Conditions: Metastatic Breast Cancer
Keywords: Metastatic Breast trastuzumab-resistant PD-L1 expressing HER2-positive
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 58
Healthy volunteers: no

Brief summary:
Panacea is a phase Ib/II trial evaluating the efficacy of MK-3475 and trastuzumab in patients with trastuzumab-resistant, HER2- positive metastatic breast cancers

Detailed description:
A significant amount of preclinical and correlative clinical data suggest that HER2-positive breast cancer could be amenable to immune¬therapeutic approaches. The presence of HER2-overexpression in breast cancers is associated with higher levels of proliferation, high histologic grade and higher levels of tumor infiltrating lymphocytes (TILs) compared with HER2-negative tumors. The investigators therefore hypothesize that for HER2-positive tumors, avoidance of destruction by the host immune system must be an important mechanism contributing to tumor growth and progression.

The term "immune evasion" refers to the ability of the tumor to suppress and change host anti-tumor immune reactions. The programmed cell death 1 (PD-1) pathway represents a major immune control switch which may be engaged by tumor cells to overcome active T-cell immune surveillance. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in various tumors. High expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in various other solid tumor types. Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion in patients with malignant melanoma. These observations suggest that the PD-1/PD-L1 pathway plays a critical role in the tumor immune evasion and could be considered an attractive target for therapeutic intervention in several solid organ types.

MK-3475 (previously known as SCH 900475) is a potent and highly-selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 strongly enhances T lymphocyte immune responses in cultured blood cells from healthy human donors, cancer patients, and primatesMK-3475 also modulates the level of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines.

The investigators therefore propose to evaluate if the addition of an immunotherapy can reverse trastuzumab resistance and improve clinical outcomes in HER2-positive disease. In this study the investigators will determine if a monoclonal antibody targeted against PD-1, a T cell negative regulator, can reverse trastuzumab resistance in patients previously progressing on trastuzumab.

Arms:
arm 1: Phase Ib: MK-3475 at dose of 2 mg/kg or 10 mg/kg (i.v.), or a fall-back dose of 1 mg/kg, together with trastuzumab 6mg/kg by (i.v.) once every 3 weeks.

Phase II: MK-3475 at a flat dose of 200mg (i.v.) together with trastuzumab 6mg/kg (i.v.) once every 3 weeks until progression, lack of tolerability, or 24 months of treatment.

A dose of 8mg/kg trastuzumab will be used in cycle 1 if prior treatment with trastuzumab was stopped more than 3 months before.

Interventions: intervention 1: MK-3475
Intervention descriptions: intervention 1: The phase Ib trial will determine the recommended dose from three MK-3475 dose levels: 1mg/kg, 2 mg/kg or 10 mg/kg.

Protocol document:
Prot_000.pdf: 
IBCSG 45-13 / BIG 4-13 PANACEA 
 
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A phase Ib/II trial evaluating the efficacy of MK-3475 and 
trastuzumab in patients with trastuzumab-resistant, HER2-
positive metastatic breast cancers 
 
PANACEA – anti-PD-1 monoclonAl aNtibody in AdvanCed, 
trastuzumab-resistant, HER2-positive breAst cancer 
 
 
 
EudraCT number: 
2013-004770-10 
NCT Number: 
NCT02129556 
 
Merck number: 
MK-3475 protocol 14 
 
Sponsor:   
International Breast Cancer Study Group 
(IBCSG) 
 
 
IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 389 93 91 
Fax: +41 31 389 93 92 
 
 
Amendment 1 
 
Protocol Version 2.1 
 
 
 
 
 
 
 
 
 
 
 
 
INTERNATIONAL BREAST 
CANCER STUDY GROUP 
IBCSG 45-13/BIG 4-13 
 
PANACEA 
 
 
 
 
 


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Trial Specific Contacts 
 
Trial Chair 
Assoc. Prof. Sherene Loi 
Department of Medical Oncology 
Peter MacCallum Cancer Centre 
St Andrew’s Place 
East Melbourne, Victoria 3002 
Australia 
Email: sherene.loi@petermac.org 
Tel: +61 (0) 396 563 642 
Fax: +61 (0) 396 561 411 
Trial Co-Chair 
Prof. Fabrice André  
Department of Medical Oncology 
Institut Gustave Roussy 
114 rue E Vaillant 
94800 Villejuif 
France 
Email: fabrice.andre@igr.fr 
Tel: +33142114371 
Fax: +33142115274 
 
Translational Research 
Committee Co-chairs: 
Prof. Mark J Smyth, Immunology in 
Cancer Laboratory, Queensland 
Institute of Medical Research, Hersten, 
QLD, Australia 
Giuseppe Curigliano, European 
Institute of Oncology, Milan, Italy 
Email: mark.smyth@qimr.edu.au 
Tel: +61 7 3845 3957 
Fax: +61 7 3362 0111 
 
Email: giuseppe.curigliano@ieo.it 
Tel: +39 (02) 57489788 
Fax: +39 (02) 94379224 
 
 
 
Trial Statistician 
Anita Giobbie-Hurder, MS 
IBCSG Statistical Center 
 
Email: agiohur@jimmy.harvard.edu 
Tel: +1 617-632-2193 
Fax: +1 617-632-5444 
 
 
 
Lead Trial Data Manager 
Trial Data Manager 
Lead Trial Coordinator 
Trial Coordinator 
Susan Fischer 
Monica Greco 
Holly Shaw 
Colleen King 
IBCSG Data Management Center 
 
Email: ibcsg45_PANACEA@fstrf.org 
Tel: +1 716-834-0900 (general) 
Fax:  +1 716-833-3990 
IBCSG Central Pathology Office 
Rosita Kammler 
Stefania Andrighetto/Elvira Benini        
 
Email: rosita.kammler@ibcsg.org 
Email: pathology.ibcsg@ieo.it 
Tel: +39 0257 489 928 
 
 Central Laboratory 
Quintiles 
Alba Campus, Rosebank 
Livingston, West Lothian 
Scotland, EH54 7EG, UK 
 
 
 
 
 
 


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IBCSG Contacts 
 
Coordinating Center 
 
 
Anita Hiltbrunner 
Dr. Barbara Ruepp 
Dr. Manuela Rabaglio 
Dr. Rudolf Maibach 
Linda Fritzsche / Sabrina Ribeli-
Hofmann  
Rosita Kammler 
IBCSG Coordinating Center 
Effingerstrasse 40 
CH-3008  Bern, Switzerland 
Email: anita.hiltbrunner@ibcsg.org  
Email: barbara.ruepp@ibcsg.org 
Email: manuela.rabaglio@ibcsg.org 
Email: rudolf.maibach@ibcsg.org 
Email: drugsupply@ibcsg.org 
 
Email: rosita.kammler@ibscg.org 
Tel: +41 31 389 9391 
Fax: +41 31 389 9392 
 
 
 
Data Management Center 
Lynette Blacher 
Karolyn Scott 
FSTRF, 
4033 Maple Rd.  
Amherst, NY  14226 USA 
Email: blacher.lynette@fstrf.org 
Email: scott.karolyn@fstrf.org 
Tel: +1 716 834-0900 
Fax: +1 716 833-3990 
 
Data Quality Control Office 
 
IBCSG Data Management Center 
 
 
Email: ib.dqc@fstrf.org 
 
Center Training Office 
 
IBCSG Data Management Center 
E-mail: ibcsg.training@fstrf.org 
 
 
 
 
Statistical Center 
Prof. Richard D. Gelber 
Dr. Meredith M. Regan 
Email: gelber@jimmy.harvard.edu 
Email: mregan@jimmy.harvard.edu 
 
Anita Giobbie-Hurder 
Email: agiohur@jimmy.harvard.edu 
 
Dept. of Biostatistics and 
Computational Biology, CLSB 11007 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215  USA 
Tel: +1 617-632-3012 
Fax: +1 617-632-5444 
 
 
 
Central Pathology Office 
Prof. Giuseppe Viale 
University of Milan & European 
Institute of Oncology 
Milan, Italy 
E-mail: giuseppe.viale@ieo.it 
Tel: +39 02 5748 9419 
Fax: +39 02 5748 9417 
 
 
 
 
Scientific Committee Chair 
Dr. Marco Colleoni  
European Institute of Oncology 
Milan, Italy 
Email: marco.colleoni@ieo.it 
Tel: +39 02 574 89 439 
Fax: +39 02 574 89 581 
 
 
 
 
In collaboration with Merck Sharp & Dohme Corp.  
 
 


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Protocol Signature Page 
 
IBCSG 45-13 
 
PANACEA 
 
 
 
 
 
 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Dr. M.M. Regan 
 
 
 
Signature on file 
 
 
 
 
 
 
14 Apr 2014 
___________________________________________________ 
______________ 
 
 
 
Date 
 
 
 
Approved by: 
Director, International Breast Cancer Study Group 
Anita Hiltbrunner 
 
 
 
Signature on file 
 
 
 
 
 
 
14 Apr 2014 
___________________________________________________ 
______________ 
 
 
 
Date 


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Protocol Signature Page Amendment 1 
 
IBCSG 45-13 
 
PANACEA 
 
 
 
 
 
 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Dr. M.M. Regan 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________ 
______________ 
 
 
 
Date 
 
 
 
Approved by: 
Director, International Breast Cancer Study Group 
Anita Hiltbrunner 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________ 
______________ 
 
 
 
Date 


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Principal Investigator Protocol Signature Page 
Amendment 1 
 
IBCSG 45-13 
PANACEA 
 
I have read the protocol and agree that it contains all necessary details for conducting this 
trial. I will conduct the trial as outlined in the following protocol and in compliance with 
GCP, and will apply due diligence to avoid protocol deviations. I will provide copies of the 
protocol and all drug information relating to pre-clinical and prior clinical experience 
furnished to me by IBCSG, to all physicians responsible to me who participate in this 
trial. I will discuss this material with them to assure that they are fully informed 
regarding the drugs and the conduct of the trial. I agree to keep records on all patient 
information (Case Report Forms and patient's Informed Consent statement), drug-shipment 
and return forms, and all other information collected during the trial for a minimum period 
of 15 years. 
 
Name of Principal Investigator: ___________________________________________ 
 
 
_____________________________________________________ ______________ 
 
 
Signature 
Date 
 


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TABLE OF CONTENTS 
Section 
 
 
 
 
 
 
 
 
 
 
Page 
Trial Specific Contacts ............................................................................................................. 2 
IBCSG Contacts ....................................................................................................................... 3 
1. 
Protocol Summary and Schema .................................................................................. 10 
2. 
Trial schedule .............................................................................................................. 21 
3. 
List of abbreviations .................................................................................................... 23 
4. 
Background and scientific rationale ............................................................................ 25 
4.1. 
HER2-positive metastatic breast cancers ............................................................ 25 
4.2. 
Rationale for combining immune checkpoint modulators and trastuzumab ....... 25 
4.3. 
Anti-PD-1 and PD-L1 antibodies ........................................................................ 27 
4.4. 
Trial hypothesis ................................................................................................... 31 
4.5. 
Overall risk-benefit assessment ........................................................................... 32 
4.6. 
Rationale for the trial design ............................................................................... 32 
5. 
Trial objectives and endpoints ..................................................................................... 33 
5.1. 
Primary endpoint ................................................................................................. 34 
5.2. 
Secondary endpoints ............................................................................................ 34 
5.3. 
Correlative objectives .......................................................................................... 34 
5.4. 
Exploratory objectives ......................................................................................... 34 
6. 
Trial design, duration and termination ........................................................................ 34 
6.1. 
Trial design .......................................................................................................... 35 
6.2. 
Trial schema ........................................................................................................ 36 
6.3. 
Clinical evaluations ............................................................................................. 36 
6.4. 
Biological evaluations ......................................................................................... 37 
6.5. 
Sample size and trial duration ............................................................................. 37 
7. 
Patient selection ........................................................................................................... 38 
7.1. 
Eligibility criteria for screening ........................................................................... 38 
7.2. 
Exclusion criteria for screening ........................................................................... 40 
7.3. 
Inclusion criteria for enrollment .......................................................................... 41 
7.4. 
Exclusion criteria for enrollment ......................................................................... 42 
8. 
Patient registration for screening and enrollment ........................................................ 43 
8.1. 
Registration for screening .................................................................................... 43 
8.2. 
Prior to enrollment ............................................................................................... 44 
8.3. 
Registration for Enrollment ................................................................................. 44 
8.4. 
Registration Help Desk ........................................................................................ 44 
9. 
Trial drugs formulation and handling .......................................................................... 45 
9.1. 
MK-3475 ............................................................................................................. 45 
9.2. 
Trastuzumab ........................................................................................................ 46 
10. 
Treatment ..................................................................................................................... 46 
10.1. 
Trial treatments .................................................................................................... 46 
10.2. 
Phase Ib: dose finding and DLTs ........................................................................ 46 
10.3. 
Phase II dose of MK-3475 ................................................................................... 48 
10.4. 
Treatment Administration .................................................................................... 48 
10.5. 
Dose modifications and delays for trastuzumab .................................................. 49 
10.6. 
Dose modifications and delays for MK-3475...................................................... 52 
10.7. 
Concomitant Medications/Vaccinations (allowed & prohibited) ........................ 60 
10.8. 
Diet/Activity/Other Considerations ..................................................................... 61 
10.9. 
Stop of treatment ................................................................................................. 62 
11. 
Safety ........................................................................................................................... 63 
11.1. 
Adverse effects of MK-3475 ............................................................................... 63 


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11.2. 
Immune-related adverse effects of MK-3475 ...................................................... 64 
11.3. 
Drug interactions with MK-3475 ........................................................................ 64 
11.4. 
Adverse effects of trastuzumab ........................................................................... 64 
11.5. 
Safety Assessment in stage 1 of phase II ............................................................. 64 
12. 
Adverse event and serious adverse event reporting .................................................... 65 
12.1. 
Adverse event reporting ....................................................................................... 65 
12.2. 
Serious adverse event (SAE) reporting ............................................................... 67 
12.3. 
Definition of Events of Clinical Interest.............................................................. 68 
12.4. 
Reporting SAEs and ECIs ................................................................................... 68 
12.5. 
Pregnancy ............................................................................................................ 69 
12.6. 
Reference Safety Information .............................................................................. 70 
13. 
Disease assessment, response and progression (RECIST 1.1) .................................... 70 
13.1. 
Introduction ......................................................................................................... 70 
13.2. 
Methods of assessment ........................................................................................ 70 
13.3. 
Measurability of tumor at baseline ...................................................................... 71 
13.4. 
Selection of target lesions .................................................................................... 72 
13.5. 
Selection of non-target lesions ............................................................................ 72 
13.6. 
Evaluation of target lesions (measurable disease) ............................................... 73 
13.7. 
Evaluation of non-target lesions .......................................................................... 73 
13.8. 
Determination of new lesions .............................................................................. 74 
13.9. 
Additional considerations .................................................................................... 74 
13.10. Confirmation ........................................................................................................ 74 
13.11. Determination of time point response ................................................................. 74 
13.12. Determination of best overall response ............................................................... 75 
13.13. Storage of imaging............................................................................................... 75 
14. 
Clinical and laboratory evaluations ............................................................................. 75 
14.1. 
Screening ............................................................................................................. 75 
14.2. 
Central confirmation of HER2+ and PD-L1 status ............................................. 76 
14.3. 
Biological samples before, during and after treatment ........................................ 77 
14.4. 
Day 1 of every treatment cycle ............................................................................ 77 
14.5. 
Every second treatment cycle .............................................................................. 77 
14.6. 
Tumor assessments .............................................................................................. 77 
14.7. 
Cardiac evaluation ............................................................................................... 77 
14.8. 
After discontinuation of trial treatment ............................................................... 78 
14.9. 
Follow-up prior to documented disease progression ........................................... 79 
14.10. At progression...................................................................................................... 80 
15. 
Biological evaluations ................................................................................................. 80 
15.1. 
Introduction and overview ................................................................................... 80 
15.2. 
Submitting pathology material to IBCSG ........................................................... 81 
15.3. 
Central testing of HER2 and PD-L1 .................................................................... 82 
15.4. 
Banking biological material ................................................................................. 82 
15.5. 
Translational research .......................................................................................... 83 
16. 
Data submission .......................................................................................................... 85 
16.1. 
Case report forms schedule .................................................................................. 86 
16.2. 
Signing and submitting forms.............................................................................. 87 
16.3. 
Data management ................................................................................................ 87 
16.4. 
Investigator Site File ............................................................................................ 88 
16.5. 
Authorization Log................................................................................................ 89 
16.6. 
Patient Identification Log .................................................................................... 89 
17. 
Statistical considerations ............................................................................................. 89 


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17.1. 
Primary and Secondary Endpoints ...................................................................... 89 
17.2. 
Definitions of Trial Populations .......................................................................... 90 
17.3. 
Design and Sample Size Determination .............................................................. 90 
17.4. 
Safety Monitoring ................................................................................................ 92 
17.5. 
Screening and Enrollment ................................................................................... 94 
17.6. 
Analysis of Demographics/Baseline Characteristics ........................................... 94 
17.7. 
Efficacy Analysis (Phase II) ................................................................................ 94 
17.8. 
Correlative Objectives ......................................................................................... 95 
17.9. 
Exploratory Objectives ........................................................................................ 97 
18. 
Ethical aspects, regulatory approval, and patient informed consent ........................... 97 
18.1. 
Ethical Review Board/Ethics Committee ............................................................ 98 
18.2. 
Regulatory approval procedures .......................................................................... 98 
18.3. 
Protection of human patients ............................................................................... 98 
18.4. 
Informed Consent ................................................................................................ 98 
18.5. 
Premature withdrawal .......................................................................................... 99 
19. 
Governance and Administrative Considerations ....................................................... 100 
19.1. 
Insurance ............................................................................................................ 100 
19.2. 
Steering Committee ........................................................................................... 100 
19.3. 
Data and Safety Monitoring Committee (DSMC) ............................................. 100 
19.4. 
Endpoint Committee .......................................................................................... 100 
19.5. 
Publication of trial results .................................................................................. 100 
19.6. 
Premature discontinuation of the trial ............................................................... 101 
19.7. 
Quality Assurance.............................................................................................. 101 
19.8. 
Protocol adherence ............................................................................................ 101 
19.9. 
Data protection .................................................................................................. 102 
19.10. Record Retention ............................................................................................... 102 
20. 
Confidentiality ........................................................................................................... 102 
21. 
References ................................................................................................................. 102 
 
Appendices  
1. Requirements for Informed Consent  
 
Index of Tables 
Table 1  Dose escalation rules ............................................................................................... 47 
Table 2  Body weight based dose levels ................................................................................ 48 
Table 3  Actions to be taken in case of trastuzumab related adverse events ......................... 49 
Table 4 NYHA functional classification ................................................................................ 51 
Table 5  Treatment delay and supportive care guidelines for drug-related adverse events ... 53 
Table 6  Infusion reaction treatment guidelines ..................................................................... 59 
Table 7  Measurable disease - overall response ..................................................................... 74 
Table 8  Tumor tissue samples............................................................................................... 80 
Table 9  Blood samples for all patients .................................................................................. 81 
Table 10  Operating characteristics of early cardiac monitoring ........................................... 93 
Table 11  Operating characteristics of early safety monitoring ............................................. 93 
 
  
 


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1. 
Protocol Summary and Schema 
 
TITLE 
A phase Ib/II trial evaluating the efficacy of MK-3475 and trastuzumab 
in patients with trastuzumab-resistant, HER2-positive metastatic breast 
cancers (PANACEA) 
SPONSOR 
International Breast Cancer Study Group (IBCSG) 
PHARMA 
PARTNER 
Merck Sharp & Dohme Corp. 
CLINICAL 
PHASE 
Phase Ib/II 
Note: The phase Ib part of the trial was completed in August 2015. 
POPULATION 
Patients with HER2-positive, PD-L1 expressing, unresectable loco-
regional or metastatic breast carcinoma which has progressed on prior 
trastuzumab-based therapy. A parallel cohort of 15 patients with HER2-
positive, PD-L1 negative disease will be enrolled in the phase II study. 
TREATMENT 
Treatment: In the phase Ib trial, three MK-3475 body weight based dose 
levels: 2 mg/kg, 10 mg/kg, or a fall-back dose of 1 mg/kg together with 
trastuzumab 6 mg/kg i.v. every 3 weeks. MK-3475 at 200 mg, 
administered by i.v. infusion, will be the dose for the phase II together 
with trastuzumab 6 mg/kg i.v. every 3 weeks until progression, lack of 
tolerability, or 24 months of treatment. A loading dose of 8 mg/kg i.v. 
trastuzumab in cycle 1 is needed if trastuzumab has been stopped more 
than 3 months before.    
 
