 1st dose study drug 
Censored 
Not known to have died at or after the 
analysis cutoff date 
The date last known alive before data 
analysis cutoff 
Censored 
Known to have died after the analysis 
cutoff date 
Date of data analysis cutoff 
Censored 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.5. 
Events of Clinical Interest for acalabrutinib 
The Events of Clinical Interest (ECIs) have been identified based on preclinical findings, emerging 
data from clinical studies relating to acalabrutinib, and pharmacological effects of approved BTK 
inhibitor.  The AEs selected for dedicated analysis were evaluated using Standardized MedDRA 
Queries (SMQs), where available, by SOC, or by Sponsor-defined baskets of MedDRA Adverse 
Event Grouped Terms. 
 
Category name 
Sub-category 
name 
Definition  
Cardiac events  
 
• 
SOC Cardiac disorders 
 
Atrial fibrillation 
• 
PT Atrial fibrillation  
• 
PT Atrial flutter 
Cytopenias –  
Anemia 
 
• 
SMQ Haematopoietic erythropenia [narrow + 
broad] 
Cytopenias – Leukopenia 
 
• 
SMQ Haematopoietic leukopenia [narrow + broad] 
 
Neutropenia 
• 
PT Febrile Neutropenia 
• 
PT Neutropenia 
• 
PT Neutropenic infection 
• 
PT Neutropenic sepsis 
• 
PT Neutrophil count decreased 
• 
PT Neutrophil percentage decreased 
 
Other Leukopenia 
• 
SMQ Haematopoietic leukopenia [narrow + broad] 
excluding PTs for neutropenia above 
Cytopenias - 
Thrombocytopenia 
 
• 
SMQ Haematopoietic thrombocytopenia [narrow + 
broad] 
Hemorrhage 
 
• 
SMQ Haemorrhage terms (excl laboratory terms) 
 
Major hemorrhage 
• 
As per Acerta definition below 
Hepatic Events 
 
• 
SMQ [narrow] Hepatic failure, fibrosis and cirrhosis 
and other liver damage-related conditions 
• 
SMQ [narrow] Liver related investigations signs  
• 
SMQ [narrow] Hepatitis, non-infectious 
Hypertension 
 
• 
SMQ Hypertension [narrow] 
Infections  
 
• 
SOC Infections and infestations 
Interstitial lung 
disease/Pneumonitis 
 
• 
SMQ [narrow] Interstitial lung disease 
Second primary 
malignancies 
 
• 
SMQ Malignant or unspecified tumours and SMQ 
Myelodysplastic syndrome [narrow] 
 
Second primary 
malignancies 
(excluding skin) 
• 
SMQ Malignant or unspecified tumours and SMQ 
Myelodysplastic syndrome [narrow], excluding skin 
(i.e. exclude SMQ Skin neoplasms, malignant and 
unspecified) 
Tumor lysis syndrome 
 
• 
PT Tumour lysis syndrome 
MedDRA version 20.1 


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Major Hemorrhage 
 
Major hemorrhage is defined as any hemorrhagic event that is serious, or Grade ≥ 3 in severity, 
or that is a central nervous system (CNS) hemorrhage (any severity grade). 
 
Search Strategy: 
I. 
Use standardized MedDRA v19.1 Query: 
o 
Haemorrhage terms (excl laboratory terms) (SMQ) [20000039] 
 