 


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TRIAL SCHEMA  
 
 
RATIONALE 
There is a clear need to develop new therapeutic agents for patients 
presenting with HER2-overexpressing or HER2-positive metastatic 
breast cancer.  
A significant amount of preclinical and correlative clinical data suggests 
that HER2-positive breast cancer could be amenable to immuno-
therapeutic approaches. Recently, new data have reported that tumor 
regressions in vivo from the anti-HER2 monoclonal antibody (mAb) 
therapy, trastuzumab, require an effective adaptive host anti-tumor 
immune response. In immunocompetent mice, combination of the anti-
HER2 mAb and anti-PD-1 therapy was shown to be synergistic and 
more effective than either monotherapy in mammary tumors that 
overexpress HER2. The presence of HER2-overexpression in breast 
cancers is associated with higher levels of proliferation, high histologic 
grade and higher levels of tumor infiltrating lymphocytes (TILs) 
compared with HER2-negative tumors. We therefore hypothesize that 
for HER2-positive tumors, avoidance of destruction by the host immune 
system must be an important mechanism contributing to tumor growth 
Screening: unresectable locoregional or metastatic breast cancer overexpressing HER2
Submit an FFPE block from core biopsy for central testing
Central Testing:
HER2 by IHC
Phase Ib: dose finding for MK-3475 in 3+3 design  ─  Phase II 200mg
Treatment in 3 week cycles:
1
2
3
4
5  etc………..… PD
T : trastuzumab  6mg/kg
T
T
T
T
T
M : MK-3475      200mg
M
M
M
M
M
HER2 neg:
not eligible
HER2 pos:
Central PD-L1 testing
PD-L1 neg: enroll 15 
patients in phase II
PD-L1 positive: enroll
40 patients in phase II
Blood samples:
whole blood
plasma prior to cycles 1, 3, 5 and then every 3 cycles, 
and 30 days after end of tx
Tissue
at enrollment:
re-biopsy at PD *:
Samples:
FFPE block
FFPE Block
Fresh frozen block *
Fresh frozen block
* if feasible
* if feasible


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and progression.  
The term “immune evasion” refers to the ability of the tumor to 
suppress and change host anti-tumor immune reactions. The 
programmed cell death 1 (PD-1) pathway represents a major immune 
control switch, which may be engaged by tumor cells to overcome 
active T-cell immune surveillance.  The ligands for PD-1 (PD-L1 and 
PD-L2) are constitutively expressed or can be induced in various 
tumors.  High expression of PD-L1 on tumor cells (and to a lesser 
extent of PD-L2) has been found to correlate with poor prognosis and 
survival in various other solid tumor types. Furthermore, PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in patients with 
malignant melanoma. These observations suggest that the PD-1/PD-L1 
pathway plays a critical role in the tumor immune evasion and could be 
considered an attractive target for therapeutic intervention in several 
solid organ types. 
MK-3475 (previously known as SCH 900475) is a potent and highly 
selective humanized mAb of the IgG4/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2. MK-3475 contains the S228P stabilizing mutation and has no 
antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-
dependent cytotoxicity (CDC) activity.  MK-3475 strongly enhances T 
lymphocyte immune responses in cultured blood cells from healthy 
human donors, cancer patients, and primates.  In T-cell activation assays 
using human donor blood cells, the EC50 was in the range of 0.1 to 0.3 
nM. MK-3475 also modulates the level of interleukin-2 (IL-2), tumor 
necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other 
cytokines.  The antibody potentiates existing immune responses only in 
the presence of antigen and does not nonspecifically activate T-cells.  
We therefore propose to evaluate if the addition of an immunotherapy 
can reverse trastuzumab resistance and improve clinical outcomes in 
HER2-positive disease. In this study, we will determine if a monoclonal 
antibody targeted against PD-1, a T-cell negative regulator, can reverse 
trastuzumab 
resistance 
in 
patients 
previously 
progressing 
on 
trastuzumab. The combination will be evaluated in the metastatic setting 
to demonstrate safety of the combination and the single arm study 
approach will be used as it is standard-of-care in the HER2-positive 
metastatic population to continue an anti-HER2 therapy back-bone (in 
this case trastuzumab) even after progression. This will be the first trial 
that will evaluate the efficacy of an immunotherapeutic approach in 
breast cancer.  
 
 


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ELIGIBILITY 
Inclusion criteria for screening: 
 Female gender 
 Age ≥18 years 
 Histologically 
confirmed 
breast 
adenocarcinoma 
that 
is 
unresectable loco-regional, or metastatic. 
 Locally confirmed HER2-positivity (immunohistochemistry score 
3+) or ERBB2-amplification (Ratio ERBB2/centromeres ≥2.0 or 
mean gene copy number ≥6) of primary tumor or of biopsy from 
metastatic or unresectable loco-regional lesion. 
 Must have trastuzumab resistant disease, defined by 
- demonstrated progression of disease while on treatment with 
trastuzumab (monotherapy or combination-based therapy) or 
trastuzumab-emtansine (T-DM1) for metastatic or unresectable 
loco-regional disease. 
- recurrence while on adjuvant trastuzumab or within 12 months 
of completing adjuvant trastuzumab.  
- Any number of prior lines of anti-HER2 therapy acceptable. 
Patients for whom the treatment with the current first-line 
combination of trastuzumab, pertuzumab and taxanes is not an 
option (e.g., due to refusal or contraindication) can be considered 
for enrollment into this trial. 
 Progression/recurrence 
must 
have 
been 
demonstrated 
by 
radiological or clinical assessment. 
 If a patient has received a subsequent anti-HER2 therapy, she must 
also have progressed on the subsequent therapy. Progression must 
have been demonstrated by radiological or clinical assessment. 
 Presence of at least one measurable lesion as defined by RECIST 
1.1. 
 LVEF  ≥50% 
 Patient agrees to submit an FFPE tumor biopsy for central 
confirmation of HER2-positivity and central assessment of PD-L1 
status. This can be from archival tissue sample from unresectable 
loco-regional or metastatic disease obtained ≤1 year prior to 
enrollment or new tissue material from a recently obtained surgical 
or diagnostic biopsy. Tissue obtained for the biopsy must not have 
been previously irradiated.  
Note: Central Pathology Review on a tumor biopsy is mandatory 
for this trial, and patients will be evaluated centrally for eligibility.  
 Written Informed Consent (IC) for screening procedures and trial 
participation must be signed and dated by the patient and the 


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Investigator prior to screening. 
 Written consent to biological material submission, indicating the 
patient has been informed of and agrees to tissue and blood material 
use, transfer and handling, must be signed and dated by the patient 
and the Investigator prior to any procedures specific for this trial, 
including consent to translational research on FFPE and fresh 
frozen tumor biopsies in case the patient is enrolled into the trial. 
 The patient has been informed of and agrees to data transfer and 
handling, in accordance with national data protection guidelines. 
 Eastern Cooperative Oncology Group (ECOG) Performance Status 
0-1. 
 Life expectancy >3 months. 
 Hematopoietic status: 
- Absolute neutrophil count ≥1.5 × 109/L, 
- Platelet count ≥100 × 109/L, 
- Hemoglobin ≥9 g/dL 
 Hepatic status: 
- Serum total bilirubin ≤1.5 × upper limit of normal (ULN). In the 
case of known Gilbert’s syndrome, a higher serum total bilirubin 
(<2 × ULN) is allowed. 
- AST and ALT ≤2.5 × ULN; if the patient has liver metastases, 
ALT and AST must be ≤5 × ULN. 
 Renal status:  
- Creatinine ≤1.5 ×ULN or creatinine clearance > 60 mL/min 
- Proteinuria <1 g/day 
 International Normalized Ratio (INR) or Prothrombin Time (PT) 
≤1.5 × ULN unless patient is receiving anticoagulant therapy as 
long as PT or PTT (partial thromboplastin time) is within 
therapeutic range of intended use of anticoagulant. 
Exclusion criteria for screening: 
 Prior therapy with other anti-PD-1, anti- PD-L1, L2 or anti-CTLA4 
therapy. 
 No FFPE material to centrally assess HER2-positivity and PD-L1 
expression. 
 Known Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies), or positive for Hepatitis B (HBsAg reactive) or 
Hepatitis C (HCV RNA [qualitative]). 
 Interstitial lung disease 
 History of or active pneumonitis requiring treatment with steroids 


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 Active central nervous system metastases, as indicated by clinical 
symptoms, cerebral edema, and/or progressive growth (patients 
with history of CNS metastases or spinal cord compression are 
eligible if they are clinically and radiologically stable for at least 4 
weeks before first dose of investigational product and have not 
required high-dose steroid treatment in the last 4 weeks).  
 Leptomeningeal disease 
 History of clinically significant or uncontrolled cardiac disease, 
including congestive heart failure (New York Heart Association 
functional classification ≥3), angina, myocardial infarction or 
ventricular arrhythmia. 
 Previous severe hypersensitivity reaction to treatment with another 
monoclonal antibody. 
 Active infection requiring systemic therapy. 
 Chronic systemic therapy with 
immunosuppressive agents 
including corticosteroids. 
 Concurrent disease or condition that would make the patient 
inappropriate for trial participation or any serious medical disorder 
that would interfere with the patient’s safety. 
 Known history of uncontrolled hypertension (≥180/110), unstable 
diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen. 
 Dementia, altered mental status, or any psychiatric condition that 
would prevent the understanding or rendering of Informed Consent. 
 Treatment with an investigational agent in the 4 weeks before 
enrollment. 
 Active autoimmune disease or a documented history of 
autoimmune disease, or a syndrome that requires systemic steroids 
or immunosuppressive agents.  Patients with vitiligo or resolved 
childhood asthma/atopy would be an exception to this rule.  Patients 
that require intermittent use of bronchodilators or local steroid 
injections would not be excluded from the trial.  Patients with 
hypothyroidism stable on hormone replacement or Sjögren’s 
syndrome will not be excluded from the trial. 
 Chemotherapy, radioactive therapy, and/or biological cancer 
therapy within 3 weeks prior to the first trial dose and has not 
recovered to CTCAE v.4.0 grade 1 or better from adverse events. 
 Pregnant or lactating women; lactation has to stop before 
enrollment. 
 The patient of childbearing potential who is unwilling to use highly 
effective contraception during treatment and up to 7 months after 


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stop of trial treatment.  Acceptable methods are intrauterine devices 
(without hormones), bilateral tubal occlusion, vasectomized partner 
or total abstinence. Oral, injectable, or implant hormonal 
contraceptives are not allowed. 
 Unresolved or unstable, serious adverse events from prior 
administration of another investigational drug. 
 Active or uncontrolled infection CTCAE v.4.0 grade 2 or higher. 
 Live vaccines within 30 days prior to the first dose of trial therapy 
and during trial treatment.  
Inclusion criteria for enrollment: 
All inclusion criteria for screening, plus: 
 Central lab confirmation on a metastatic biopsy (or biopsy from 
unresectable loco-regional disease) of:  
- HER2-positivity (immunohistochemistry score 3+) or ERBB2- 
amplification (Ratio ERBB2/centromeres ≥2.0 or mean gene 
copy number ≥ 6), 
- Presence of PD-L1 expression assessed by IHC (During the 
phase II portion of the trial a parallel, secondary cohort of 15 
patients with PD-L1 negative disease will be enrolled see note in 
section 7.3.1). 
 Patient agrees to submit tumor tissue for translational research: 
- tissue biopsy from unresectable loco-regional or metastatic 
disease obtained ≤1 year prior to enrollment or new tissue 
material from a recently obtained surgical or diagnostic biopsy. 
For patients who have presented with stage 4 disease de novo, a 
biopsy taken from the presumed primary breast lesion is 
acceptable (provided this was taken ≤1 year prior to enrollment). 
- if available: FFPE tumor block from primary surgery or 
diagnostic biopsy. 
- if available: pre-treatment fresh frozen tumor biopsy. 
- if feasible: FFPE tumor block from post-treatment biopsy will be 
taken at time of disease progression or end of all treatment if 
ended prior to progression. This re-biopsy is strongly advised. 
- if feasible: fresh frozen tumor biopsy from post-treatment biopsy 
will be taken at time of disease progression or end of all 
treatment if ended prior to progression. 
 Patient agrees to submit baseline (pre-treatment) blood and serial 
plasma for translational research, as detailed in Table 9 (see body of 
the protocol). 
 For patient of childbearing potential, negative serum pregnancy 


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test. Pregnancy test has to be repeated within 72h before treatment 
start. 
 All anti-cancer treatment including endocrine therapy, with the 
exception of trastuzumab, must stop 3 weeks prior to first dose of 
trial treatment. 
Exclusion criteria for enrollment: 
All exclusion criteria for screening apply for enrollment as well. 
Excluded are especially patients who have received any of the 
treatments below: 
 Live vaccines within 30 days prior to the first dose of trial therapy 
and during trial treatment.  
 History of CNS metastases or spinal cord compression if they have 
not been clinically stable for at least 4 weeks before first dose of 
investigational product and require high-dose steroid treatment. 
 Treatment with an investigational agent in the 4 weeks before 
enrollment. 
 Patient has not recovered to CTCAE v.4.0 grade 1 or better from 
adverse events of prior therapy, except alopecia grade 2. 
 Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or 
positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV 
RNA [qualitative]). 
TRIAL  
OBJECTIVES 
AND 
ENDPOINTS 
Primary objective 
The primary objectives of this phase Ib/II study are to determine the 
recommended dose of the anti-PD-1 mAb, MK-3475, in combination 
with standard dose trastuzumab, and to evaluate the efficacy and safety 
profile of the drug combination in patients with PD-L1 expressing, 
HER2-positive, unresectable loco-regional or metastatic breast cancer 
who have experienced progression during prior trastuzumab-based 
therapy. 
Note: The phase Ib part of the trial was completed in August 2015. 
The secondary objective is to explore the efficacy and safety of the drug 
combination in patients with PD-L1 negative, HER2-positive 
unresectable loco-regional or metastatic breast cancer who have 
experienced progression during prior trastuzumab-based therapy. 
Primary endpoint 
Phase Ib (dose finding): Dose-limiting toxicity of the anti-PD-1 mAb 
MK-3475 in combination with standard dose trastuzumab (defined in 
section 10.2.1) 
Phase II: Objective response (confirmed CR or PR as best overall 
response) based on RECIST 1.1 criteria (defined in section 13) 


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Secondary endpoints 
For a precise definition of secondary endpoints please see section 17.1:  
 Safety and tolerability as documented according to CTCAE v.4.0 
 Disease control (DC)  
 Duration of response (DoR)  
 Time to progression (TTP)  
 Progression-free survival (PFS)  
 Overall survival (OS) 
Correlative objectives 
Correlative studies will investigate: 
 Responses according to levels of PD-L1, measured by IHC in 
metastatic (or unresectable loco-regional) lesion.  
 Responses according to levels of tumor infiltrating lymphocytes. 
 Responses according to ER status.  
 Responses according to FISH ratio and HER2 copy number.  
 Tumor dynamics during the disease course as well as emergence of 
new clones (i.e., resistance mechanisms) by determination of 
circulating plasma DNA (cpDNA). 
 Sequencing of material from tumor biopsies to determine molecular 
characteristics profiles of responders and non-responders 
Exploratory objectives 
 To describe TTP for patients with moderate partial response (MPR) 
compared with very good partial response (VGPR). 
 To explore the prognostic ability of pre-treatment ER, PD-L1, and 
TILs with respect to MPR and VGPR. 
TRANSLA-
TIONAL 
RESEARCH 
This is a proof-of-concept trial exploring a new therapeutic area for 
breast cancer. A complete collection of biological materials is requested 
in order to be able to comprehensively define the molecular and 
immune landscape of these tumors. The goals of the translational 
research will be to determine mechanisms and biomarkers for MK-3475 
efficacy and resistance.  
 Paired metastatic biopsies (FFPE +/- fresh frozen) at screening prior 
to enrollment and at progression after trial treatment for PD-L1 
expression assessment and evaluation of tumor infiltrating 
lymphocytes.  
- Quantification of PD-L1 expression will be done by a certified 
IHC test in a central lab.  
- Quantification of tumor infiltrating lymphocytes will be 


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performed independently by two pathologists. 
- Frozen and FFPE biopsies will be retained for sequencing using 
next generation technologies at the completion of the trial. 
 A whole blood sample to be taken prior to the start of trial treatment 
for future research purposes. This should be taken, processed and 
stored at -80°C anytime prior to start of study treatment. 
 Serial plasma samples for the characterization of circulating plasma 
DNA (cpDNA). 
Translational research proposals not outlined in this protocol will be 
assessed by the IBCSG Biological Protocols Working Group for merit 
and feasibility. 
Biomarkers that are published in the future and considered to be of 
relevance can then also be assessed in the context of this trial. 
STATISTICAL 
CONSIDE-
RATIONS 
Phase Ib: A standard “3+3” dose escalation design will be used to 
establish the RP2D of MK-3475 in combination with standard-dose 
trastuzumab. Two MK-3475 body weight based dose levels, and a 
fallback dose, will be tested. 
Phase II: PD-L1 expressing: A Simon's two-stage design will be used. 
The null hypothesis that the true objective response rate is 7% will be 
tested against a one-sided alternative of 22%. In the first stage, 17 
patients will be enrolled. If there are 1 or fewer responses in these 17 
patients, enrollment will be stopped. Otherwise, 23 additional patients 
will be accrued for a total of 40. The null hypothesis will be rejected if a 
total of 6 or more objective responses are observed in 40 patients. This 
design yields a type I error rate of 0.05 and power of 85% when the true 
objective response rate is 22%. 
PD-L1 negative: A single-stage design with an enrollment of 15 patients 
will be used to compare a null response rate of 1% with a desirable 
response rate of 20%.  The decision rule is based on zero responses: the 
drug combination would not be considered worthy of further 
investigation if no patients have objective response. 
NUMBER OF 
PATIENTS 
This trial will enroll between 6 and 61 patients.   
DURATION OF 
TRIAL 
Assuming that the accrual rate will be approximately 4 patients per 
month, the recruitment will be completed within approximately 12-18 
months after a start-up period of 6 months as the trial is activated by 
participating Centers. Clinical visits will end approximately 3 years 
after enrollment of the first patient, and sites will be contacted for a 
final update on survival status of the patients. 
 


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2. 
Trial schedule  
(See section 14 for detailed examinations schedule) 
 
≤3 
months 
prior to 
treat-
ment 
start 15 
≤42 
days 
prior to 
treat-
ment 
start 15 
≤28 
days 
prior to 
treat-
ment 
start 16 
Day 1 
of 
every 
21 
days 
cycle 
Every 
second 
cycle: 
day 1 of 
cyc 3, 5, 
7… 
Weeks 
12, 18, 
24, 
36…  
Within 
30 days 
after 
end of 
treat-
ment 
Follow-
up 12 & 
24 
weeks 
prior 
PD7  
At pro-
gres-
sion 
Informed consent 
 
 
x 
 
 
 
 
 
 
Medical history 
 
 
x 
 
 
 
 
 
 
Physical examination, 
vital signs1, weight,  
ECOG PS 
 
 
x 
x 
 
 
x 
x 
 
Serum pregnancy test2 
 
 
x 
 
 
 
 
 
 
Baseline symptoms and 
AEs3 
 
 
x 
 
 
 
 
 
 
Adverse events3 
 
 
 
x 
 
 
x 
x 
 
Concomitant medications 
 
 
……………continuously………………. 
x 
 
Central HER2 and PD-L14 
 
 
x 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
MK-3475
 
 
 
 
x 
 
 
 
 
 
Trastuzumab 
 
 
 
x 
 
 
 
 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
Complete blood count5 
 
 
x 
x 
 
 
x 
 
 
Chemistry6 
 
 
x 
x 
 
 
x 
 
 
T3, T4, TSH 
 
x15 
 
 
x 
 
x 
 
 
Coagulation profile 
 
x15 
 
 
√ 
 
x 
 
 
Hepatitis B and C, HIV 
 
x15 
 
 
 
 
 
 
 
CA 15-3 
 
 
x 
 
x 
 
x 
 
 
Urinalysis 
 
x15 
 
 
x 
 
 
 
 
Tumor Evaluation 
 
 
 
 
 
 
 
 
 
Clinical7 
 
 
x 
 
 
x 
 
x 
x8 
CT or MRI7 
 
 
x 
 
 
x 
x1 
x 
x8 
Bone scan7 
 
 
√ 
 
 
√ 
 
√ 
x8 
Cardiac evaluation9 
 
 
 
 
 
 
 
 
 
ECG 
x15 
 
 
 
 
x 
 
x 
 
Echocardiography or 
MUGA scan 
x15 
 
 
 
 
x 
 
x 
 
Cardiac enzymes 
 
 
x 
 
 
x 
 
 
 
Biological samples 
 
 
 
 
 
 
 
 
 
Metastatic FFPE biopsy10 
 
 
x 
 
 
 
 
 
x 
Metastatic fresh frozen 
biopsy11 
 
 
x 
 
 
 
 
 
x 
Prim. surg. FFPE biopsy12 
 
 
x 
 
 
 
 
 
 
Blood sample13 
 
 
x 
 
 
 
 
 
 
Blood plasma 14 
 
 
…….. see footnote 14 …….. 
 
x = mandatory √ = if medically indicated 
Legend for trial schedule: 
1. Vital signs include blood pressure, heart rate, respiratory rate and temperature. Blood pressure should be 
measured in both arms after sitting for 5 minutes. Weekly self- monitoring at home is recommended. 


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2. Pregnancy test for patient of childbearing potential (i.e., who are not yet menopausal and with their last 
period less than 12 months previously, no surgery to occlude the fallopian tubes, ovaries and/or womb 
not surgically removed). Test has to be repeated before treatment start, if treatment does not start within 
72 hours of the previous test.  
3. Baseline symptoms and adverse events should be recorded from signature of informed consent to prior to 
start of treatment. Adverse events should be reported at end of every cycle, at end of treatment visit and 
up to 30 days after stop of trial treatment. Serious adverse events and pregnancies should be collected for 
90 days following the end of treatment. 
4. HER2 and PD-L1 must be determined centrally on an FFPE biopsy of either the archival metastatic 
tumor or a re-biopsy of a metastatic lesion (or unresectable loco-regional disease). 
Laboratory tests 
5. Hemoglobin, platelet count, white blood cell count including differential (absolute neutrophil count).  
6. Biochemistry: serum potassium, sodium, calcium, serum amylase, lipase and LDH;  
Liver function tests: albumin, total bilirubin, ALT, AST, ALP, GGT; 
Kidney function tests: urea, creatinine and uric acid. 
At baseline: All labs need to be repeated within 7 days prior to first dose (not on day 1). 
Subsequent treatment cycles: All labs need to be performed within 3 days prior to next dose. 
Tumor evaluation 
7. Clinical and radiological tumor assessments will be performed by CT scan or MRI at baseline, at 12, 18 
and 24 weeks (+/- 1), then every 12 (+/- 2) weeks until progression or a maximum of 24 weeks after stop 
of treatment. Patients who have received 24 months of trial treatment will have no further evaluations 
after the End of Treatment visit. Bone scan will be performed if clinically indicated at the same time 
points. CR, PR or PD need to be confirmed with second assessment 4-6 weeks after first assessment. 
CT/MRI images must be stored (preferably in electronic format) at the sites for potential central review.           
8. Disease progression needs to be confirmed with repeat imaging 4 to 6 weeks later. 
Cardiac evaluation 
9. All cardiac evaluations will be done at baseline, at weeks 12, 24, 36, etc. (every 12 +/- 2 weeks).  
Biological studies (see section 15) 
10. Two formalin-fixed, paraffin-embedded (FFPE) tumor blocks, one from the diagnostic biopsy of an 
unresectable loco-regional or metastatic lesion (preferably obtained in the screening phase, otherwise 
from evaluation of metastatic disease ≤1 year prior to enrollment) and one from a re-biopsy at 
progression (or end of trial treatment if prior to progression) must be submitted for central pathology 
review and stored in the IBCSG Tissue Bank for future translational research studies. This re-biopsy is 
strongly encouraged wherever feasible, except in cases of complete response (or minimal disease left) or 
or cases where too dangerous for the patient or impossible. If central evaluation at screening of archival 
tissue from a previous biopsy yields a negative test results, a new biopsy may be taken and submitted for 
central evaluation. For patients who have presented with stage 4 disease de novo, a biopsy taken from the 
presumed primary breast lesion is acceptable, provided that it was taken ≤1 year prior to enrollment. 
11. When taking a biopsy, a fresh frozen (for RNA extraction) should be planned as well. 
12. If the patient had primary surgery with curative intent, one tumor block from resection should be 
submitted. 
13. Prior to first dose of MK-3475, EDTA whole blood sample for confirmation of somatic nature of 
mutations found in tumor samples. 
14. For determination of circulating plasma DNA: plasma sample to be taken before the administration of the 
next dose of trial treatment at the start of cycles 1, 3, 5, 8 etc. (every 3 cycles thereafter), and within 30 
days after end of trial treatment (corresponding with End of Treatment visit). See section 15.1 for details. 
15. If taken as routine examination prior to signature of informed consent, and within the delays indicated 
(<3 months / ≤42 days), then they are acceptable for screening. HIV test prior to enrollment. All 
examinations taken specifically for screening purposes have to be done after signature of informed 
consent. Results of the examinations should be available at the time of registration of a new patient. 
16. Informed consent may be signed before the ≤28 days period to facilitate the screening process.  


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3. 
List of abbreviations 
ADCC  
Antibody dependent cellular cytotoxicity 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST  
Aspartate transaminase 
BNP 
B-type natriuretic peptide 
CBR 
Clinical benefit rate 
CCL2 
Chemokine (C-C motif) ligand 2 
CD8/28/ 
Cluster of differentiation 8 / 28 / .. 
CE 
Cardiac events 
CISH 
Chromogenic in situ hybridization 
cpDNA 
Circulating plasma DNA 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTLA4 
Cytotoxic T-lymphocyte-associated protein 4 
DC 
Disease control 
DILI 
Drug-induced liver injury 
DLT 
Dose-limiting toxicity  
DMC 
Data Management Center 
DoR 
Duration of response  
DSMC 
Data Safety Monitoring Committee 
EC50 
Half maximal effective concentration 
ECG 
Electrocardiogram 
ECI 
Event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ER 
Estrogen receptor 
EU 
European Union 
FCGR-2A/3A Low affinity immunoglobulin gamma Fc region receptor gene 2A or 3A 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FISH 
Fluorescence in situ hybridization 
GCP 
Good clinical practice 
GnRH 
Gonadotropin-releasing hormone 
H&E 
Hematoxylin and eosin stain 
HER2 
Human Epidermal growth factor Receptor 2 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC 
Informed consent 
ICH 
International Conference on Harmonization 
iDF 
iDataFax  
IFNγ 
Interferon gamma 
IHC 
Immunohistochemistry 
IL 
Interleukin 


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IMP 
Investigational Medicinal Product 
ITSM 
Immunoreceptor tyrosine-based switch motif 
irAE 
Immune-related adverse event 
LPBC 
Lymphocyte-predominant breast cancer 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MPR 
Moderate partial response 
MRI 
Magnetic resonance imaging 
MSD 
Merck Sharp & Dohme Corp. 
MTD 
Maximum tolerated dose 
MUGA 
Multi gated acquisition -scan 
CTCAE 
Common toxicity criteria for adverse events 
NK-cells 
Natural killer cells 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association  
ORR 
Overall response rate 
PD 
Progressive disease 
PD-1 
Programmed death receptor 1 
PD-L1 
Programmed death receptor 1 ligand 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PgR 
Progesterone receptor 
PI 
Principal Investigator 
PIS/IC 
Patient information sheet / informed consent 
PK 
Pharmacokinetics  
PR 
Partial response 
 
PS 
Performance status 
Q3W 
Every 3 weeks 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase II dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SERM 
Selective estrogen receptor modulator 
SNP 
Single nucleotide polymorphism 
SPC 
Summary of Product Characteristics 
T3 
Triiodothyronine 
T4 
Thyroxine 
T-DM1 
trastuzumab-emtansine 
TIL 
Tumor infiltrating lymphocyte 
TSH 
Thyroid Stimulating Hormone 
TTP 
Time to progression 
ULN 
Upper limit of normal 
VGPR 
Very good partial response 
 


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4. 
Background and scientific rationale 
4.1. 
HER2-positive metastatic breast cancers 
The development of therapies targeted against HER2 antibodies has dramatically changed 
the natural history of HER2/neu overexpressing (or HER2-positive) breast cancer. 
Trastuzumab is a monoclonal antibody (mAb) targeting human epidermal growth factor 
receptor 2 (HER2). In the pivotal trial, Slamon et al [1] have reported that adding 
trastuzumab to paclitaxel improves both progression free and overall survival. Since then, 
trastuzumab has become the standard of care for patients presenting HER2-positive 
metastatic breast cancer. Large phase III trials in the adjuvant setting have confirmed that its 
addition to standard cytotoxic chemotherapy has significantly improved clinical outcomes 
for women with this once devastating disease [2].  
Recently, there have been some significant advances in the treatment of HER2-positive 
disease. The use of combination targeted anti-HER2 therapies have been shown to improve 
outcome of patients with HER2-positive metastatic breast cancer. These therapies include 
lapatinib [3], pertuzumab [4] and trastuzumab-emtansine (T-DM1) [5], the latter two 
therapies were recently approved by the US Food and Drug Administration (FDA). T-DM1 
has been shown to improve progression-free survival as compared with the combination of 
trastuzumab and docetaxel. In addition, pertuzumab has been shown to improve outcome 
when added to a trastuzumab-docetaxel regimen in the first line metastatic setting. Recent 
developments suggest that the combination of T-DM1 and pertuzumab will further improve 
outcome and become standard of care in the first line setting [6]. Lapatinib is currently 
being evaluated in the adjuvant setting in combination with trastuzumab and in patients who 
develop brain metastases. Nevertheless, despite all these advances, the majority of patients 
presenting with stage IV HER2-positive breast cancer will ultimately become resistant to 
these agents and die of their disease. Thus, there is still a need to develop new therapeutic 
agents for patients presenting with HER2-positive metastatic breast cancer.  
4.2. 
Rationale 
for 
combining 
immune 
checkpoint 
modulators 
and 
trastuzumab 
Despite the significant improvements in clinical outcome for women with HER2 
overexpressing disease, there is still a need to improve therapy and to better identify women 
that may respond best to such treatments. There are currently no prognostic biomarkers that 
can help physicians identify the women with HER2-positive disease that are resistant to 
trastuzumab in addition to standard chemotherapy. This may be due to the fact that despite a 
significant amount of research, the dominant mechanism of trastuzumab’s efficacy is still 
debatable. Signaling blockade is important but antibody dependent cellular cytotoxicity 
(ADCC) via interactions with Fcγ receptors on leucocytes has also been implicated as an 
important mechanism of action as mice that lack Fcγ receptors do not respond to 
trastuzumab. Variations of single nucleotide polymorphisms (SNPs) in FCGR3A and 
FCGR2A genes that affect binding of antibodies to Fcγ receptors in 1286 patients were not 
associated with lack of trastuzumab efficacy [2]. 


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Whilst breast cancer has traditionally not been considered “immunogenic” when compared 
to disease such as melanoma and renal cell carcinoma, increasing data suggests the contrary. 
For example, tumor infiltrating lymphocytes (TILs) seen in the breast cancers at the time of 
diagnosis have been associated with clinical outcome and therapeutic responses. Infiltrating 
lymphocytes have been associated with a good prognosis in a number of other solid tumor 
types. Recently large cohort studies have confirmed this association also for breast cancer, 
in particular, for HER2-positive and triple negative breast cancer subtypes [3-5]. HER2-
positive and triple negative breast cancers also have significantly higher levels of 
lymphocytic infiltration at diagnosis, as compared with tumors that are of the luminal 
subtype (ER+/HER2-). 
Prognostic gene expression profiling studies in primary breast cancer also support this 
concept and have consistently shown an association between high expression of immune-
related genes and a good prognosis in HER2-positive disease. The analysis of microarray 
data from thousands of patients has shown that a high expression of a STAT1 metagene is 
strongly associated with better prognosis in HER2-positive disease [7-10]. Interrogating 
public microarray data also illustrates that significantly higher levels of PD-L1 (CD274) are 
seen in HER2-positive breast cancers (unpublished data, p<0.0001). Higher levels of PD-L1 
expression have been associated with poor clinic-pathological characteristics in breast 
cancer [11]. 
As high levels of the STAT1 signature were correlated with increasing lymphocytic 
infiltration on tumor Hematoxylin and Eosin stain (H&E) sections, TILs were examined as a 
potential biomarker of response to trastuzumab in HER2-positive disease. Samples from a 
phase III adjuvant clinical trial that randomized HER2-positive breast cancer patients to 
trastuzumab vs. no trastuzumab were analyzed to determine the association between the 
amount of lymphocytic infiltration in the tumor and the degree of trastuzumab benefit. It 
was reported that higher levels of lymphocytic infiltrate was associated with a higher 
magnitude of benefit from trastuzumab treatment in addition to cytotoxic chemotherapy 
[12]. This data also suggested that a pre-existing immune response seemed to be necessary 
for trastuzumab efficacy and that trastuzumab may release immunosuppression induced by 
the tumor microenvironment through one or more yet to be defined mechanisms.  
Recent preclinical data have reported that tumor regressions from anti-HER2 therapy in a 
preclinical mouse model require both effective innate and adaptive immunity [13, 14]. As 
proof-of-concept, enhancement of T-cell responses in combination with trastuzumab was 
evaluated in an immunocompetent transgenic HER2 mammary mouse model. In this model, 
the combination of the anti-HER2 mAb and anti-PD-1 therapy was synergistic and more 
effective than either monotherapy [14]. These data suggest that HER2-overexpressing 
tumors use immunosuppression as a mechanism to facilitate growth and progression. 
The concept that oncogene inhibition and immune modulation cooperate has been 
demonstrated preclinically in other solid cancer types. For example, in melanoma, it has 
been reported that PLX4720 treatment can downregulate tumor CCL2 gene expression and 
decrease tumor CCL2 expression in both BrafV600E mouse melanoma transplants and in de 
novo melanomas in a manner that was coincident with reduced tumor growth. These data 


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implicate host CCL2 in the mechanism of action of type I BRAF inhibitors and support the 
therapeutic potential of combining BRAF inhibitors with immunotherapy [15]. A similar 
concept has been recently reported that links efficacy of the tyrosine kinase inhibitor 
therapy, imatinib, in gastrointestinal stromal tumor (GIST), with reduction of tumor 
expression of IDO1 [16-18]. Interestingly, in this situation, imatinib has been shown to 
promote both T-cell and natural killer (NK) cell responses in mice and humans, 
respectively, while both NK-cells and CD8+ T-cells have been implicated in the activity of 
a trastuzumab-like molecule in the mouse [19]. Furthermore, Rakhra and colleagues have 
shown that an intact immune system is required for tumor regressions related to inhibition of 
the driving oncogene in “oncogene addicted” cancers [19]. Host immunity was shown to 
participate in cellular senescence, angiogenesis decrease and release of chemokines, which 
ultimately leads to tumor regressions on withdrawal of the driving oncogene. Together these 
data suggest that oncogene addiction mechanisms can also suppress anti-tumor immunity. 
Together, the preclinical and clinical data suggest that one of trastuzumab’s main 
mechanisms of action is through facilitating functional anti-tumor immunity in HER2-
positive breast cancers. This background provides the rationale for the present trial, which 
will evaluate if patients with HER2-positive disease will benefit from therapies that 
modulate the immune environment. 
4.3. 
Anti-PD-1 and PD-L1 antibodies 
The importance of immunity in controlling tumor initiation, progression and growth has 
been speculated on for decades. In general, tumors must learn to evade and avoid immune 
surveillance and destruction. This is supported by a higher frequency of cancer incidence in 
transplant patients on immunosuppression. However, whilst there is no increase in breast 
cancer incidence in transplant compared with the normal population, suggesting that 
immunosurveillance does not regulate the initiation of primary breast tumors, outcomes 
seem to be worse [20]. Data have shown that immunosurveillance is important in regulating 
breast cancer metastases and that pathways that control metastases have effects independent 
of the primary tumor [21-23]. 
The term immune evasion refers to the ability of the tumor to suppress and change host anti-
tumor immune reactions. The programmed cell death 1 (PD-1) pathway represents a major 
immune control switch which may be engaged by tumor cells to overcome active T-cell 
immune surveillance [24]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively 
expressed or can be induced in various tumors [25-28]. High expression of PD-L1 on tumor 
cells (and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and 
survival in various other solid tumor types, including renal cell carcinoma (RCC) [29], 
pancreatic carcinoma [30], hepatocellular carcinoma [31], ovarian carcinoma [32] and non-
small cell lung cancer (NSCLC) [33]. Furthermore, PD-1 has been suggested to regulate 
tumor-specific T-cell expansion in patients with malignant melanoma [34]. This observed 
correlation suggests that the PD-1/PD-L1 pathway plays a critical role in the tumor immune 
evasion and could be considered an attractive target for many solid organ types. 


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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[35, 36]. The structure of murine PD-1 has been resolved [37]. PD-1 and family members 
are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the 
tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade [36, 38-40]. The mechanism by 
which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 
as both molecules regulate an overlapping set of signaling proteins [41]. PD-1 was shown to 
be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-
cells, regulatory T-cells (Tregs) and NK-cells [42, 43]. Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells [44]. The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors [25, 26, 28]. Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs. Binding of 
either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. 
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues [27]. Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor. 
The observed correlation of clinical prognosis with PD-L1 expression in multiple cancers 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other 
treatment modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a monotherapy in models of squamous cell carcinoma, pancreatic 
carcinoma, melanoma and colorectal carcinoma. 


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Recent data of nivolumab (MDX-1106, BMS-936558), an IgG4 antibody against PD-1, 
have validated PD-1 as an attractive target for clinical therapeutic intervention. In a recent 
report of the clinical trial data of nivolumab a total of 296 patients with advanced NSCLC, 
castration resistant prostate cancer, or RCC or colorectal cancer were treated at a dose of 
0.1, 0.3, 1, 3, or 10 mg/kg every 2 weeks. Among 236 evaluable patients, cumulative 
response rates (all doses) defined by the Response Evaluation Criteria in Solid Tumors 
[RECIST] were 18% among patients with NSCLC, 28% among patients with melanoma, 
and 27% among patients with RCC. Responses were reported to be durable; 20 of 31 
responses lasted 1 year or more in patients with 1 year or more of follow-up. The most 
common adverse events were fatigue, decreased appetite, diarrhea, nausea, cough, dyspnea, 
constipation, vomiting, rash, pyrexia, and headache. Grade 3 or 4 adverse events were 
observed in 49% of patients, while 14% of patients had treatment-related Grade 3 or 4 
adverse events. Drug-related adverse events of special interest (e.g., those with potential 
immune-related causes) occurred in 41% of patients and included pneumonitis, vitiligo, 
colitis, hepatitis, hypophysitis, and thyroiditis. There were three deaths from treatment 
related pneumonitis, two in NSCLC and one in colorectal cancer patients. No maximum 
tolerated dose was defined for nivolumab [33, 45]. Interestingly, PD-L1 expression was 
highly predictive for the efficacy of anti-PD-1 antibodies. In the PD-L1-non expressing 
population, no response was observed. At the opposite, 9 out of 25 patients with PD-L1 
expressing cancer had presented an objective response.  
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2. Both MK-3475 and nivolumab contain the S228P stabilizing 
mutation and have no antibody-dependent cell-mediated cytotoxicity (ADCC) or 
complement-dependent cytotoxicity (CDC) activity. MK-3475 strongly enhances T-
lymphocyte immune responses in cultured blood cells from healthy human donors, cancer 
patients, and primates. In T-cell activation assays using human donor blood cells, the EC50 
was in the range of 0.1 to 0.3 nM. MK-3475 also modulates the level of interleukin-2 (IL-2), 
tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines. The 
antibody potentiates existing immune responses only in the presence of antigen and does not 
nonspecifically activate T- cells. 
KeytrudaTM (pembrolizumab, MK-3475) was approved in the United States for the 
treatment of patients with melanoma in September 2014. In 2015, it was approved in 
Australia, the European Union (EU), as well as in several other countries. Recently, the drug 
was approved in the US for the treatment of non-small cell lung cancer. 
Overall, these data suggest that anti PD-L1 / PD-1 antibodies present antitumor activity in 
PD-L1 expressing cancers. This drug family has not been tested in breast cancer patients. 
Preclinical and correlative data suggests that HER2-positive breast cancer could be 
particularly amenable to immunotherapeutic approaches. We therefore propose to evaluate 
if a monoclonal antibody targeted against PD-1, a T-cell negative regulator, can reverse 
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4.3.1. 
Preliminary efficacy data in breast cancer 
The KEYNOTE-012 study was a phase Ib study of pembrolizumab (MK-3475) in patients 
with advanced triple-negative breast cancer [46]. In this phase 1b study, 32 patients with 
metastatic triple negative breast cancer were treated at a dose of 10 mg/kg intravenously 
every 2 weeks. Patients were required to have a PD-L1 positive tumor, defined as any 
immunohistochemical staining in the tumor stroma or on greater than or equal to 1% of 
tumor cells. The rate of PD-L1 positivity was 58% in the screening population. Over 90% of 
the enrolled patients were previously treated with taxane, anthracycline, capecitabine or 
platinum based chemotherapy, with 21 of 32 having had more than 1 line of therapy. 56.3% 
patients experienced a treatment related adverse event of any grade. Grade 3 treatment-
related events consisted of anemia, headache, aseptic meningitis and pyrexia. One patient 
developed disseminated intravascular coagulation that resulted in death, which was 
attributed to treatment. The median time on therapy with MK-3475 was 59.5 days. The 
overall response rate by RECIST 1.1 was 18.5% (5/27 patients evaluable), with 1 complete 
response and 4 partial responses. Of the 5 responding patients, 4 had received greater than 2 
lines of prior chemotherapy. Three patients did not receive a post-baseline response 
evaluation due to rapid progression. Responding patients continued on therapy for 40 weeks 
or more, with the median duration of response not reached at the time of reporting. The 
authors noted that due to the small number of patients, they were unable to establish whether 
higher levels of PD-L1 positivity were associated with improved response. A phase II study 
is planned for 2015 (KEYNOTE-086, NCT02447003). 
Another phase Ia study used an anti-PD-L1 antibody MPDL3280A in patients with PD-L1 
positive triple negative breast cancers [47]. PD-L1 on tumor infiltrating immune cells was 
assessed using a proprietary immunohistochemistry assay developed by the trial sponsor. 
The presence of PD-L1 on greater than or equal to 5% of tumor infiltrating immune cells 
was considered a positive result. Of the 21 evaluable patients, the overall response rate was 
19%. Three cases of pseudo-progression were also observed. Amongst the screening 
population, the number of PD-L1 positive patients was 23%. Based on this promising data, a 
phase III study is ongoing (NCT02425891). This study will randomize newly diagnosed 
patients with advanced triple negative breast cancer to abraxane +/- MPDL3280A. Notably, 
patients will be unselected for PD-L1 positivity. 
4.3.2. 
Rationale for the PD-L1 negative cohort 
Lately MK-3475 has been evaluated in NSCLC independent of PD-L1 expression. In 
KEYNOTE-001, the response rate for all NSCLC patients was  ~23%; high PD-L1 
positivity (≥50%) was associated with increased ORR (45%), but patients with PD-L1-
negative (<1%) tumors also showed responses (ORR ~9-12%) [48].  
In patients for whom PD-L1 staining using the clinical trial IHC assay was available, the 
objective response rate (ORR), PFS (hazard ratio, HR, 0.52), and OS (HR, 0.59) were 
higher in patients with strong PD-L1 expression (≥50% staining) than in patients with 
weak/negative PD-L1 expression [48]. 