II. 
Identify Major Events that are a subset of the Haemorrhage SMQ:   
o 
Grade > 3 AE 
o 
Any SAE  
o 
All Grades of CNS hemorrhage   
CNS hemorrhage Preferred Terms (MedDRA v19.1): 
Acute haemorrhagic leukoencephalitis 
Haemorrhagic transformation stroke 
Basal ganglia haematoma 
Intracerebral haematoma evacuation 
Basal ganglia haemorrhage 
Intracranial haematoma 
Basilar artery perforation 
Intracranial tumour haemorrhage 
Brain contusion 
Intraventricular haemorrhage 
Brain stem haematoma 
Intraventricular haemorrhage neonatal 
Brain stem haemorrhage 
Meningorrhagia 
Brain stem microhaemorrhage 
Ocular retrobulbar haemorrhage 
Central nervous system haemorrhage 
Optic disc haemorrhage 
Cerebellar haematoma 
Optic nerve sheath haemorrhage 
Cerebellar haemorrhage 
Periventricular haemorrhage neonatal 
Cerebellar microhaemorrhage 
Pituitary haemorrhage 
Cerebral aneurysm perforation 
Putamen haemorrhage 
Cerebral aneurysm ruptured syphilitic 
Ruptured cerebral aneurysm 
Cerebral arteriovenous malformation haemorrhagic 
Spinal cord haematoma 
Cerebral artery perforation 
Spinal cord haemorrhage 
Cerebral haematoma 
Spinal epidural haematoma 
Cerebral haemorrhage 
Spinal epidural haemorrhage 
Cerebral haemorrhage foetal 
Spinal subarachnoid haemorrhage 
Cerebral haemorrhage neonatal 
Spinal subdural haematoma 
Cerebral microhaemorrhage 
Spinal subdural haemorrhage 
Encephalitis haemorrhagic 
Subarachnoid haematoma 
Epidural haemorrhage 
Subarachnoid haemorrhage 
Extradural haematoma 
Subarachnoid haemorrhage neonatal 
Haemorrhage intracranial 
Subdural haematoma 
Haemorrhagic cerebral infarction 
Subdural haematoma evacuation 
Haemorrhagic stroke 
Subdural haemorrhage 
Subdural haematoma evacuation 
Subgaleal haematoma 
Subdural haemorrhage 
Thalamus haemorrhage 
Subdural haemorrhage neonatal 
Traumatic intracranial haemorrhage 
 
 


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12.6. 
Events of Clinical Interest for a combination of acalabrutinib and 
pembrolizumab 
The Events of Clinical Interest (ECIs) for a combination treatment have been identified based on 
preclinical findings, emerging data from clinical studies, and finding from post marketing (for 
pembrolizumab).  
The AEs selected for dedicated analysis were evaluated using Standardized MedDRA Queries 
(SMQs), where available, by SOC, by PT or by Sponsor-defined baskets of MedDRA Adverse 
Event Grouped Terms. 
 
Category name 
Sub-category 
name 
Definition  
Cytopenias –  
Anemia 
 
• 
SMQ Haematopoietic erythropenia [narrow + 
broad] 
Cytopenias – Leukopenia 
 
• 
SMQ Haematopoietic leukopenia [narrow + broad] 
 
Neutropenia 
• 
PT Febrile Neutropenia 
• 
PT Neutropenia 
• 
PT Neutropenic infection 
• 
PT Neutropenic sepsis 
• 
PT Neutrophil count decreased 
• 
PT Neutrophil percentage decreased 
 
Other Leukopenia 
• 
SMQ Haematopoietic leukopenia [narrow + broad] 
excluding PTs for neutropenia above 
Infections  
 
• 
SOC Infections and infestations 
Transaminases elevation 
 
• 
PT Alanine aminotransferase increased  
• 
PT Aspartate aminotransferase increased  
• 
PT Transaminases increased   
Immune-mediated 
pneumonitis 
 
• 
PT Pneumonitis 
Immune-mediated colitis 
 
• 
PT Colitis 
Immune-mediated 
hepatitis 
 
• 
PT Hepatitis 
• 
PT Autoimmune hepatitis 
Immune-mediated 
endocrinopathies - 
Hypophysitis 
 
• 
PT Hypophysitis 
• 
PT Hypopituitarism 
• 
PT Adrenal insufficiency 
Immune-mediated 
endocrinopathies - Thyroid 
disorders 
 
• 
PT Hyperthyroidism 
• 
PT Hypothyroidism 
• 
PT Thyroiditis 
Immune-mediated 
endocrinopathies - Type 1 
diabetes 
 
• 
PT Type 1 diabetes mellitus 
• 
PT Diabetic ketoacidosis 
Immune-mediated 
nephritis 
 
• 
PT Nephritis 
Immune-mediated skin 
adverse reactions 
 
• 
PT Stevens-Johnson syndrome 
• 
PT Toxic epidermal necrolysis 
MedDRA version 20.1