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Across studies conducted thus far it appears that patients whose tumors express PD-L1, as 
detected by the various IHC assays, have numerically higher responses to PD-1/PD-L1 
blockade than those who do not. However, durable and long lasting responses have also 
been observed in solid tumor types without PD-L1 expression and these patients should also 
be considered eligible for PD-1/PD-L1 blocking agents [33, 49-51]. Also, in a recently 
conducted meta-analysis of 20 trials (1,475 patients) with nivolumab, pembrolizumab, and 
atezolizumab in NSCLC, melanoma, and genitourinary cancers, correlations between the 
tumor PD-L1 expression and response were investigated. Significant differences were seen 
in NSCLC and melanoma, but not genitourinary cancers. Ignoring the different cutoffs for 
PD-L1 expression in different trials, responses to nivolumab and pembrolizumab were 
observed in 34.1% and 19.9% of patients with PD-L1-positive and PD-L1-negative tumors, 
respectively. This difference was statistically significant, but also showed that absence of 
tumor PD-L1 expression is not a good enough biomarker to exclude patients from receiving 
an anti-PD-1 drug, as such patients may still derive benefit from PD-1 blockade [52].  
It remains unclear if the differential expression or the expression on infiltrating lymphocytes 
vs. tumor will account for the differences in response rates seen and how this will vary by 
tumor type. Further research is needed to understand the technical limitations of the test, 
tumor heterogeneity and the significance of varying degrees and location of PD-L1 
expression. As such, current recommendations are that patients should not be selected for 
treating according to PD-L1 status and thus this forms the rationale for an inclusion of a PD-
L1 negative expression cohort in this study [53]. 
4.4. 
Trial hypothesis 
This is a proof-of-concept clinical trial to evaluate the hypothesis that the combination of an 
immune re-activation approach and anti-HER2 therapy can reverse trastuzumab resistance 
and improve clinical outcomes in HER2-positive disease. The trial will investigate the 
efficacy of an anti-PD-1 mAb in the setting of trastuzumab resistant, HER2-positive 
metastatic breast cancer. The aim of this trial is to demonstrate that immune reactivation by 
inhibition of PD-1 is associated with objective evidence of efficacy in this population. 
Patients included in this trial will have metastatic or incurable disease as it is essential to 
demonstrate the safety of the combination first in this setting.  
While there are no overlapping toxicities between trastuzumab and MK-3475, a phase Ib 
run-in will be performed first to evaluate the safety profile of the drug combination.  Three 
doses of MK-3475 will be considered: 1 mg/kg, 2 mg/kg and 10 mg/kg. These three doses 
have all been shown to be associated with tumor responses. For the phase II part, the 
primary assessment of efficacy will be based on a single-arm trial design in a trastuzumab-
resistant population with PD-L1-expressing disease.  As a secondary objective, efficacy in 
patients with PD-L1 negative disease will be based on a parallel cohort, single-arm design. 
As it is standard-of-care in the HER2-positive metastatic population to continue an anti-
HER2 therapy back-bone even after progression, trastuzumab will be given to the patient in 
combination with MK-3475. Given that the immune mechanisms are unknown and may be 
quite different in combinations of trastuzumab plus pertuzumab, trastuzumab with taxanes 
and trastuzumab-emtansine (T-DM1), demonstration of proof-of-concept first with the 


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combination of trastuzumab alone plus MK-3475 was deemed essential prior to moving on 
to combination anti-HER2 therapies.  
4.5. 
Overall risk-benefit assessment 
The metastatic or advanced setting was chosen to evaluate this new therapy combination. 
The setting of incurable disease is acceptable to justify the evaluation of a potential new 
combination in breast cancer. As these patients are resistant to the standard therapy of 
trastuzumab, an investigational therapy that could potentially reverse this resistance is of 
high interest in this patient population. The available pharmacokinetics and 
pharmacodynamics data provide scientific rationale for exploring the 3-weekly schedule in 
combination with the 3-weekly trastuzumab dose. Safety will be carefully monitored 
throughout the trial. 
4.6. 
Rationale for the trial design 
A MK-3475 monotherapy arm was not considered ethical in this population as continued 
HER2-blockade is standard of care in this population. Supporting this, in a potential follow-
on phase III trial, combinations with trastuzumab and other anti-HER2 will be used. As the 
current standard-of-care for this population is changing, with docetaxel, pertuzumab and 
trastuzumab receiving US FDA approval for the first line setting and trastuzumab-emtansine 
(T-DM1) (+/- pertuzumab) likely to be also registered in the next 2 years for this indication, 
women with previous exposure to these combinations will be eligible for this trial. As 
immunotherapy is yet to be tested in breast cancer patients, this trial will use a phase Ib/II 
approach to evaluate the safety profile of the combination of MK-3475 and trastuzumab and 
provide estimates of efficacy and tolerability.  
4.6.1. 
Rationale for Dose Selection/Regimen/Modification  
An open-label phase I trial (KEYNOTE-001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors. All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of MK-3475 showed evidence 
of target engagement and objective evidence of tumor size reduction at all dose levels (1 
mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date.  In addition, two 
randomized cohort evaluations of melanoma subjects receiving MK-3475 at a dose of 2 
mg/kg versus 10 mg/kg Q3W have been completed, and one 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. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). 
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days). This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q2W and Q3W dosing schedule.   


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A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
flat dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication. The differences in exposure for a 200 mg flat dose 
regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain 
well within the established exposure margins of 0.5 – 5.0 mg/kg for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of MK-3475  in solid 
tumors is based on: 1) similar efficacy and safety of MK-3475 when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients; 2) the flat exposure-response relationships of MK-
3475 for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W; 3) 
the lack of effect of tumor burden or indication on distribution behavior of MK-3475 (as 
assessed by the population PK model); and 4) the assumption that the dynamics of MK-
3475  target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of MK-3475 showing that 
the flat dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks; 2) will maintain 
individual patient exposures in the exposure range established in melanoma as associated 
with maximal efficacy response; and 3) will maintain individual patients’ exposure in the 
exposure range established in melanoma that are well tolerated and safe.  
A flat 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. 
5. 
Trial objectives and endpoints 
The primary objectives of this phase Ib/II study are to determine the recommended dose of 
the anti-PD-1 mAb, MK-3475, in combination with standard dose trastuzumab, and to 
evaluate the efficacy and safety profile of the drug combination in patients with PD-L1 
expressing, HER2-positive, unresectable loco-regional or metastatic breast cancer who have 
experienced progression during prior trastuzumab-based therapy. 
Note: The phase Ib part of the trial was completed in August 2015. 


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The secondary objective is to explore the efficacy and safety of the drug combination in 
patients with PD-L1 negative, HER2-positive unresectable loco-regional or metastatic breast 
cancer who have experienced progression during prior trastuzumab-based therapy.   
5.1. 
Primary endpoint 
Phase Ib (dose finding): Dose-limiting toxicity of the anti-PD-1 mAb MK-3475 in 
combination with standard dose trastuzumab (defined in section 10.2.1) 
Phase II: Objective response (confirmed CR or PR as best overall response) based on 
RECIST 1.1 criteria (defined in section 13). 
5.2. 
Secondary endpoints 
For a precise definition of secondary endpoints please see Section 17.1:  
 
Safety and tolerability as documented according to CTCAE version 4.0 
 
Disease control (DC)  
 
Duration of response (DoR)  
 
Time to progression (TTP)  
 
Progression-free survival (PFS)  
 
Overall Survival (OS) 
5.3. 
Correlative objectives 
Correlative studies will investigate: 
 
Responses according to levels of PD-L1, measured by IHC in metastatic (or 
unresectable loco-regional) lesion.  
 
Responses according to levels of tumor infiltrating lymphocytes. 
 
Responses according to ER status.  
 
Responses according to FISH ratio and HER2 copy number.  
 
Tumor dynamics during the disease course as well as emergence of new clones 
(i.e., resistance mechanisms) by determination of circulating plasma DNA 
(cpDNA). 
 
Sequencing of material from tumor biopsies to determine molecular characteristics 
profiles of responders and non-responders. 
5.4. 
Exploratory objectives 
5.4.1. 
To describe TTP for patients with moderate partial response (MPR) compared with 
very good partial response (VGPR). 
5.4.2. 
To explore the prognostic ability of pre-treatment ER, PD-L1, and TILs with 
respect to MPR and VGPR. 
6. 
Trial design, duration and termination 


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6.1. 
Trial design 
This is a phase Ib/II, open-label, multi-center trial with primary objectives for patients with 
HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast 
carcinoma who have previously progressed on prior trastuzumab-based therapy. During the 
phase II portion of the trial, a secondary cohort of 15 patients with PD-L1 negative disease 
will be enrolled.  
The phase Ib trial will use a standard 3+3 dose-escalation design to determine the RP2D of 
the anti-PD-1 mAb, MK-3475, in combination with standard dose trastuzumab using 3 
possible body weight based dose levels.  The phase II portion of the trial will use a flat dose 
of 200 mg MK-3475 in combination with standard dose trastuzumab.  
Each patient will receive combination trastuzumab and anti-PD-1 mAb MK-3475 until 
disease progression, lack of tolerability, completion of 24 months after start of treatment 
with MK-3475, or patient declines further protocol treatment.  
For the primary objectives, patients’ disease must be confirmed to express PD-L1 based on 
an FFPE biopsy taken from an unresectable loco-regional or metastatic lesion using a 
certified IHC test in a designated lab. HER2 status of the tumor will also be centrally 
confirmed at the same time. Patients whose disease is both PD-L1 expressing and HER2-
positive (IHC 3+ or FISH/chromogenic in situ hybridization [CISH] positive) are eligible to 
be enrolled. For the secondary objective, a cohort of 15 patients with PD-L1 negative 
disease will be enrolled during the phase II portion of the trial. 
It is expected that a maximum of 61 evaluable patients will be enrolled.  
 
 


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6.2. 
Trial schema 
 
 
Section 8.1 describes central testing in the screening phase. 
Treatment: The phase Ib dose-escalation part of the trial will determine the RP2D of MK-
3475 from 3 possible body weight based dose levels based on the tolerability observed in 
cycle 1: trastuzumab 6 mg/kg and MK-3475 at 2 mg/kg, 10 mg/kg, or a fall-back dose of 
1 mg/kg. The phase II, single-arm trial will use a flat dose of 200 mg MK-3475 in 
combination with standard dose trastuzumab. Patients will receive combination trastuzumab 
and anti-PD-1 mAb until progression, lack of tolerability, completion of 24 months of 
treatment with MK-3475, or patient declines further protocol treatment. 
6.3. 
Clinical evaluations 
Tumor response will be evaluated according to RECIST version 1.1 (see Section 13) using 
computed tomography (CT) or magnetic resonance imaging (MRI) of the thorax, abdomen 
and pelvis. For each patient the same technique must be used to evaluate each lesion through 
the trial. 
 Tumor assessments will be performed at screening (prior to therapy), at 12, 18 and 
24 weeks (+/- 1) and every 12 (+/- 2) weeks thereafter until progressive disease is 
Screening: unresectable locoregional or metastatic breast cancer overexpressing HER2
Submit an FFPE block from core biopsy for central testing
Central Testing:
HER2 by IHC
Phase Ib: dose finding for MK-3475 in 3+3 design  ─  Phase II 200mg
Treatment in 3 week cycles:
1
2
3
4
5  etc………..… PD
T : trastuzumab  6mg/kg
T
T
T
T
T
M : MK-3475      200mg
M
M
M
M
M
HER2 neg:
not eligible
HER2 pos:
Central PD-L1 testing
PD-L1 neg: enroll 15 
patients in phase II
PD-L1 positive: enroll
40 patients in phase II
Blood samples:
whole blood
plasma prior to cycles 1, 3, 5 and then every 3 cycles, 
and 30 days after end of tx
Tissue
at enrollment:
re-biopsy at PD *:
Samples:
FFPE block
FFPE Block
Fresh frozen block *
Fresh frozen block
* if feasible
* if feasible


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observed or for a maximum of 24 weeks after treatment stop (see also Section 14.9).  
 A response (CR or PR) must be confirmed with repeat imaging between 4 and 6 
weeks later.  
If the imaging shows progressive disease (PD), imaging must also be repeated 
between 4 and 6 weeks later in order to confirm PD. 
 Note: Patients deemed clinically unstable are not required to have repeat imaging 
for confirmation. It is at the discretion of the Investigator to keep the patient on trial 
treatment as long as PD has not been confirmed by a second imaging, or stop trial 
treatment immediately. The decision whether to continue trial treatment should be 
based on clinical judgment, including the patient’s overall condition, performance 
status, symptoms and laboratory values. See detailed instructions in Section 10.9. 
6.4. 
Biological evaluations 
Biopsies taken pre-therapy are used to confirm HER2-positivity and PD-L1 expression 
status. New tissue material from a recently obtained surgical or diagnostic biopsy is 
preferred. A previous biopsy from an unresectable loco-regional or metastatic lesion 
obtained ≤1 year prior to enrollment may be used (i.e., prior to a previous line of therapy), 
however if this is negative for PD-L1, another biopsy may be taken (i.e., if during a period 
of the trial when only patients with PD-L1 expressing disease are being enrolled).  
Collection of tumor tissue and repeat blood specimens is mandatory on this trial. Please see 
Section 15 for a complete overview of types of samples and collection times.  
6.5. 
Sample size and trial duration 
 The sample size for the phase Ib trial will be between 6 and 12 enrolled patients and 
will depend on the number of dose cohorts needed to determine the RP2D.  A patient 
in the phase Ib portion of the trial will be replaced if determination of DLT cannot be 
adequately assessed because of rapid disease progression during the first cycle of 
therapy, or if treatment and/or follow-up is stopped during the first cycle of therapy 
for reasons other than toxicity. 
Note: The phase Ib part of the trial was completed in August 2015 with 6 patients 
enrolled. 
 The phase II trial will enroll two parallel cohorts.  The primary cohort of patients 
with PD-L1 expressing disease will use a Simon two-stage design with a total target 
sample size of 40 patients. A secondary cohort of 15 patients with PD-L1 negative 
disease will also be enrolled, using a single-stage design. 
 We estimate that the total sample size will be between 6 and 61 patients. The 
minimum would occur if the trial is stopped quickly in the phase Ib phase due to 
toxicity. 
 The enrollment of 61 patients is expected to occur over a period of 12 to 18 months 
after a start-up period of 6 months as the trial is activated by participating Centers. 


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After cessation of treatment, patients will be followed in clinic until documented 
disease progression or 24 weeks after stop of treatment, whichever occurs first. 
Clinical visits will therefore end approximately 3 years after enrollment of the first 
patient. Sites will be contacted for a final update on subsequent therapy and survival 
status of the patients. 
The trial will be conducted in 11 Centers in 5 countries. Under the assumption that 
approximately two thirds of patients will not meet the inclusion/exclusion criteria, it is 
estimated that around 120 patients will be screened to enroll 61 patients.  
7. 
Patient selection 
7.1. 
Eligibility criteria for screening 
7.1.1. 
Female gender 
7.1.2. 
Age ≥18 years 
7.1.3. 
Histologically confirmed breast adenocarcinoma that is unresectable loco-regional, 
or metastatic. 
7.1.4. 
Locally confirmed HER2-positivity (immunohistochemistry score 3+) or ERBB2- 
amplification (Ratio ERBB2/centromeres ≥2.0 or mean gene copy number ≥6) of 
primary tumor or of biopsy from metastatic or unresectable loco-regional lesion. 
 
Note: Do not submit for central review if the metastatic or unresectable loco-
regional biopsy tested HER2-negative locally. 
7.1.5. 
Must have trastuzumab resistant disease, defined by 
- demonstrated progression of disease while on treatment with trastuzumab 
(monotherapy or combination-based therapy) or trastuzumab-emtansine (T-
DM1) for metastatic or unresectable loco-regional disease. 
- recurrence while on adjuvant trastuzumab or within 12 months of completing 
adjuvant trastuzumab. 
- Any number of prior lines of anti-HER2 therapy acceptable. Patients for whom 
the treatment with the current first-line combination of trastuzumab, pertuzumab 
and taxanes is not an option (e.g., due to refusal or contraindication) can be 
considered for enrollment into this trial. 
Progression/recurrence must have been demonstrated by radiological or clinical 
assessment. 
7.1.6. 
If a patient has received a subsequent anti-HER2 therapy, she must also have 
progressed on the subsequent therapy. Progression must have been demonstrated 
by radiological or clinical assessment. 


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7.1.7. 
Presence of at least one measurable lesion as defined by RECIST 1.1. 
7.1.8. 
LVEF  ≥50% 
7.1.9. 
Patient agrees to submit an FFPE tumor biopsy for central confirmation of HER2-
positivity and central assessment of PD-L1 status. This can be from archival tissue 
from unresectable loco-regional or metastatic disease obtained ≤1 year prior to 
enrollment or new tissue material from a recently obtained surgical or diagnostic 
biopsy. Tissue obtained for the biopsy must not have been previously irradiated.  
 
Note: Central Pathology Review on a tumor biopsy is mandatory for this trial, and 
patients will be evaluated centrally for eligibility.  
7.1.10. Written Informed Consent (IC) for screening procedures and trial participation 
must be signed and dated by the patient and the Investigator prior to screening. 
7.1.11. Written consent to biological material submission, indicating the patient has been 
informed of and agrees to tissue and blood material use, transfer and handling, 
must be signed and dated by the patient and the Investigator prior to any procedures 
specific for this trial, including consent to translational research on FFPE and fresh 
frozen tumor biopsies in case the patient is enrolled into the trial. 
7.1.12. The patient has been informed of and agrees to data transfer and handling, in 
accordance with national data protection guidelines. 
7.1.13. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 (see 
below*). 
7.1.14. Life expectancy >3 months. 
7.1.15. Hematopoietic status: 
- Absolute neutrophil count ≥1.5 × 109/L, 
- Platelet count ≥100 × 109/L, 
- Hemoglobin ≥9 g/dL 
7.1.16. Hepatic status: 
- Serum total bilirubin ≤1.5 × upper limit of normal (ULN). In the case of known 
Gilbert’s syndrome, a higher serum total bilirubin (<2 × ULN) is allowed. 
- AST and ALT ≤2.5 × ULN; if the patient has liver metastases, ALT and AST 
must be ≤5 × ULN. 
7.1.17. Renal status:  
- Creatinine ≤1.5 ×ULN or creatinine clearance >60 mL/min 
- Proteinuria <1 g/day 


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7.1.18. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN 
unless patient is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulant. 
7.2. 
Exclusion criteria for screening 
7.2.1. 
Prior therapy with other anti-PD-1, anti- PD-L1, L2 or anti-CTLA4 therapy. 
7.2.2. 
 No FFPE material to centrally assess HER2-positivity and PD-L1 expression. 
7.2.3. 
Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or positive 
for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).  
7.2.4. 
Interstitial lung disease 
7.2.5. 
History of or active pneumonitis requiring treatment with steroids 
7.2.6. 
Active central nervous system metastases, as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth (patients with history of CNS 
metastases or spinal cord compression are eligible if they are clinically and 
radiologically stable for at least 4 weeks before first dose of investigational product 
and have not required high-dose steroid treatment in the last 4 weeks).  
7.2.7. 
Leptomeningeal disease 
7.2.8. 
History of clinically significant or uncontrolled cardiac disease, including 
congestive heart failure (New York Heart Association functional classification ≥3, 
see Table 4), angina, myocardial infarction or ventricular arrhythmia. 
7.2.9. 
Previous severe hypersensitivity reaction to treatment with another monoclonal 
antibody. 
7.2.10. Active infection requiring systemic therapy. 
7.2.11. Chronic systemic therapy with immunosuppressive agents including cortico-
steroids. 
7.2.12. Concurrent disease or condition that would make the patient inappropriate for trial 
participation or any serious medical disorder that would interfere with the patient’s 
safety. 
7.2.13. Known history of uncontrolled hypertension (≥180/110), unstable diabetes 
mellitus, dyspnea at rest, or chronic therapy with oxygen. 
7.2.14. Dementia, altered mental status, or any psychiatric condition that would prevent the 
understanding or rendering of Informed Consent. 
7.2.15. Treatment with an investigational agent in the 4 weeks before enrollment. 
7.2.16. Active autoimmune disease or a documented history of autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents. Patients 
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. 


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Patients that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the trial. Patients with hypothyroidism stable on 
hormone replacement or Sjögren’s syndrome will not be excluded from the trial. 
7.2.17. Chemotherapy, radioactive therapy, and/or biological cancer therapy within 3 
weeks prior to the first trial dose and has not recovered to CTCAE v.4.0 grade 1 or 
better from adverse events. 
7.2.18. Pregnant or lactating women; lactation has to stop before enrollment. 
7.2.19. The patient of childbearing potential who is unwilling to use highly effective 
contraception during treatment and up to 7 months after stop of trial treatment.  
Acceptable methods are intrauterine devices (without hormones), bilateral tubal 
occlusion, vasectomized partner or total abstinence. Oral, injectable, or implant 
hormonal contraceptives are not allowed. 
7.2.20. Unresolved or unstable, serious adverse events from prior administration of another 
investigational drug. 
7.2.21. Active or uncontrolled infection CTCAE v.4.0 grade 2 or higher. 
7.2.22. Live vaccines within 30 days prior to the first dose of trial therapy and during trial 
treatment.  
7.3. 
Inclusion criteria for enrollment 
The criteria from Section 7.1 apply for enrollment as well. The following criteria should be 
(re-)checked at the time of enrollment. The patient may only be included in the trial if ALL 
the following inclusion criteria are fulfilled: 
7.3.1. 
Central lab confirmation on a metastatic biopsy (or biopsy from unresectable loco-
regional disease) of  
- HER2-positivity (immunohistochemistry score 3+) or ERBB2-amplification 
(Ratio ERBB2/centromeres ≥2.0 or mean gene copy number ≥6), 
- Presence of PD-L1 expression assessed by IHC (During the phase II portion of 
the trial a parallel, secondary cohort of 15 patients with PD-L1 negative disease 
will be enrolled, see section below). 
Note for the secondary cohort of 15 patients with PD-L1 negative disease: 
Patients previously screened (under protocol version 1.1 or 1.2) with a negative PD-
L1 result can be included once Amendment 1 has been approved, provided all 
eligibility criteria as specified in this protocol version are met, all tests and scans 
have been performed within the timelines specified, and biopsy is ≤1 year from 
enrollment. Patients must have demonstrated progression on current treatment. 
Center will need to register the patient again and get a new patient ID in the IBCSG 
Registration/Randomization System. 


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7.3.2. 
Patient agrees to submit tumor tissue for translational research: 
- tissue biopsy from unresectable loco-regional or metastatic disease obtained ≤1 
year prior to enrollment or new tissue material from a recently obtained surgical 
or diagnostic biopsy. For patients who have presented with stage 4 disease de 
novo, a biopsy taken from the presumed primary breast lesion is acceptable, 
(provided this was taken ≤1 year prior to enrollment). 
- if available: FFPE tumor block from primary tumor. 
- if available: pre-treatment fresh frozen tumor biopsy. 
- if feasible: FFPE tumor block from post-treatment biopsy will be taken at time 
of disease progression or end of all treatment if ended prior to progression. This 
re-biopsy is strongly advised. 
- if feasible: fresh frozen tumor biopsy from post-treatment biopsy will be taken at 
time of disease progression or end of all treatment if ended prior to progression. 
7.3.3. 
Patient agrees to submit baseline (pre-treatment) blood and serial plasma for 
translational research, as detailed in Table 9. 
7.3.4. 
For patient of childbearing potential, negative serum pregnancy test. Pregnancy test 
has to be repeated within 72h before treatment start. 
7.3.5. 
All anti-cancer treatment including endocrine therapy, with the exception of 
trastuzumab must stop 3 weeks prior to first dose of trial treatment. 
* ECOG Performance Status: 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work 
PS 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 
PS 3 
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
7.4. 
Exclusion criteria for enrollment 
All criteria from Section 7.2 apply for enrollment as well. Excluded are patients who have 
received any of the treatments below: 
7.4.1. 
Live vaccines within 30 days prior to the first dose of trial therapy and during trial 
treatment.  
7.4.2. 
History of CNS metastases or spinal cord compression if they have not been 
clinically stable for at least 4 weeks before first dose of investigational product and 
require high-dose steroid treatment. 
7.4.3. 
Treatment with an investigational agent in the 4 weeks before enrollment. 


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7.4.4. 
Patient has not recovered to CTCAE v.4.0 grade 1 or better from adverse events of 
prior therapy, except alopecia grade 2. 
7.4.5. 
Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), or positive for 
Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]). 
8. 
Patient registration for screening and enrollment 
This trial will use a web-based registration system. Specific details for registration are in the 
“IBCSG Registration/Randomization Procedures Manual” which is available on the 
IBCSG website (www.ibcsg.org). 
Note: In the phase Ib and in phase II the trial may suspend the enrollment of additional 
patients. The IBCSG Registration/Randomization System will display a message indicating 
whether the trial currently can accept more patients. A slot reservation procedure for 
enrollment will be implemented; prior to enrolling a patient, the site should contact IBCSG 
to ascertain that there is an open slot for this patient. The Data Management Center will 
reserve the slot for the site. Please refer to the “IBCSG 45-13 PANACEA- Enrollment 
Slotting Procedures” for more details. 
8.1. 
Registration for screening 
8.1.1. 
Patient needs to give informed consent to trial participation and screening 
procedures and central determination of eligibility, prior to any screening 
intervention. If tumor material from a biopsy of a metastatic or unresectable loco-
regional lesion (newly taken or obtained ≤1 year prior to enrollment) is available, 
then this material can be used for central determination. Otherwise, patient needs to 
consent to new biopsy. 
8.1.2. 
Verify eligibility (see Section 7, including local determination of HER2-positivity). 
In general, screening procedures need to be done within 28 days before start of 
treatment (see Section 14.1 for exceptions). 
8.1.3. 
Directly access the IBCSG Registration/Randomization System and provide the 
requested information as indicated on the Screening Form. The date the Informed 
Consent Form and the Biological Material Consent were signed by the patient and 
the date signed by the Investigator are both required to complete registration for 
screening. 
The IBCSG Registration/Randomization System will provide the following 
information via e-mail: 
 Patient ID (registration number)  
 Date of registration 


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8.1.4. 
Submit the Screening (45-A1) electronic case report form (eCRF) via iDataFax. 
The patient binder of eCRFs will be available in iDataFax within 24 hours of 
successful registration.  
8.1.5. 
Ship FFPE block from the metastatic tumor biopsy to the central laboratory for 
determination of HER2 status. The central laboratory will forward five 5 µm 
sections (FFPE) to the certified laboratory for PD-L1 status determination. The 
determination of HER2 and PD-L1 status will take approximately 2 weeks. 
 
8.2. 
Prior to enrollment 
All patients will have central review of the biopsy to assess HER2-positivity and PD-L1 
status.  For the primary objectives, only patients with central confirmation of HER2-
positivity and presence of PD-L1 expression on metastatic biopsy (or biopsy from 
unresectable loco-regional disease) after registration for screening will be eligible to enroll. 
During the phase II portion of the trial, a secondary cohort of 15 patients with PD-L1 
negative disease will be enrolled. Results from HER2 and PD-L1 testing will be 
communicated to the Investigator. If the patient meets the eligibility guidelines, the Trial 
Coordinator will open an enrollment slot for that Center. If the first submitted sample tests 
negatively, the Center has the option to submit a second sample. 
Complete the following steps to enroll a patient. 
8.2.1. 
Verify eligibility for enrollment (see Section 7). If not done within 7 days before 
expected start of treatment, repeat hematology and chemistry lab. 
8.2.2. 
Directly access the IBCSG Registration/Randomization System, enter the Patient 
ID assigned at screening, and provide the requested information as indicated on the 
Confirmation of Enrollment (45-A2) Form.   
8.3. 
Registration for Enrollment 
Complete the following steps to enroll a patient on this trial. 
8.3.1. 
Submit the Confirmation of Enrollment (45-A2) electronic case report form (eCRF) 
via iDataFax. The patient binder of eCRFs will be available in iDataFax within 24 
hours of successful registration.  
8.3.2. 
The site will receive an e-mail with information about the dose level of MK-3475 
to use for the patient. 
8.4. 
Registration Help Desk 
The IBCSG Data Management Center (located at Frontier Science (FSTRF)) is responsible 
for developing and maintaining the IBCSG Registration/Randomization System. The Help 
Desk includes technical personnel and administrators of the registration programs at the 
Data Management Center in Amherst, NY, USA. 


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Business Hours:  24 hours.  Closed five US holidays: New Year's Day, Memorial Day, 
Independence Day, Thanksgiving Day and Christmas Day. Refer to the DMC Holiday 
Calendar on the IBCSG website for specific dates. 
FSTRF Randomization Help Desk 
Frontier Science & Technology Research Foundation (FSTRF) 
4033 Maple Rd, Amherst, NY 14226 USA 
Phone: +1 716-834-0900 x7301 or 716-834-0900 x7200 
Fax: +1 716-832-8437 
Email: bc.helpdesk@fstrf.org  
9. 
Trial drugs formulation and handling 
MK-3475 is the Investigational Medicinal Product (IMP) used in this trial; IMP will be 
supplied. 
Trastuzumab will also be supplied in Europe. 
Complete details of the trial drug logistics, distribution, packaging, labeling and handling as 
well as accountability are described in a separate Drug Supply Manual. 
9.1. 
MK-3475 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances 
functional activity of the target lymphocytes to facilitate tumor regression and ultimately 
immune rejection. 
9.1.1. 
Formulation 
Refer to the current version of the MK-3475 Investigator’s Brochure for pharmaceutical 
formulation information. 
Clinical Supplies will be provided by Merck as follows: 
Product Name & Potency 
Dosage Form 
MK-3475 50 mg/ vial 
white to off-white lyophilized powder 
for infusion, it is reconstituted with 
sterile water for injection prior to use 
The drug product is stored under refrigerated conditions (2°C - 8°C). 
The reconstituted lyophilized product is intended for i.v. administration. 
 
9.1.2. 
Packaging and labeling 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 


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9.1.3. 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, IBCSG and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text. 
9.1.4. 
Storage and handling 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. The Investigator shall take responsibility for and shall take 
all steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations.  
9.2. 
Trastuzumab 
9.2.1. 
Packaging and labeling  
Commercial trastuzumab will be affixed with a clinical label in accordance with regulatory 
requirements.  
Each vial contains 150 mg powder for concentrate for solution for infusion (i.v.) of 
trastuzumab. Each carton contains one vial. 
9.2.2. 
Storage and handling 
Store trastuzumab in a refrigerator (+2°C – +8°C). Instructions for proper handling and 
disposal of trastuzumab should be followed. All drugs will be stored as per the current 
version of the product’s SPC (Summary of Product Characteristics) and the standard 
hospital procedures. Pharmacy will maintain temperature logs of all storage conditions and 
comply with hospital pharmacy standard operating procedures.  
10. 
Treatment 
10.1. 
Trial treatments 
Trial treatment should start within one week after enrollment. Trial treatments will be 
administered in 3-week (21-day) cycles until progression, lack of tolerability, completion of 
24 months of treatment with MK-3475, or until further protocol treatment is declined. 
Trastuzumab can be continued in case of MK-3475 cessation due to toxicity. Similarly, 
MK-3475 can be continued if trastuzumab has been ceased. In case of cardiac dysfunction 
both drugs must be stopped.  
Treatment administration should comply with the protocol; compliance will be monitored 
by the Monitoring Team or Data Management Center. Complete details of dispensation and 
dosing are recorded on the eCRF.  
10.2. 
Phase Ib: dose finding and DLTs 
The primary objective of the phase Ib part of the trial is to determine the recommended 
phase II dose of the anti-PD-1 mAb, MK-3475, in combination with standard dose 


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trastuzumab. A patient in the phase Ib portion of the trial will be replaced if determination 
of DLT cannot be adequately assessed during the first cycle of therapy because of rapid 
disease progression, or if treatment and/or follow-up is stopped during the first cycle of 
therapy for reasons other than toxicity. Patients who do not receive trastuzumab in the first 
cycle of therapy, e.g., due to an infusion reaction to MK-3475, will also be replaced, but will 
not be counted as having a DLT. Replaced patients will be followed for safety. 
10.2.1. Definition of dose-limiting toxicity 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as suspected to be trial treatment related (possible, probable or definite) and 
unrelated to disease or disease progression that occurs within the first cycle (21 days) of 
treatment with MK-3475 and trastuzumab. Toxicities and lab values will be graded 
according to CTCAE v4.0. Dose-limiting toxicities will be defined as:  
 any grade-3 or greater non-hematological adverse event lasting at least one week  
OR  
 any grade-4 hematological toxicity,  
OR  
 adverse event resulting in >14 days delay in starting cycle 2.  
10.2.2. Dose-escalation rules 
Dose escalation will occur using a standard ‘3+3’ dose escalation approach, beginning in 
dose level 1, with rules for escalation and de-escalation described in Table 1, below. The 
RP2D is defined as the highest dose level at which <33% (0 of three patients, or 0 or 1 of six 
patients) has experienced a DLT in cycle 1. Once dose escalation for MK-3475 reaches a 
dose of 10 mg/kg, no further escalation will occur.  
Intra-patient dose escalation is not permitted. Patients enrolled in the phase Ib part of the 
trial should be treated on the assigned dose level as long as tolerable, for up to 24 months of 
MK-3475.  
Table 1  Dose escalation rules 
Number of patients with 
DLT at a given dose level 
Dose Escalation Rule 
0 out of 3 
Proceed to the next dose level and enroll 3 patients 
1 out of 3 
Enroll and treat 3 additional patients at this dose 
level. 
≥2 out of 3 
Dose escalation will be stopped. The RP2D will be 
one dose below this dose level.   


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Number of patients with 
DLT at a given dose level 
Dose Escalation Rule 
1 out of 6 
Proceed to the next dose level. 
≥2 out of 6 
Dose escalation will be stopped. The RP2D will be 
one dose below this dose level.  
If ≥2/3 or ≥2/6 patients at dose level 1 experience DLTs, dose level -1 will be used.  
If dose level -1 proves too toxic, the trial will stop. 
10.2.3. Dose levels 
All patients will be treated with the same dose of trastuzumab: 6 mg/kg i.v. (8 mg/kg i.v. in 
cycle 1, in case the last dose of trastuzumab was administered more than 3 months ago). 
At enrollment, IBCSG will notify the Center about which dose level of MK-3475 to use. 
Table 2  Body weight based dose levels 
 
 
 
 
 
 
* 8 mg/kg i.v. in cycle 1 if last dose trastuzumab administered more than 3 months prior 
Within-patient dose escalation for MK-3475 is not permitted.  
10.3. 
Phase II dose of MK-3475 
The phase II part of this trial will use MK- 3475 at a flat dose of 200 mg. The dose of MK-
3475 used in the study may be adjusted based upon emerging data.  IBCSG reserves the 
right to adjust the dose without amending the protocol. Investigators will be notified in 
writing before such a change takes place. 
10.4. 
Treatment Administration 
10.4.1. MK-3475 Administration 
MK-3475 will be administered as a 30-minute i.v. infusion every 3 weeks (+/- 3 days). 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 of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Planning the time of trial drug infusion (e.g., time of the week for first administration; time 
of the day for each administration) should take trial visit procedures into consideration. 
Dose Level 
MK-3475 
Trastuzumab* 
-1 
1 mg/kg i.v. 
6 mg/kg i.v. 
1 
2 mg/kg i.v. 
6 mg/kg i.v. 
2 
10 mg/kg i.v. 
6 mg/kg i.v. 


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The pharmacists will prepare the MK-3475 medication for administration. The Drug supply 
Manual contains specific instructions for MK-3475 dose calculation, reconstitution, 
preparation of the infusion fluid, and administration. This document is available for 
reference by the pharmacist and trial personnel. 
10.4.2. Trastuzumab administration 
Trastuzumab will be administered at a dose of 6 mg/kg, every 3 weeks (+/- 3 days) (cycle 
duration: 21 days). If in cycle 1 a loading dose of trastuzumab of 8 mg/kg is administered, 
this has to be done over 90 minutes. In further cycles, trastuzumab will be administered over 
30 minutes. The administration is by i.v. infusion according to local guidelines. A loading 
dose of 8 mg/kg i.v. trastuzumab in cycle 1 is needed if trastuzumab was stopped more than 
3 months before start of treatment in this trial. 
Trastuzumab should be given after MK-3475. In case of infusion reaction to MK-3475, 
delay the administration of trastuzumab and re-start MK-3475, within the same cycle, 
according to Table 5 in Section 10.6. If no second infusion reaction, then administer 
trastuzumab.  
10.5. 
Dose modifications and delays for trastuzumab 
Refer to standard of care guidance or current clinical practice for patients receiving 
trastuzumab treatment. 
Efforts should be made so that the patient misses no more than one dose of three-weekly 
trastuzumab. 
Table 3  Actions to be taken in case of trastuzumab related adverse events 
Adverse Events  
graded according to NCI-CTCAE v.4.0 
Action 
Non-hematological, grade 1 or 2 (excluding 
cardiac) 
Continue trastuzumab therapy. 
Non-hematological, grade 3 or 4 (excluding 
cardiac), and adverse events resolved to 
grade <2 within a maximum of 5 weeks 
from last administration. 
Hold trastuzumab therapy until recovery to 
grade <2. 
Non-hematological, grade 3 or 4 (excluding 
cardiac), and adverse events NOT resolved 
to grade <2 within a maximum of 5 weeks 
from last planned administration. 
Discontinue 
trastuzumab 
therapy 
permanently. 
Non-hematological, grade 3 or 4 (excluding 
cardiac), upon rechallenge with trastuzumab 
Discontinue 
trastuzumab 
therapy 
permanently. 


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Adverse Events  
graded according to NCI-CTCAE v.4.0 
Action 
Cardiac* (asymptomatic drop in LVEF or 
symptomatic congestive heart failure) 
Trastuzumab therapy to be held, continued, 
or 
resumed 
according 
to 
Figure 
1. 
Trastuzumab therapy to be discontinued 
permanently in case of symptomatic CHF. 
Cardiac (CTCAE: other cardiac toxicities 
not covered in Figure 1) 
Actions 
must 
follow 
rules 
for 
non-
hematological toxicities (above). 
Hematological 
Trastuzumab dose should not be held. 
*Severity corresponding to NYHA functional classification: 
 
 


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Table 4 NYHA functional classification 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical 
activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort 
increases. 
 
Figure 1: Algorithm for continuation and discontinuation of trastuzumab based on interval 
LVEF assessments, for patients with NYHA class I or II congestive heart failure. LVEF 
drop>10 points: Temporarily discontinue both drugs and repeat LVEF in 3 weeks. If LVEF 
drop>10 points not confirmed, then resume treatment and administer MK-3475 at the same 
dose level. 
 
 
 
 


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10.6. 
Dose modifications and delays for MK-3475 
Dose increase of MK-3475 will not be permitted. Dose reductions in phase II are not 
permitted. 
10.6.1. Dose reductions in phase Ib 
Only the three body weight-based dose levels in Table 2 in Section 10.2 may be used. If 
dose level -1 is not tolerated by the patient, MK-3475 has to be permanently discontinued. 
10.6.2. Dose delays and supportive care for phase Ib and phase II 
Adverse events (both non-serious and serious) associated with MK-3475 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. MK-3475 must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 5 below.  


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Table 5  Treatment delay and supportive care guidelines for drug-related adverse events 
 
Toxicity 
Grade 
Treatment delay/stop 
Supportive care 
Diarrhea/Colitis 
Any 
grade 
 
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).   
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 i.v. infusion.  For 
Grade 2 or higher diarrhea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 
2 
 
Restart treatment once toxicity resolves to Grade 0-1. 
If 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, stop treatment. 
Administer oral corticosteroids1. 1–2 mg/kg/day 
prednisone or equivalent followed by a taper. 
3 
Restart treatment once toxicity resolves to Grade 0-1. 
If 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, stop treatment. 
Treat with intravenous steroids followed by high dose 
oral steroids1. 1–2 mg/kg/day prednisone or equivalent 
followed by a taper. 
4 
Permanently discontinue. 
Treat with intravenous steroids followed by high dose 
oral steroids1. 1–2 mg/kg/day prednisone or equivalent 
followed by a taper. 


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Toxicity 
Grade 
Treatment delay/stop 
Supportive care 
AST, ALT, or 
increased 
Bilirubin 
2 
Restart treatment once toxicity resolves to Grade 0-1. 
Stop treatment if toxicity does not resolve within 12 
weeks of last dose. 
Monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
Treat with i.v. or oral corticosteroids1. Initial dose of 
0.5–1 mg/kg/day prednisone or equivalent followed by 
a taper. 
3-4 
Permanently discontinue 
 
Exception: patients with liver metastasis who begin 
treatment with Grade 2 AST or ALT can resume 
treatment, if AST or ALT increases by less than 50% 
relative to baseline and for less than 1 week. 
Treat with intravenous corticosteroids for 24 to 48 
hours1. 1–2 mg/kg/day prednisone or equivalent 
followed by a taper. 
Type 1 diabetes 
mellitus (if new 
onset, including 
diabetic 
ketoacidosis 
[DKA]) or 
≥Grade 3 
Hyperglycemia, 
if associated 
with ketosis 
(ketonuria) or 
metabolic 
acidosis (DKA) 
T1DM 
or 
3-4 
Hold MK-3475 for new onset Type 1 diabetes 
mellitus or Grade 3-4 hyperglycemia associated with 
evidence of beta cell failure. Resume MK-3475 when 
patients are clinically and metabolically stable. 
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.  
 


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Toxicity 
Grade 
Treatment delay/stop 
Supportive care 
Hypophysitis 
2 
Restart treatment once toxicity resolves to Grade 0-1. 
Therapy with MK-3475 can be continued while 
endocrine replacement therapy is instituted. If 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, 
stop treatment. 
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. 
 
3-4 
Restart treatment once toxicity resolves to Grade 0-1. 
Therapy with MK-3475 can be continued while 
endocrine replacement therapy is instituted. If 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, 
stop treatment. 
Treat with an initial dose of i.v. 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 
2 
 
Non-selective beta-blockers (e.g., propranolol) are 
suggested as initial therapy. 
3 
Restart treatment once Toxicity resolves to Grade 0-1. 
Stop treatment if 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. 
Treat with an initial dose of i.v. corticosteroid followed 
by oral corticosteroids1 
Replacement of appropriate hormones may be required 
as the steroid dose is tapered. 
 
4 
Permanently discontinue. 
Treat with an initial dose of i.v. corticosteroid followed 
by oral corticosteroids1 
Replacement of appropriate hormones may be required 
as the steroid dose is tapered. 
 


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Toxicity 
Grade 
Treatment delay/stop 
Supportive care 
Hypothyroidism 
2-4 
Therapy with MK-3475 can be continued while 
thyroid replacement therapy is instituted. 
Thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard 
of care. 
Infusion 
Reaction 
 
 
Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely 
within 24 hours of completion of infusion.  
Table 6 below shows treatment guidelines for subjects 
who experience an infusion reaction associated with 
administration of MK-3475. 
2 
Restart treatment once toxicity resolves to Grade 0-1.  
Permanently discontinue if toxicity develops despite 
adequate premedication. 
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 6 – Infusion 
Reaction Treatment Guidelines for further management 
details. 
 
3-4 
Permanently discontinue 
 
Pneumonitis 
Any 
grade 
 
Add prophylactic antibiotics for opportunistic 
infections in the case of prolonged steroid 
administration. 
2 
Restart treatment once toxicity resolves to Grade 0-1.  
Discontinue treatment if 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. Permanently 
discontinue if event recurs. 
Treat with systemic corticosteroids1. Initial dose of 1–2 
mg/kg/day prednisone or equivalent followed by a 
taper. 
 


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Toxicity 
Grade 
Treatment delay/stop 
Supportive care 
3-4 
Permanently discontinue treatment. 
Immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as 
needed. 
Renal Failure or 
Nephritis 
2 
Restart treatment once toxicity resolves to Grade 0-1. 
Stop treatment if 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. 
Treat with corticosteroids1. Initial dose of 1–2 
mg/kg/day prednisone or equivalent followed by a 
taper. 
3-4 
Permanently discontinue 
Treat with systemic corticosteroids1. Initial dose of 1–2 
mg/kg/day prednisone or equivalent followed by a 
taper. 
All Other Drug-
Related Toxicity 
2 
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 or 
Severe 
Restart treatment once toxicity resolves to Grade 0-1. 
Stop treatment if 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 
 
 
1) When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
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. 
Note: Permanently discontinue for any Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs, or any life-threatening event. 


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In case toxicity does not resolve or improve to ≤Grade 1 within 12 weeks after last 
administration of MK-3475, MK-3475 should be discontinued. In exceptional cases, 
continuation may be considered after discussion with IBCSG (ibcsg45_panacea@fstrf.org 
and medical.affairs@ibcsg.org). With Investigator and IBCSG agreement, patients still at 
Grade 2 may continue in the trial only if asymptomatic and controlled.  
Two dosing delays due to the same toxicity will be permitted. In the event of a third 
occurrence of the same toxicity, which would require dosing delay, MK-3475 will be 
discontinued permanently. 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Patients should be placed back on trial treatment within 3 weeks 
of the next scheduled dose, unless otherwise discussed with IBCSG. The reason for 
interruption should be documented in the patient's record. 
Table 6 shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of MK-3475. 
 
 


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Table 6  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 patient is 
deemed medically stable in the opinion of 
the Investigator. 
 
None. 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, i.v. fluids); 
prophylactic medications indicated 
for < =24 hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
i.v. fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the patient 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 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
 
Patient may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with: 
 
Diphenhydramine 50 mg p.o. 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg p.o. (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., 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: 
i.v. fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the Investigator. 
Hospitalization may be indicated. 
Patient 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. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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10.7. 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required. The Investigator should discuss any questions regarding this with IBCSG. The 
final decision on any supportive therapy or vaccination rests with the Investigator and/or the 
patient's primary physician. However, the decision to continue the patient on trial therapy or 
vaccination schedule requires the mutual agreement of the Investigator, IBCSG, and the 
patient. 
10.7.1. Acceptable Concomitant Medications 
All treatments that the Investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards 
of medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC), herbal supplements, and i.v. medications and fluids. If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date must also be included on the CRF. 
All concomitant medications received within 28 days before start of trial treatment and up to 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 12.4. 
10.7.2. Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phase (including retreatment for post-complete response relapse) of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy 
 Immunotherapy not specified in this protocol 
 Endocrine treatment (SERMs, aromatase inhibitors, GnRH analogs) 
 Chemotherapy not specified in this protocol 
 Investigational agents other than MK-3475 
 Radiation therapy  
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed 
after 
consultation 
with 
IBCSG 
(medical.affairs@ibcsg.org 
and 
ibcsg45_panacea@fstrf.org ). 
 Live vaccines within 30 days prior to the first dose of trial treatment and while under 
trial treatment. 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 (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 


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 Glucocorticoids for any purpose other than to modulate symptoms from an event of 
suspected immunologic etiology. The use of physiologic doses of corticosteroids 
(prednisone 10 mg orally daily or equivalent) is at the discretion of the Investigator. 
The exclusion criteria in Section 7.2 describe other medications, which are prohibited in this 
trial. There are no prohibited therapies during the post-treatment follow-up phase.  
10.8. 
Diet/Activity/Other Considerations 
10.8.1. Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
10.8.2. Contraception 
MK-3475 may have adverse effects on a fetus in utero. Non-pregnant, non-breast-feeding 
women of childbearing potential may be enrolled if they are willing to use effective 
contraception. Allowed are: intrauterine devices (without hormones), bilateral tubal 
occlusion, vasectomized partner or total abstinence. Oral, injectable, or implant hormonal 
contraceptives are not allowed. Patients should start using birth control from the start of trial 
treatment throughout the trial period up to 7 months after the last dose of any trial treatment 
(MK-3475 and/or trastuzumab).  
Patients should be informed that taking the trial medication may involve unknown risks to 
the fetus if pregnancy were to occur during the trial. In order to participate in the trial they 
must adhere to the contraception requirement (described above) for the duration of the trial 
treatment and up to 7 months after the last dose of any trial treatment. If there is any doubt 
whether a patient will reliably comply with the requirements for contraception, that patient 
should not be entered into the trial. 
10.8.3. Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with MK-3475, trial 
treatment will be stopped immediately for the patient and the event reported immediately, 
see Section 12.5. The site will contact the patient at least monthly and document the 
patient’s status until the pregnancy has been completed or terminated. The outcome of the 
pregnancy will be reported to IBCSG without delay and within 24 hours if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or 
life-threatening complication to the mother or newborn). The trial Investigator will make 
every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to IBCSG.  
10.8.4. Use in Nursing Women 
It is unknown whether MK-3475 is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, patients who are breast-feeding are not eligible for enrollment. 


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10.9. 
Stop of treatment  
Patients will receive combination trastuzumab and anti-PD-1 mAb until progression, lack of 
tolerability, completion of 24 months of treatment with MK-3475, or until further protocol 
treatment is declined by the patient. 24 months of MK-3475 is calculated from the date of 
first dose. Trastuzumab can be continued until progression in case of MK-3475 cessation 
due to toxicity. Similarly, MK-3475 can be continued until progression if trastuzumab has 
been ceased, except in the case of cardiac dysfunction where both drugs must be stopped.  
Asymptomatic patients may receive trial treatment for a maximum of 24 months. 
10.9.1. Criteria to continue treatment in case of progression 
The first radiological assessment is at week 12, unless progressive disease is suspected 
earlier. Imaging should then be at weeks 18, 24 and every 12 weeks after this, or earlier if 
clinically indicated. 
A patient with unconfirmed progression of disease should continue trial treatment until 
progression of disease according to RECIST 1.1 is confirmed by radiographic imaging 
obtained at 4-6 weeks later.  
Patients with confirmed progression of disease may still benefit from the continuation of 
trial treatment. This includes patients who develop new symptomatic brain lesions without 
extracranial progression.  Continuation of trial treatment for such patients must be discussed 
with IBCSG (please contact ibcsg45_panacea@fstrf.org and medical.affairs@ibcsg.org). 
In both cases (confirmed and unconfirmed progression), patients have to meet the following 
criteria to continue treatment: 
 Absence of signs and symptoms (including significant laboratory values) indicating 
worsening of disease. 
 No decline in ECOG performance status. 
 Absence of rapid progression of disease. 
 Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
10.9.2. Criteria to stop trial treatment 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. Asymptomatic patients may receive trial treatment for a maximum of 24 months. 
The treatment of the individual patient will be discontinued in case of: 
 Confirmed disease progression as defined in Section 13.10, except for patients who 
may benefit from treatment continuation, as described at the end of Section 10.9.1. 
 Cardiac dysfunction. 
 Unacceptable adverse event(s). 
 Intercurrent illness that prevents further administration of trial treatment. 


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 Need for more than 2 dose delays due to the same toxicity as per dose modification 
guidelines described in Section 10.5. 
 Patient demonstrates an inability or unwillingness to comply with the treatment 
regimen and/or trial requirements. 
 Patient has confirmed positive serum pregnancy test. 
 Patient declines further trial treatment. 
 General or specific changes in the patient’s condition which render her 
unacceptable for further trial treatment in the opinion of the treating Investigator. 
 Patient withdraws consent to continue trial treatment. 
Patients who have a confirmed complete response (CR) by two scans ≥4 weeks apart and 
who have been on MK-3475 treatment for at least 6 months may discontinue MK-3475 
treatment at the discretion of the Investigator after receiving at least two doses beyond the 
initial determination of CR, whereas trastuzumab can continue. MK-3475 and trastuzumab 
may be resumed upon disease recurrence in these patients, provided they fulfill the original 
clinical and laboratory value eligibility criteria (see Section 7). Patients will resume therapy 
at the same dose and schedule used at the time of initial discontinuation. If a patient with a 
CR has discontinued treatment but then resumes treatment upon disease recurrence, the 
procedures will be followed as described in Section 14. 
For scheduling reasons or patient's personal reason unrelated to toxicity, patients who have 
been on MK-3475 trial therapy for at least 24 weeks may have a treatment-free interval of 
up to 12 weeks if considered in a patient’s best interest by the Investigator. Any longer 
interval requires discussion with and approval by IBCSG on an individual basis. 
11. 
Safety 
11.1. 
Adverse effects of MK-3475 
As of 30 June 2015, 9400 patients had been treated with MK 3475 at several dose schedules. 
The safety of MK-3475 has been evaluated in 1012 patients across three doses (2 mg/kg 
every 3 weeks or 10 mg/kg every 2 or 3 weeks) in clinical studies. In this patient population, 
the most common adverse reactions (>10%) with MK-3475 were diarrhea (15%), nausea 
(12%), pruritus (25%), rash (25%), arthralgia (13%) and fatigue (33%). The majority of 
adverse reactions reported were of Grade 1 or 2 severity. The most serious adverse reactions 
were immune-related adverse reactions and severe infusion-related reactions. 
As of 14 August 2015, data of 409 patients treated with 200 mg flat dose were reviewed. A 
review of these adverse events demonstrated them to be consistent with the known adverse 
event profile for MK-3475; no new significant findings were evident. 
 


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11.2. 
Immune-related adverse effects of MK-3475 
An irAE is defined as a clinically significant adverse event of any organ that is associated 
with trial drug exposure, is of unknown etiology, and is consistent with an immune-related 
mechanism.  
Immune-mediated adverse reactions are presented based on 2117 patients with melanoma 
and with NSCLC. The safety profile was generally similar for patients with melanoma and 
NSCLC. The most commonly reported immune-related adverse events across the dose-
schedules are hypothyroidism (7.8%), hyperthyroidism (2.9%), pneumonitis (2.4%), and 
colitis (1.7 %).  
For the occurrence and management of immune-related adverse effects, please refer to 
Section 10.6.2 in conjunction with the latest version of the MK-3475 Investigator’s 
Brochure. See Section 12.3 for an overview of ECIs. 
11.3. 
Drug interactions with MK-3475 
No conventional drug-drug interactions (DDI) that could affect pharmacokinetics of either 
MK-3475 or trastuzumab are to be expected (and have not been described). Therefore, no 
dedicated DDI study is required. 
11.4. 
Adverse effects of trastuzumab 
See the updated IB or SPC for adverse effects of trastuzumab. 
11.5. 
Safety Assessment in stage 1 of phase II 
Data from the first-in-human phase I trial of MK-3475 in patients with metastatic melanoma 
and other solid tumors were presented at the American Society of Clinical Oncology 
(ASCO) 2012 annual meeting. In the dose-escalation phase of the melanoma trial, MK-3475 
appeared to be well-tolerated at 1, 3, and 10 mg/kg administered every 2 weeks, with no 
immunogenicity or dose-limiting toxicities reported. However, there is no experience of 
combining MK-3475 with trastuzumab. Thus, as an early assessment of safety, data from 
the initial 17 patients in the phase II primary cohort with PD-L1 expressing disease 
receiving the combination of MK-3475 and trastuzumab will be evaluated for safety in the 
first 4 cycles of therapy. This evaluation will coincide with the first assessment of response 
for the two-stage design. Recruitment into the trial will be interrupted after enrollment of the 
17th patient with PD-L1 expressing disease if two objective responses have not yet been 
observed in that cohort. The safety assessment will also include data from patients in the 
secondary cohort with PD-L1 negative disease who are enrolled prior to the 17th patient 
with PD-L1 expressing disease. The incidence of the following cardiac events will be 
analyzed: 
 cardiac death 
 heart failure manifested by dyspnea with normal activity or at rest 
 decline in LVEF of >10 percentage points from baseline and to a value <50 percent.  


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The report will be submitted within one month to the DSMC. From the perspective of 
safety, the trial will continue (or resume) enrollment should the incidence of such events not 
be greater than what would be expected for trastuzumab alone (5%) (see also Section 17.4). 
Rationale: HER2 signaling is important for embryonic cardiac development, myocyte 
survival as well as protection from potential cardiotoxins. Trastuzumab-related cardiac 
toxicity is thought not to be dose-dependent and related to signaling inhibition (HER2 
blockade) rather than myocyte destruction. Endomyocardial biopsies from patients with 
trastuzumab-related cardiac dysfunction do not show typical anthracycline-related damage. 
Interestingly however, lapatinib rarely causes cardiac dysfunction. Certain risk factors are 
associated with a higher risk of developing trastuzumab-related cardiotoxicity. These 
include previous or concurrent anthracycline use and age greater than 50. Concurrent 
treatment with trastuzumab and adjuvant radiation therapy does not seem to be associated 
with increased risk. Other risk factors are preexisting cardiac dysfunction (i.e., decreased 
left ventricular ejection fraction), older age, obesity, and hypertension, while diabetes, 
valvular heart disease, and coronary artery disease seem not to significantly increase risk. 
Trastuzumab-related cardiotoxicity is largely reversible in the majority of cases, and 
treatment can often be continued after resolution of cardiac abnormalities. Cardiac cells are 
thought to be stunned rather than permanently damaged. 
In case of cardiac toxicity, the algorithm in Section 10.5 should be followed. Both MK-3475 
and trastuzumab should be temporarily discontinued. Both can be re-introduced at the dose 
indicated in Section 10.5 after resolution as per cardiac algorithm.  
All patients will undergo cardiac evaluation at 12 weeks with an assessment of LVEF, ECG, 
Troponin I and BNP. Antibodies against Troponin I are thought to be the pathogenesis of 
some causes of dilated cardiac myopathy (unrelated to trastuzumab). Following this first 
evaluation (and provided the patients in the safety assessment show no concerning safety 
signal) all other patients will undergo cardiac evaluations every 12 weeks [54]. 
12. 
Adverse event and serious adverse event reporting 
12.1. 
Adverse event reporting 
The main criterion for tolerability is the occurrence of toxicities and adverse events. The 
severity and causality will be classified according to the NCI CTCAE Version 4. The 
CTCAE 
is 
available 
for 
downloading 
on 
the 
internet 
at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. An interactive version can be found at 
https://safetyprofiler-ctep.nci.nih.gov/. 
An adverse event is defined as any untoward medical occurrence that occurs from the date 
of signature of informed consent until 30 days after all treatment discontinuation, regardless 
of whether it is considered related to a medication. 
Any grade of any observed adverse event should be reported on the AE form. Symptoms of 
the targeted cancer (if applicable) should not be reported as adverse events. 


IBCSG 45-13 / BIG 4-13 PANACEA 
 
V2.1  Amendment 1   11 January 2016 
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An overdose, accidental or intentional, whether or not it is associated with an AE, of an 
investigational product should be reported as an SAE. For the definition of overdose, see 
section 12.3.  
12.1.1. Severity / intensity 
The adverse event severity grade provides a qualitative assessment of the extent or intensity 
of an adverse event, as determined by the Investigator or as reported by the patient. The 
severity grade does not reflect the clinical seriousness of the event, only the degree or extent 
of the affliction or occurrence (e.g., severe nausea, mild seizure), and does not reflect the 
relationship to trial drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required 
Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible 
Grade 4 = Life threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
Grade 5 = Death – the event results in death 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This criterion is not the same as 
“serious” which is based on patient/event outcome or action criteria associated with events 
that pose a threat to a patient’s life or functioning.   
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
12.1.2. Causality 
The Investigator must determine the relationship between the administration of trial drug(s) 
and the occurrence of an AE/SAE as Not Suspected or Suspected as defined below: 
Not suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship unlikely or remote, 
or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed 
event. 
Suspected 
The temporal relationship of the adverse event to trial drug(s) 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event. 


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12.1.3. Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of 
the event. 
12.1.4. Action taken 
The Investigator will report the action taken with trial drug(s) as a result of an AE or SAE, 
as applicable (e.g., discontinuation of trial drug(s)) and in case of an SAE report if 
concomitant and/or additional treatments were given for the event. 
12.2. 
Serious adverse event (SAE) reporting 
12.2.1. Definition 
An SAE is defined, in general, as any undesirable medical occurrence/adverse drug 
experience that occurs during treatment or within 90 days after stopping all trial treatment 
that, at any dose, results in any of the following:  
 fatal (any cause) 
 life-threatening 
 requires or prolongs inpatient hospitalization 
 persistent or significant disability/incapacity 
 congenital anomaly or birth defect (including neonatal deaths) 
 secondary (non-breast) malignancy 
 constitutes an important medical event 
 event of clinical interest (see Section 12.3) 
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. 
After completion of trial treatments, report all SAEs beyond 90 days that are considered at 
least possibly related to previous trial treatment. Cases of second (non-breast) malignancies 
and congenital abnormalities are to be regarded as SAEs, regardless of whether they occur 
during or after trial treatment. These events should be reported during the whole trial 
duration on the Serious Adverse Event eCRFs (SAE/ECI-A and SAE/ECI-B). 
A suspected unexpected serious adverse reaction (SUSAR) is an adverse event that is 
serious, related to the investigational drug and not listed as a known toxicity of the 
investigational drug in the Investigator’s brochure. 
Note: Progression of the cancer under study must be reported as a serious adverse event if it 
has resulted in hospitalization or death. 


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12.2.2. Exceptions to the definition 
Hospitalizations occurring under the following circumstances are not considered to be 
serious adverse events:  
 elective surgery 
 occur on an outpatient basis and do not result in admission (hospitalization <24h) 
 are part of the normal treatment or monitoring of the studied treatment 
12.3. 
Definition of Events of Clinical Interest 
Selected non-serious and serious adverse events described below are also known as Events 
of Clinical Interest (ECI) and must be recorded as such on the SAE forms and reported 
within 24 hours to IBCSG. IBCSG will inform Merck Global Safety within one business 
day.  
Overdose 
An overdose is defined as ≥1000 mg (5 times the dose) of MK-3475 and as any dose ≥20% 
over the prescribed dose for trastuzumab. No specific information is available on the 
treatment of overdose of MK-3475. In the event of overdose, MK-3475 should be 
discontinued and the patient should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. If an adverse event(s) is 
associated with (“results from”) the overdose, then the adverse event(s) has to be reported as 
a serious adverse event, even if no other seriousness criteria are met. If a dose meeting the 
protocol definition of overdose is taken without any associated clinical symptoms or 
abnormal laboratory results, the overdose is reported as a non-serious ECI, using the 
terminology “accidental or intentional overdose without adverse effect.” All reports of 
overdose with and without an adverse event must be reported by the Investigator within 24 
hours to IBCSG. 
Drug-induced liver injury (DILI):  
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing, is considered drug-induced liver injury (DILI). 
12.4. 
Reporting SAEs and ECIs 
Any Serious Adverse Event and any Event of Clinical Interest occurring in a patient after 
providing Informed Consent must be reported, including death due to any cause other than 
progression of breast cancer, which occurs within 90 days following cessation of treatment 
or the initiation of a new anticancer therapy, whichever is earlier, whether or not related to 
the investigational product. Information about all such events will be collected and recorded 
on the IBCSG Serious Adverse Event eCRFs (SAE/ECI–A and SAE/ECI–B). 


IBCSG 45-13 / BIG 4-13 PANACEA 
 
V2.1  Amendment 1   11 January 2016 
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To ensure patient safety, the IBCSG must be informed of each SAE and each ECI using the 
procedures described below: 
 The Investigator/MD responsible for the patient must complete a Serious Adverse 
Event (SAE/ECI-A) eCRF in English within 24 hours of awareness via iDataFax. A 
copy is automatically forwarded to the IBCSG Safety Office for medical review. 
 Queries may be issued by the IBCSG Safety Office; a timely response by the 
Investigator to all SAE-related queries is crucial. 
 Follow-up information should be completed, via iDataFax, on the Serious Adverse 
Event (SAE-B) eCRF as early as possible but within 15 days of the initial report, 
even if the event reported in the SAE/ECI-A eCRF is not yet resolved.  If the event 
is not resolved within 15 days, revise the original Serious Adverse Event (SAE-B) 
eCRF in iDataFax to report the final resolution. 
 All SAEs or ECIs that have not resolved upon discontinuation of the patient’s 
participation in the trial must be followed until recovered, recovered with sequelae, 
not recovered (death due to another cause) or death (due to the SAE). 
 If a non-serious adverse event becomes serious, this and other relevant follow-up 
information must also be provided within 24 hours. 
 Photocopies of all examinations carried out with the dates on which they were 
performed should be sent by fax or DFSend into the DataFax system. Care should be 
taken to ensure that the patient's identity is protected and the patient’s Registration 
ID Number is properly included on ALL pages of any reports. For laboratory results, 
include the laboratory normal ranges. Please also note on each page that the 
information is “SAE related” so it can be properly categorized in iDF. 
 In the event the eCRF system is not working, the SAE Forms can be found in the 
trial site file or downloaded from the IBCSG trial webpage and sent via fax or 
DFSend into the DataFax system. 
If an SAE/ECI (SAE/ECI-A and SAE/ECI–B forms) was submitted by fax or DFSend, the 
original forms and the fax confirmation sheet(s) must be kept at the Participating Center. 
The IBCSG will inform Merck Global Safety and other appropriate persons about all SAEs 
and ECIs within 24 hours of receipt at the IBCSG. 
The IBCSG will record the SAE/ECI and prepare a monthly SAE/ECI report. Principal 
Investigators will receive the summary report on a monthly basis, and these reports can be 
found on the IBCSG web site (www.ibcsg.org). 
12.5. 
Pregnancy 
Pregnancies and suspected pregnancies of a patient occurring during trial treatment, or 
within 7 months of the last dose of trial drug(s), are considered immediately reportable 
events. Trial drug(s) are to be discontinued immediately and the patient instructed to return 
any unused portion of the trial drug(s) to the Investigator. The pregnancy, suspected 


IBCSG 45-13 / BIG 4-13 PANACEA 
 
V2.1  Amendment 1   11 January 2016 
Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
pregnancy, or positive pregnancy test must be reported within 24 hours of the Investigator’s 
knowledge using the Pregnancy Form (Form 45-PREG) to the IBCSG who will inform 
MSD immediately. 
The patient should be referred to an obstetrician-gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling.   
The Investigator will follow the patient until completion of the pregnancy, and must notify 
IBCSG immediately about the outcome of the pregnancy by completing the corresponding 
section on the pregnancy form (45-PREG). 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to trial drug(s) should also be reported within 24 hours of 
the Investigator’s knowledge of the event using the SAE Forms. 
12.6. 
Reference Safety Information 
The Pembrolizumab/MK-3475 Investigator’s Brochure Edition 10 Section 7 serves as 
reference document for the determination of the expectedness of the serious adverse events 
of MK-3475. 
The currently EU approved Summary of Product Characteristics (SPC) of trastuzumab 
serves as reference safety information to assess the expectedness of trastuzumab related 
serious adverse events. 
13. 
Disease assessment, response and progression (RECIST 1.1) 
13.1. 
Introduction 
All enrolled patients will be assessed for disease response and progression according to the 
revised Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) (Eisenhauer 
EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 45:228-2247, 2009). In this trial, patients 
must have measurable disease (see definitions below). Patients will be re-evaluated after 4 
cycles (12 weeks), 6 cycles (18 weeks), 8 cycles (24 weeks) and then every 12 weeks (every 
4 cycles) until confirmed progression. 
Objective response (primary endpoint) will be assessed using RECIST 1.1 criteria. 
13.2. 
Methods of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during treatment and follow-up. Imaging-
based evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment. 
CT scan is the best currently available and reproducible method to measure lesions selected 
for response assessment. CT scan should generally be performed using a ≤5 mm contiguous 
reconstruction algorithm. MRI is acceptable for certain situations (e.g., body scans). 


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Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules) and ≥10 mm. In the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended. 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT scan is preferable. 
Ultrasound is not useful in assessment of lesion size and is not accepted as a method of 
assessment. 
FDG-PET (fludeoxyglucose positron emission tomography) is not foreseen for regular 
response assessments. It may, however, be used to detect or confirm the appearance of new 
lesions. Attenuation correction CT scans performed as part of a PET/CT scan frequently 
show lower resolution; therefore, dedicated CT scans are preferred. However, if the site can 
demonstrate that the CT scan performed as part of a PET/CT is of the same diagnostic 
quality as a diagnostic CT scan (with i.v. and oral contrast), then the CT scan portion of the 
PET/CT can be used for RECIST measurements. 
13.3. 
Measurability of tumor at baseline 
13.3.1. Measurable disease 
Measurable disease is defined as the presence of at least one measurable lesion. 
Measurable lesions: 
 Tumor 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: 
o 10 mm by CT scan (CT scan slice thickness no greater than 5mm). 
o 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable). 
o 20 mm by chest X-ray. 
Reminder: A lesion in a previously irradiated area is not eligible for measurable 
disease. 
 Malignant lymph nodes: to be considered pathologically enlarged and measurable, 
a lymph node must be ≥15 mm in short axis when assessed by CT scan, assuming 
the slice thickness is ≤5 mm. At baseline and in follow-up, only the short axis will be 
measured. 
13.3.2. Non-measurable disease 
Non-measurable disease is defined as lesions or sites of disease that cannot be measured.  
Non-measurable lesions/sites of disease and special considerations:  
 Small non-nodal lesions (longest diameter <10 mm in CT scan). 
 Small lymph nodes (short axis ≥10 and <15 mm). Lymph nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or 
followed as measurable or non-measurable disease. 


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 Bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above. Blastic bone 
lesions are non-measurable. 
 Leptomeningeal disease 
 Ascites 
 Pleural or pericardial effusion 
 Inflammatory breast disease 
 Lymphangitic involvement of skin or lung 
 Cystic lesions. Cystic lesions thought to represent cystic metastases may be 
considered as measurable lesions. However, if non-cystic lesions are present, these 
are preferred as target lesions. 
 Tumor lesions situated in a previously irradiated area, or subjected to other loco-
regional therapy. Such lesions may be considered measurable if there has been 
demonstrated progression in the lesion. 
 Abdominal masses/abdominal organomegaly identified by physical exam that are 
not measurable by reproducible imaging techniques. 
13.4. 
Selection of target lesions 
Target lesions should be identified, measured and recorded at baseline (Form 45-TEV-B). 
At baseline, there can be up to a maximum of 5 lesions representative of all involved organs, 
and up to 2 per organ. Target lesions should be selected on the basis of their size and their 
suitability for accurate repetitive measurements. A sum of diameters for all target lesions 
will be calculated and reported as the baseline sum of diameters. Lymph nodes selected as 
target lesions should always have the short axis recorded. All other lesions should always 
have their longest diameters recorded. The sum of diameters will be used as reference to 
further characterize the objective tumor response of the measurable dimension of the 
disease. 
13.5. 
Selection of non-target lesions  
Non-target lesions should be identified. All other lesions (or sites of disease) not identified 
as target lesions should also be recorded as non-target lesions at baseline.  
For non-target lesions, measurements are not required, but the presence or absence of each 
should be noted throughout follow-up (Form 45-TEV). It is possible to record multiple non-
target lesions as a single item on the eCRF (e.g., "multiple liver metastases"). 


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V2.1  Amendment 1   11 January 2016 
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13.6. 
Evaluation of target lesions (measurable disease) 
All target lesions will be measured at each tumor assessment, and the sum of their diameters 
will be compared to previous assessments in order to assign the response status as specified 
below. 
 Complete Response (CR): Disappearance of all target lesions. Lymph nodes 
selected as target lesions must each have reduction in the short axis to <10 mm in 
order for the response to be considered complete. In this case, the sum of diameters 
may be >0. 
 Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions taking as reference the baseline sum of diameters. 
 Progression (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum recorded on trial. In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. The appearance of one or more new lesions (see Section 13.8) denotes disease 
progression. 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters recorded 
on trial. 
Note: All target lesions, including lymph nodes, should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). If the 
radiologist does not feel comfortable assigning an exact measure and reports a lesion as "too 
small to measure", a default value of 5 mm should be recorded. If a target lesion is thought 
likely to have disappeared, use "0 mm." 
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. 
13.7. 
Evaluation of non-target lesions  
 Complete Response (CR): Disappearance of all non-target lesions; lymph nodes 
selected as non-target lesions must be non-pathological in size (<10 mm). 
 Non-CR/non-PD: Persistence of one or more non-target lesions (non-CR). 
 Progression (PD): Unequivocal progression of existing non-target lesions. 
Unequivocal means: comparable in magnitude to the increase that would be required 
to declare PD for measurable disease or an overall substantial increase in tumor 
burden that merits treatment discontinuation. 


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When no imaging is done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. If only a subset of lesions are evaluated 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. 
13.8. 
Determination of new lesions 
The appearance of any new malignant lesions denotes disease progression. The finding of a 
new lesion should be unequivocal (i.e., not attributable to differences in scanning technique 
or findings thought to represent something other than tumor). If a new lesion is equivocal, 
(e.g., because of its small size) the patient will stay on treatment (if the decision on PD is 
based on this lesion only).  
Lesions or sites of disease found in a new location not included in the baseline scan (e.g., 
brain metastases) are considered new lesions. 
Note: The "re-appearance" of a previously "disappeared" target or non-target lesion does not 
in itself necessarily qualify as PD; this is the case only if the overall evaluation meets the 
PD criteria, or if the patient was previously in CR. 
13.9. 
Additional considerations 
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 needle aspirate/biopsy) before 
confirming the complete response status. 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 
13.10. Confirmation 
In this trial, a partial response (PR), complete response (CR) or disease progression (PD) 
needs to be confirmed by repeat clinical and radiological assessment 4 to 6 weeks after the 
first assessment. 
In each situation, it is the date of the first radiological assessment that is declared as the date 
of response or of progression. 
13.11. Determination of time point response 
Based on the responses of target lesions, non-target lesions, and the presence or absence of 
new lesions, the overall response will be determined at each tumor evaluation time point, 
according to Table 7 below. 
Table 7  Measurable disease - overall response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 


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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 
*Non-CR/non-PD should be used rather than SD for categorizing non-target lesions.  
13.12. Determination of best overall response  
Objective response (confirmed CR or PR as best overall response) is the primary endpoint 
of the phase II portion of the trial. Best overall response will be determined centrally by an 
Endpoint Review Committee (see Section 19.4) based on tumor assessment eCRFs. 
13.13. Storage of imaging 
CT/MRI images must be stored locally in electronic format for potential central review, see 
separate instructions on the IBCSG website. 
14. 
Clinical and laboratory evaluations 
14.1. 
Screening  
14.1.1. Obtain informed consent for screening evaluations and trial participation. 
14.1.2. Cardiac evaluation: ECG, echocardiography or MUGA scan has to be performed 
within 3 months before treatment start. 
Results of the screening examinations should be available in the patient file at the time of 
registration of a new patient. 
The following examinations should be done within a maximum of 28 days before start of 
treatment. If examinations were done prior to 28 days before start of treatment, they have to 
be repeated before treatment start. For examinations marked below with an * the results of a 
test within the timeline of the 28 days before treatment start do not need to be present before 
sending the tumor material to the central office. Eligibility for screening can be judged on 
tests performed earlier but the tests will have to be repeated before treatment start. In cases 
where central confirmation of HER2+ and PD-L1 expression status takes more than 10 
working days the treatment start can be within 35 days of the examinations. 
14.1.3. Clinical and radiological tumor assessments by CT scan or MRI.  
14.1.4. Bone scan if clinically indicated. 
14.1.5. * Physical examination including vital signs, ECOG Performance Status, body 
weight. 
14.1.6. * Hematology: Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count). To be repeated if not done within 7 days 


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prior to first dose of trial treatment. 
14.1.7. * Biochemistry: serum potassium, sodium, calcium, serum amylase, lipase and 
LDH; 
Liver function tests: albumin, total bilirubin, ALT, AST, ALP, GGT; 
kidney function tests: urea, creatinine and uric acid. 
Note: Biochemistry, liver and kidney function labs needs to be repeated if not done 
within 7 days prior to first dose of trial treatment. 
14.1.8. * For patients of childbearing potential: Serum pregnancy test; the test has to be 
repeated before treatment start, if treatment does not start within 72 hours of the 
previous test. 
14.1.9. Medical history including details of malignancy: date of diagnosis, primary tumor 
type characteristics (histology, grade). 
14.1.10. * Baseline symptoms (record on baseline adverse events form) and concomitant 
medication. 
14.1.11. * CA 15-3 
The following examinations should be done within a maximum of 42 days before start of 
treatment. If examinations were done prior to 42 days before start of treatment, they have to 
be repeated: 
14.1.12. T3, T4, TSH 
14.1.13. Coagulation profile: according to local standards 
14.1.14. Hepatitis B and C test,  
14.1.15. * HIV test (needed for enrollment, not for screening) 
14.1.16. Urinalysis: proteins, glucose and blood using a dipstick.   
14.2. 
Central confirmation of HER2+ and PD-L1 status 
The HER2 and PD-L1 status need to be evaluated centrally before enrollment to determine 
the eligibility of the patient.  
14.2.1. Ship FFPE block of unresectable loco-regional or metastatic biopsy to central 
laboratory. Shipment from the participating center to the IBCSG Central Pathology 
Office may take between 2-5 business days. 
Note: Do not submit for central review if the metastatic or unresectable loco-
regional biopsy tested HER2-negative locally. 
14.2.2. Central laboratory will evaluate HER2. In case HER2-positivity is confirmed, the 
central laboratory will forward tissue to the certified lab for determination of PD-
L1 status.  
14.2.3. Results of HER2 and PD-L1 assessments will be communicated to the site and are 


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expected to be available within 10 business days from the time the FFPE block 
arrives at the IBCSG Central Pathology Office, in Milan, Italy.  
14.3. 
Biological samples before, during and after treatment 
Please consult Section 15.1 for a complete schedule of biological samples (FFPE and fresh 
frozen tumor tissue, whole blood, plasma) to be taken at baseline, during and after 
treatment. The “Blood Sample Logistics Manual” gives details on collection, storage and 
shipment. 
14.4. 
Day 1 of every treatment cycle 
Investigations marked with * need to be repeated prior to start of treatment if not done 
within 3 days prior to this day. 
14.4.1. Physical examination including vital signs, ECOG Performance Status, and body 
weight. 
14.4.2. * Hematology: Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count). 
14.4.3. * Biochemistry: serum potassium, sodium, calcium, serum amylase, lipase and 
LDH; 
Liver function tests: albumin, total bilirubin, ALT, AST, ALP, GGT; 
Kidney function tests: urea, creatinine and uric acid. 
14.4.4. Collection of any adverse event observed in the previous cycle and assignment of 
appropriate adverse events grade according to the NCI CTCAE Version 4. 
14.4.5. Record all concomitant medication. 
14.5. 
Every second treatment cycle 
On day 1 of cycles 3, 5, 7 etc., or within 7 days before these dates: 
14.5.1. T3, T4, TSH 
14.5.2. Coagulation profile: if medically indicated, according to institutional standard 
14.5.3. CA 15-3 
14.5.4. Urinalysis: proteins, glucose and blood using a dipstick.   
14.6. 
Tumor assessments 
Tumor measurements according to RECIST 1.1 criteria (see Section 13) have to be done at 
baseline, at 12, 18 and 24 weeks (+/- 1), then every 12 (+/- 2) weeks until progression, or for 
a maximum of 24 months (see also Section 14.9):  
14.6.1. Clinical and radiological tumor assessments will be done by CT scan or MRI.  
14.6.2. Bone scan will be done if clinically indicated at the same time points. 
14.7. 
Cardiac evaluation 


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14.7.1. Electrocardiogram (ECG): at baseline (≤42 days prior to treatment start) and at 
weeks 12, 24 etc. (every 12 +/- 2 weeks).  
14.7.2. Echocardiography or MUGA scan: at baseline (≤42 days prior to treatment start), 
and at weeks 12, 24 etc. (every 12 +/- 2 weeks).  
14.7.3. Cardiac enzymes BNP and Troponin: at baseline (≤42 days prior to treatment start), 
then every 12 (+/- 2) weeks until end of treatment. 
14.8. 
After discontinuation of trial treatment 
Trastuzumab can be continued in case of MK-3475 cessation due to toxicity. Similarly, 
MK-3475 can be continued if trastuzumab has been ceased, except in the case of cardiac 
dysfunction where both drugs must be stopped. 
End of treatment visit within 30 days of the last dose of trial treatment. If the decision to 
stop trial treatment comes more than 30 days after the last dose, this visit should be done as 
soon as possible. 
14.8.1. Physical examination, vital signs, ECOG Performance Status, and body weight. 
14.8.2. Collection of any adverse event and assignment of appropriate adverse events grade 
according to the NCI CTCAE Version 4. 
14.8.3. Record all concomitant medication. 
14.8.4. Hematology: Hemoglobin, platelet count, white blood cell count including 
differential (absolute neutrophil count). 
14.8.5. Biochemistry: serum potassium, sodium, calcium, serum amylase, lipase and LDH; 
Liver function tests: albumin, total bilirubin, ALT, AST, ALP, GGT; 
Kidney function tests: urea, creatinine and uric acid 


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14.8.6. T3, T4, TSH 
14.8.7. Coagulation profile: according to institutional standard 
14.8.8. If not done in the 30 days prior to this visit, clinical and radiological tumor 
assessments by CT scan or MRI.  
14.8.9. If not done in the 30 days prior to this visit, tumor measurements according to 
RECIST 1.1 criteria for determination of response (see Section 13). 
14.8.10. CA 15-3 
14.8.11. If treatment discontinued prior to progression, take two biopsies for translational 
research from a readily accessible lesion. Store one biopsy at -80°C and the second 
biopsy as a formalin-fixed, paraffin embedded block until shipment to the central 
lab. 
14.9. 
Follow-up prior to documented disease progression 
14.9.1. Patients stopping treatment early (prior to maximum treatment duration of 24 
months), for any reason other than progression, will have a visit 12 (+/- 2) and 24 
(+/- 2) weeks after stop of treatment. 
14.9.2. Patients that progress and stop treatment as well as patients taking treatment all the 
way to 2 years will have no further visits after the end of treatment visit; physical 
examination, vital signs, ECOG Performance Status, and body weight. 
14.9.3. Collection of any adverse event having occurred up to 30 days after last dose of 
trial treatment, and assignment of appropriate adverse events grade according to the 
NCI CTCAE Version 4. 
14.9.4. Record all concomitant medication up to 30 days after last dose of trial treatment. 
14.9.5. Electrocardiogram (ECG)  
14.9.6. Echocardiography or MUGA scan.  
14.9.7. Clinical and radiological tumor assessments by CT scan or MRI.   
14.9.8. Bone scan if clinically indicated. 
14.9.9. Tumor measurements according to RECIST 1.1 for determination of response. 
If feasible, as soon as all trial treatment has been stopped or at PD, whichever occurs first, a 
biopsy should be taken (see 14.10.3). 


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14.10. At progression 
14.10.1. Progressive disease is required to be confirmed 4 to 6 weeks later by the same 
imaging procedure. 
14.10.2. Tumor measurements according to RECIST 1.1 for determination of progression  
14.10.3. If not done already at time of discontinuation of trial treatment, take two biopsies 
for translational research from a readily accessible lesion. Store one biopsy at -
80°C and the second biopsy as a formalin-fixed, paraffin embedded block until 
shipment to the central lab.  
Note: After cessation of treatment, patients will have an End of Treatment visit as described 
in Section 14.8 and will afterwards be followed in clinic until confirmed progression or 24 
weeks after stop of treatment, whichever occurs first. 
15. 
Biological evaluations 
15.1. 
Introduction and overview 
Tumor tissue taken prior to start of treatment will be used to define biomarkers that could 
identify patients with a high chance of responding to MK-3475 combination with 
trastuzumab therapy. Biopsies at time of treatment discontinuation (usually at progression) 
will be used to understand resistance and response mechanisms.  
Therefore, eligible patients should have lesions potentially suitable for serial biopsies. 
Patients will be asked to undergo biopsies pre-therapy (unless a biopsy was previously taken 
from a metastatic or loco-regional lesion) and on progression or at trial treatment 
discontinuation (and if possible, also from responders who stop trial treatment without 
progression). Lesions at time of end of trial treatment, usually at progression, can be exempt 
from repeat biopsy if too small (<1cm), or too dangerous. Tissue from the archival primary 
tumor (if breast tumor was removed at primary surgery) will also be requested; however, 
patients do not wait to enter the trial while the archival tumor is being obtained. 
Biopsies from bone or bone marrow are not acceptable for screening. 
The following tumor tissue samples will be taken and shipped to the central laboratory: 
 
Table 8  Tumor tissue samples 
Sample 
Timepoint for 
submission 
required 
Purpose 
Pre-treatment FFPE 
tumor block 
(including 
corresponding 
pathology report)  
At screening; 
from biopsy of 
advanced disease, newly 
taken (preferred) or 
obtained ≤1 year prior to 
enrollment 1 
Mandatory 
- Central testing HER2 and 
PD-L1 for eligibility 
- Tumor infiltrating 
lymphocytes 
- DNA extraction for deep 
sequencing 
- ER/PgR status 


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Sample 
Timepoint for 
submission 
required 
Purpose 
FFPE tumor block 
from primary 
surgery (including 
corresponding 
pathology report)  
At enrollment 
Required, if 
available  
- Central testing HER2 and 
PD-L1 
- Tumor infiltrating 
lymphocytes 
- DNA extraction for 
sequencing 
Pre-treatment fresh 
frozen tumor 
biopsy(+ path report) 
Take at enrollment, from 
pre-treatment biopsy or 
primary surgery. Bank 
locally and submit upon 
request 
Required, if 
available 
- DNA extraction for 
sequencing 
- RNA extraction for RNA-
seq 
Post-treatment FFPE 
tumor block (+ path 
report) 
A re- biopsy at time of 
progressive disease or 
end of all tx if ended 
prior to PD is strongly 
recommended 
Required, if 
feasible 
- Central testing HER2 and 
PD-L1  
- Tumor infiltrating 
lymphocytes 
- DNA extraction for 
sequencing 
Post-treatment fresh 
frozen tumor biopsy 
(+ path report) 
From lesion biopsied at 
time of progressive 
disease or end of all tx if 
ended prior to PD. Bank 
locally and submit upon 
request 
Required, if 
feasible 
- DNA extraction for 
sequencing 
- RNA extraction for RNA-
seq 
1 If central evaluation of archival tissue from a previous biopsy obtained ≤1 year from time 
of trial enrollment yields a negative test result, a new biopsy may be taken and submitted for 
central evaluation.   
Table 9  Blood samples for all patients 
 
15.2. 
Submitting pathology material to IBCSG 
All FFPE blocks and copies of Pathology Reports must be marked with the IBCSG Patient 
ID number. Please erase or black out any other identifiers like name or date of birth. Refer 
to the IBCSG website for additional FFPE specimen shipping recommendations. 
All FFPE samples should be submitted within 4 weeks after being available. The biopsy 
used for central determination of HER2 and PD-L1 must be submitted prior to enrollment. 
Mailing address for the FFPE blocks and Pathology Reports: 
Purpose 
Type of 
sample 
Cycle 1 
Cycle 3 
Cycle 5, 8, 
11, … 
(every 3 
cycles) 
30 days 
after 
treatment 
stop 
cpDNA 
Plasma from 
8-10 mL 
whole blood 
Before 
dose 
Before 
dose 
Before 
dose 
Yes 
Confirmation of somatic nature of 
mutations found in tumor biopsies 
10 mL whole 
blood 
Before 
dose 
 
 
 


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IBCSG Central Pathology Office 
European Institute of Oncology, EIO  
Division of Pathology  
Via Ripamonti 435  
20141 Milano, Italy  
E-mail: pathology.ibcsg@ieo.it 
NOTE: Pathology Reports must also be submitted to DataFax via fax or DFsend. 
Fresh frozen tumor blocks will be stored locally at -80°C and collected later. 
15.3. 
Central testing of HER2 and PD-L1 
The IBCSG Central Pathology Office at European Institute of Oncology, Milan, Italy, will 
determine the HER2 status for submitted biopsies. Five 5 µm sections (FFPE) will be sent to 
the certified lab for PD-L1 determination by IHC. 
HER2 status will be quantified by copy number and FISH ratio. 
The certified lab is Quintiles, Scotland, UK. 
15.4. 
Banking biological material 
All FFPE blocks will be banked in the IBCSG Tissue Bank, to have available for 
Translational Research, and tumor DNA will be extracted and cryopreserved (to avoid DNA 
degradation in FFPE). All biological material will be logged in the IBCSG Pathology 
Material Tracking System /Translational Research Information Management System and 
banked in the IBCSG Tissue Bank.   
The use of the biological material for not yet specified future research will be under the 
auspices of the IBCSG Biological Protocols Working Group. As part of the Informed 
Consent process, patients are asked to agree to donate their sample for not yet specified 
future research. 
15.4.1. FFPE 
Remaining FFPE tumor blocks from the metastatic lesion will be stored in the IBCSG tissue 
biobank (pre-treatment and at treatment discontinuation). See Section 15.2 for shipping 
address and also the “IBCSG 45-13 PANACEA Pathology Procedures Manual”. FFPE 
material from patients screened negative for PD-L1 will be kept in the biobank as well. 
Archived primary tumor material is also requested from the patient. 
15.4.2. Frozen tumor biopsies 
We request that one to two frozen tumor biopsies are taken, prior to start of treatment and at 
treatment discontinuation, and stored in liquid nitrogen or O.C.T. (Optimal Cutting 
Temperature) Compound – the latter is preferred. Bank the fresh frozen tumor blocks locally 
and submit upon request. The fresh frozen biopsies will be centralized at IBCSG at the end 
of the trial, shipped in one single batch. The IBCSG will coordinate this temperature 


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controlled transfer.  Please refer to the “IBCSG 45-13 PANACEA Pathology Procedures 
Manual” for more details on the OCT or on alternative methods, such as Snapfrost. 
15.4.3. Blood samples 
At the end of the trial, blood and plasma samples will be collected by courier and sent to: 
Harriet Johansson 
Lab Senior Assistant 
Division of Cancer Prevention and Genetics 
European Institute of Oncology 
Via Ripamonti 435, 20141 Milan, Italy 
Please consult the “Blood Sample Logistics Manual” for details. 
15.5. 
Translational research 
Given that this is a proof-of-concept trial exploring a new therapeutic area for breast cancer, 
a complete collection of biological materials is requested in order to be able to 
comprehensively define the molecular and immune landscape of these tumors. The goals of 
the translational research will be to determine mechanisms and biomarkers for MK-3475 
efficacy and resistance.  
Planned correlative studies: 
15.5.1. Biomarkers of PD-1/PD-L1 
Quantification of PD-L1 and PD-1 expression will be done by a Merck CLIA-certified IHC 
test in a central lab. This marker will be performed in the primary tumor and unresectable 
loco-regional or metastatic biopsies pre-treatment and at time of trial treatment 
discontinuation. 
15.5.2. Multiparametric  IHC  
Spatial association of PD-1+ tumor infiltrating lymphocytes (TILs) and PD-L1+ cells 
(tumor and myeloid cells) suggests “induction” of PD-L1. Interferon-gamma production by 
antigen-specific PD-1+ CD8+ T-cells is hypothesized to drive local intra-tumoral 
upregulation of PD-L1 on adjacent tumor and myeloid cells, leading to a “stalled Cytotoxic 
T Lymphocyte (CTL)” response which may be predictive of response to MK-3475 therapy.  
By assessing both of the required elements, (i.e., PD-L1 expressing cells and PD-1+ T-cells) 
an IHC assay may be a better predictor of response than PD-L1 expression alone. 
15.5.3. Characterization of tumor infiltrating lymphocytes 
Quantification of tumor infiltrating lymphocytes will be performed independently by two 
pathologists (Giuseppe Viale and Carsten Denkert). The percentage infiltration in the 
adjacent stromal areas as previously described [3,4] will be recorded. This assessment will 
be performed in the primary tumor and metastatic biopsies pre-treatment and at time of trial 
treatment discontinuation. 
Agreement between assessments by pathologists will be analyzed. 


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Objective responses will be assessed as a function of TILs adjusted for other clinico-
pathological factors, the hypothesis being that high levels of TILs will be associated with a 
higher rate of objective responses in this trial. 
15.5.4. Characterization of circulating plasma DNA (cpDNA) 
Plasma of cancer patients contains cell-free tumor DNA that carries information on tumor 
mutations and tumor burden. This information may be useful as a non-invasive way of 
monitoring advanced disease using cancer genetic alterations (mutations, rearrangements) 
that are specific to the individual’s tumor. This information may allow us to track and 
monitor tumor dynamics during the disease course as well emergence of new clones (i.e., 
resistance mechanisms). Individual mutations may be assessed using technologies such as 
Sequenom Mass Spectrometry or deep sequencing. 
Plasma needs to be stored at −80°C until shipment. See Section 15.1 for an overview of 
sampling timepoints. 
For cpDNA extraction, plasma will be thawed at ambient temperature and cpDNA extracted 
from 2 mL of plasma using a QIAamp DNA Blood Midi Kit (Qiagen, Valencia, CA, USA), 
according to the manufacturer's instructions, with the following modifications: for each 2 
mL sample of plasma, an additional centrifugation step (16000 g, 5 min, RT) was added 
before the extraction procedure in order to eliminate cellular debris from the plasma. At the 
end of the procedure, the DNA will be eluted in 100 µL of AE elution buffer. DNA 
concentration will be measured with fluorescent staining, using the Quant-iT™ Pico-
Green® double stranded DNA (dsDNA) Assay Kit (Invitrogen, Carlsbad, CA) and the 
SynergyHT microplate reader (Biotek).  
15.5.5. Sequencing of tumor biopsies (DNA and RNA) 
Frozen and FFPE biopsies will be retained for deep sequencing using next generation 
technologies at the completion of the trial. Nucleic acids will be extracted according to 
standard protocols. Sequencing will be performed using the Illumina Hi-Seq, though the 
technology is improving at a rapid rate. 
The aim of the sequencing is to understand the molecular landscape (mutations, 
rearrangements and copy number changes) associated with HER2-positive, PD-L1 
expressing tumors as well as response or resistance to the trial therapy. Specific mutational 
patterns may be associated with increasing PD-L1 expression or lack of TILs (i.e., 
chromosomal instability, certain somatic mutations) which could imply a means by which 
the tumor escapes and subverts host immunity. This may be amenable to targeting with 
another compound. Similarly, tumors may upregulate specific pathways in order to avoid 
immune destruction after the PD-1 pathway has been inhibited. The presence of intra-
tumoral heterogeneity will be investigated for in tumor biopsies and if this correlates with 
tumor responses. 
Paired metastatic lesions will be compared for the changes that occur during progression 
and resistance to the MK-3475/trastuzumab combination. This will be also compared with 
the primary tumor. New data are emerging that suggest we can define certain tumor types as 


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being ‘hypermutated’. There is a potential that this hypermutated state may correlate with 
response to MK-3475 therapy, and/or that the converse, ‘hypomutated’ state may correlate 
with non-response.  
If enough RNA is also able to be extracted, gene expression of these tumors will be 
evaluated using a genome-wide, deep sequencing technology (RNA-seq). Specific markers 
of immune response (immunosuppression as well as activation) can be then assessed for 
changes during the treatment course. For example, the expression of Tregs (FOXP3) as well 
as IDO1, an immunosuppressive soluble factor may be increased at progression. Gene 
signatures that are published in the literature representing various aspects of immunity could 
also be assessed for their change during treatment. 
Whole blood will be collected at baseline prior to treatment. The sample will be processed 
and stored at -80°C. It will be used to confirm the somatic nature of any interesting 
mutations found. This will not be used for analysis of germline abnormalities. 
DNA and RNA will be analyzed to attempt to define a gene set critical for clinical response 
to MK-3475. The hypothesis to be tested is that MK-3475 responders will exhibit a “stalled 
Cytotoxic T Lymphocyte (CTL)” response within the tumor reflected in the physical 
proximity between PD-1 and PD-L1 expression and the presence of an aborted  (e.g., weak 
but discernible) interferon-gamma transcriptional program will be detectable by profiling 
analyses. Significant alterations identified with these technologies can also be evaluated 
using cpDNA. 
15.5.6. Further exploratory biomarkers 
Merck will perform IHC evaluation, minimally to include PD-1 and PD-L1 IHC, as well as 
Nanostring-based gene expression analysis. This can be accomplished with 10-20 unstained 
4-5 micron slides. Merck will deliver the results to IBCSG.  
15.5.7. Not yet specified translational research 
Translational research proposals not outlined in this protocol will be assessed by a trial-
specific research committee for merit and feasibility. 
Biomarkers that are published in the future and considered to be of relevance can then also 
be assessed in the context of this trial. 
For example, an anti-HER2 adaptive response could be assessed and monitored in plasma 
samples should a suitable antibody be found. 
16. 
Data submission 
We will conduct the trial according to the ICH Good Clinical Practice (GCP) guidelines.  
Keeping accurate and consistent records is essential to a cooperative trial. Forms need to be 
submitted within 1 week of visit (unless otherwise indicated in table below). The following 
forms are to be submitted at the indicated times by the participating institutions for each 
patient: 


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16.1. 
Case report forms schedule 
Forms 
Description/Name 
Forms Submission 
Registration  
ALL data should be completed  in iDataFax 
(iDF) (unless otherwise specified) 
Informed 
Consent Form 
Consent to participation in clinical 
trial 
Obtain before registration and keep with patient 
records as documentation (hard copy only). 
45-A1  
Confirmation of Registration Form 
Complete in iDF after you have registered the 
patient in the IBCSG 
Registration/Randomization System 
Enrollment 
45-A2 
Confirmation of Enrollment Form 
Complete in iDF after you have enrolled the 
patient in the IBCSG 
Registration/Randomization System.  
Baseline  
45-H 
History Form 
Complete in iDF within 1 week of enrollment. 
Path. Report 
Pathology Report 
Submit Report(s) of unresectable loco-regional 
and/or metastatic lesion to DataFax System 
within 1 week of enrollment via fax or DFsend. 
45-BAE 
Baseline Adverse Events and 
Symptoms Form 
Complete in iDF within 1 week of enrollment.   
45-CE 
Cardiac Evaluation Form 
Complete in iDF within 1 week of enrollment.   
45-CCM 
Concomitant Medication Form  
Complete in iDF each time a medication is 
started, amended, or ended, including 
medications taken within 28 days prior to start 
of treatment (excluding prior treatment for 
primary/metastatic breast cancer). 
45-TEV-B 
Tumor Evaluation Baseline Form 
Complete in iDF within 1 week of enrollment.  
45-FFBI-PT 
Fresh Frozen Biopsy Information – 
Pre-Treatment Form 
Complete in iDF within 1 week of enrollment 
for biopsy taken ≤28 days prior to treatment 
start. 
During trial treatment 
45-CYC 
Treatment Cycle Form 
Complete in iDF at the end of each cycle until 
treatment stops. 
45-DLT 
Dose Limiting Toxicity Form 
(during cycle 1 only) 
Complete in iDF for cycle 1 immediately if 
DLT is observed, otherwise at end of cycle 1 
for all patients in dose finding phase 1b part of 
the trial. 
45-AE 
Adverse Events Form 
Complete in iDF at the end of cycle 1 of trial 
treatment. At the end of each subsequent cycle, 
review the original AE Form in iDF. Update 
AEs if needed and add any new AEs. 
45-CCM 
Concomitant Medication Form 
Review the original CCM Form in iDF at the 
end of each cycle. Update any current 
medications if needed and add new medications 
taken. 
45-BSC 
Blood Sample Collection Form 
Complete/Update in iDF at each blood sample 
collection. 
45-FFBI-PRO 
Fresh Frozen Biopsy Information – 
Progression Form 
Complete in iDF at progression if re-biopsy is 
taken.  
45-CE 
Cardiac Evaluation Form 
Complete in iDF every 12 weeks while on 
treatment 
45-TEV 
Tumor Evaluation Form 
Complete in iDF at weeks 12, 18 and 24, then 
every 12 weeks while on treatment. A 
confirmatory TEV Form should also be 
submitted 4-6 weeks after CR, PR and PD 
 
 


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The Data Managers’ Manual for this trial contains instructions for submitting forms using 
the iDataFax system. 
16.2. 
Signing and submitting forms 
An Authorization Log (see Section 16.5) should be completed at each Participating Center 
to identify the persons who are authorized to complete CRFs. 
CRFs should be completed on-line in iDataFax. Reports (lab, pathology, etc.) and any other 
non-CRF data will need to be sent to the DataFax system via fax or DFsend. Full 
instructions on submitting forms will be available on the IBCSG website (www.ibcsg.org). 
Also available on the website is a list of fax numbers that are available for faxing CRFs. 
16.3. 
Data management 
Data collected in this trial will be submitted to the IBCSG Data Management Center in 
Amherst, NY, USA. The Data Management Center will process the data and will generate 
queries and forms requests. The Data Quality Control Office will oversee overall data 
submission and query resolution. The IBCSG Coordinating Center in Bern, Switzerland will 
provide medical review and summary of SAEs. The IBCSG Statistical Center in Boston, 
MA, USA will perform the data analysis. 
Forms 
Description/Name 
Forms Submission 
Follow Up (after discontinuation of trial treatment) 
45-EoT 
End of Treatment Form 
Complete in iDF 30 days after ALL protocol 
treatment stops. 
45-E 
Follow up Form 
Complete in iDF 12 and 24 weeks after all 
protocol treatment stops, if patient discontinued 
trial treatment prior to documented progression. 
45-TEV 
Tumor Evaluation Form 
If patient discontinued trial treatment prior to 
documented progression:  every 12 weeks until 
progression.  
45-AE 
Adverse Events Form 
Review and submit the AE Form in iDF 30 days 
after the last dose of trial treatment. Update AEs 
if needed and add any new AEs.  
Path. Report 
Pathology Report 
Submit Report of re-biopsy post-progression (if 
available) to DF via fax or DFsend. 
Event Driven  
 
45-SAE/ECI-A 
Serious Adverse Event/Event of 
Clinical Interest Form - Initial report 
Complete in iDF within 24 hours of the SAE or 
ECI. If iDF is not available, fax the form within 
24 hours to DataFax. 
45-SAE/ECI-B 
Serious Adverse Event/Event of 
Clinical Interest Form B - Follow-up 
report 
Complete in iDF within 15 days of the initial 
report (45-SAE/ECI-A). If event is not resolved 
in 15 days, complete 45-SAE/ECI-B again at the 
time of resolution. 
45-PREG 
Pregnancy Form 
Complete in iDF if a patient becomes pregnant 
on trial treatment or within 7 months of last 
dose. Complete the second section of the form at 
the outcome of pregnancy. 
45-COC 
Change of Consent Form 
Complete in iDF if there is any change in 
patient's consent to participate in the trial, see 
Section 18.5.2.  
45-Death 
Death Form 
Complete in iDF if a patient dies. 


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16.4. 
Investigator Site File 
Each Participating Center should keep documentation about this trial in an Investigator Site 
File, which should include the following documents: 
 Protocol and appendices 
 Amendments 
 Signed Protocol Signature Pages 
 Sample CRFs including blank SAE Forms 
 Data Managers’ Manual 
 Obvious Corrections Document and Signature Page 
 Randomization Manual 
 iDataFax (iDF) Manual 
 Drug Supply Manual 
 Latest version of MK-3475 Immune-Related Adverse Event Guidance document 
(Only for Centers activated to original protocol, who have received this document) 
 Manual for Blood Sample Logistics 
 Pathology Procedures Manual 
 Slotting Procedures document 
 Patient information and Informed Consent templates approved by Ethics Committee 
 Investigator's Brochure and updates 
 Ethics Committee (and Health Authority, if applicable) approval of protocol, Patient 
Information Sheet and Informed Consent, amendments 
 Ethics Committee review of SAE, Investigators' alert, and other documents 
 Correspondence with Ethics Committee and Health Authority (if applicable) 
 Certificate of clinical trial insurance 
 Agreement with IBCSG 
 Center Activation email from DMC 
 Correspondence with IBCSG Coordinating Center, Data Management Center 
 SAE Reports sent from IBCSG Data Management Center 
 Normal laboratory values/reference ranges 
 Laboratory Certifications 
 CV of Principal Investigator and Co-Investigators, GCP certificates  
 Trial Training Certificates issued by IBCSG Center Training Office 
 Authorization Log 
 Patient Identification Log (see Section 16.6) 
 Drug Accountability Log (including certificates of destruction if applicable)   
 Temperature logs 
 ICH GCP guidelines/Declaration of Helsinki and updates 
 Audit certificates / monitoring reports 


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16.5. 
Authorization Log 
The Principal Investigator (PI) should identify the other members of the Clinical Trial Team 
who are supervised by the PI and approved to provide information in CRFs, queries, etc. 
Instructions for completing the Authorization Log can be found in the “Authorization Log 
Manual”, posted on the IBCSG website.   
16.6. 
Patient Identification Log 
No patients’ names should be used in CRFs or any other documentation transmitted to 
IBCSG central offices. The only item used to identify a patient is the patient ID number. It 
is therefore imperative that the local data manager keep an identification log for all patients 
entered in this trial including: 
 Patient's name 
 Patient ID issued by the Registration/Randomization System 
 Date of birth 
Other items that could be included are date of enrollment and dose. 
17. 
Statistical considerations 
This is a multi-center, open-label phase Ib/II trial of the combination of the anti-PD-1 
monoclonal antibody, MK-3475, with trastuzumab with primary objectives for patients with 
confirmed HER2-positive and PD-L1-expressing, unresectable loco-regional or metastatic 
breast cancer who have experienced progression with previous trastuzumab-based therapy. 
The primary objective of the dose escalation (phase Ib) portion of the trial is to determine 
the RP2D of MK-3475 in combination with standard dose trastuzumab. The primary 
objective of the phase II portion of the trial will evaluate the efficacy and safety of the drug 
combination.  
The secondary objective will explore the efficacy and safety of the drug combination in a 
parallel cohort of patients with confirmed HER2-positive, PD-L1 negative disease. 
17.1. 
Primary and Secondary Endpoints 
Phase Ib: 
Primary Endpoint: The incidence of dose-limiting toxicity of MK-3475 in combination 
with standard dose trastuzumab (defined in Section 10.2.1). 
Phase II: 
Primary Endpoint: Objective response (confirmed CR or PR as best overall response) 
according to RECIST criteria (Version 1.1) as defined in Section 17.7.1. 
Secondary Endpoints:  


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17.1.1. Safety and tolerability according to CTCAE version 4.0. 
17.1.2. Disease control (DC) defined as best overall response of confirmed CR, PR, or SD 
lasting for 24 weeks or longer, measured from the start of trial treatment until first 
documentation of progressive disease. 
17.1.3. Duration of response (DoR) is defined among patients with objective response 
(confirmed CR or PR as best overall response) as the interval between dates of first 
documentation of objective response and first documentation of progressive 
disease. In the absence of documented progressive disease, follow-up will be 
censored at date of last disease assessment.  
17.1.4. Time to progression (TTP) defined as the interval between the dates of the start of 
trial treatment and first documentation of progressive disease.  In the absence of 
documented progressive disease, follow-up will be censored at date of last disease 
assessment.  
17.1.5. Progression-free survival (PFS) is defined as time from start of trial treatment until 
documented 
disease 
progression 
or 
death, 
whichever 
occurs 
first.  
Patients with new non-breast cancer malignancy must continue to be followed for 
progression of the original breast cancer. For patients without progression, follow-
up will be censored at the date of last disease assessment without progression, 
unless death occurs within 12 weeks following the date last known progression-
free, in which case the death will be counted as a PFS event. 
17.1.6. Patients who discontinue or initiate non-protocol treatment prior to documented 
disease progression will be followed for disease progression.  
17.1.7. Overall Survival (OS) is defined as the time from start of trial treatment to death 
from any cause. For patients who are lost to follow-up or who have no 
documentation of death at the time of final analysis, follow-up will be censored at 
the date of last assessment of vital status. 
17.2. 
Definitions of Trial Populations 
Safety population: All patients receiving at least one dose of MK-3475 will be included in 
assessments of safety. 
Evaluable population:  All patients receiving one or more doses of MK-3475 and 
trastuzumab will be considered evaluable. In the phase Ib study, patient data will be 
summarized according to the assigned MK-3475 dose.  
The phase II study population will be comprised of evaluable patients enrolled in the two 
parallel cohorts.  The assessment of the primary efficacy objective will be based on patients 
with PD-L1 expressing disease.  The secondary objective will be based on patients with PD-
L1 negative disease. 
17.3. 
Design and Sample Size Determination 
Phase Ib: Determination of the recommended dose for the phase II part of the trial will be 
based on a standard 3+3 dose-escalation design. See Section 10.2 for the definition of DLT, 
the dose escalation scheme, and dose levels. A patient in the phase Ib portion of the trial will 


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be replaced if determination of DLT cannot be adequately assessed because of rapid disease 
progression or if treatment and/or follow-up is stopped during the first cycle of therapy for 
reasons other than toxicity. Patients who do not receive trastuzumab in the first cycle of 
therapy due to an infusion reaction to MK-3475 will also be replaced and will not be 
counted as having a DLT. 
The following table summarizes the probability that the dose will be escalated (i.e., that 0 in 
3 patients or 1 in 6 patients experiences DLT) given the true but unknown rate of DLT in 
cycle 1. 
True, but Unknown, DLT Rate 
Probability of Dose Escalation 
10% 
91% 
20% 
71% 
30% 
49% 
40% 
31% 
50% 
17% 
60% 
8% 
 
Phase II:  
PD-L1 Expressing:  A Simon optimal two-stage design [55] was used to estimate the sample 
size for the primary efficacy objective of the phase II trial.   
The null hypothesis of a true objective response rate (ORR) of 7% will be tested against a 
one-sided alternative objective response rate of 22%. The rationale for the null and 
alternative hypotheses is based on several trials. In a comparable trial population of patients 
progressing on trastuzumab therapy, single-agent lapatinib yielded an ORR of 6.9% and 
clinical benefit rate (CBR) of 12% compared with lapatinib and trastuzumab (ORR 10.3%, 
CBR 24.2%) [56]. Lapatinib has recently been shown to be inferior to trastuzumab in a 
head-to-head comparison in the metastatic setting, and the single-agent arm was dropped 
due to an inferior outcome in the phase III, ALTTO adjuvant trial. In a single-arm, multi-
site, phase II trial of combination trastuzumab and pertuzumab in patients progressing on 
previous trastuzumab, an ORR of 24.7% was observed with a CBR of 50% [57]. 
Subsequently, this combination was approved by the FDA in the first-line metastatic setting 
with docetaxel [58] and is currently being evaluated in an adjuvant, phase III trial in 3800 
women (APHINITY). This trial was conducted in a time where patients were generally not 
exposed to other anti-HER2 agents such as lapatinib and trastuzumab-emtansine, hence this 
objective response rate is unlikely to be seen in today’s population where all metastatic 
patients receive a second anti-HER2 therapy prior to receiving investigational therapy. This 
is supported by recent data from the combination of BKM120 (an oral pan-class I PI3K 
inhibitor) and trastuzumab in patients with advanced or metastatic breast cancer who 
progressed while on trastuzumab, reported an ORR of 8% and CBR of 49% [59]. However, 
we have selected the alternative objective response rate to be slightly less than the reported 
response rate of the combination of trastuzumab and pertuzumab given that a reasonable 
ORR should be seen in order to move into the phase III setting. 


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The optimal two-stage design will be based on a total of 40 evaluable patients. Seventeen 
(17) evaluable patients will be enrolled in the first stage, and if 1 or fewer objective 
responses are observed in 17 patients, then enrollment will stop completely. If there are 2 or 
more objective responses, then an additional 23 patients will be enrolled, for a total of 40 
evaluable patients. The null hypothesis will be rejected if a total of 6 or more objective 
responses are observed in 40 evaluable patients. This design yields a type I error rate of 0.05 
(target type I error of 0.05) and power of 85% (target type II error of 0.15) when the true 
objective response rate is 22%. If the null hypothesis is true, the probability is 0.66 that 
enrollment will stop at the end of the first stage. Enrollment will pause at the end of the first 
stage to allow for an early assessment of response if two objective responses have not yet 
been observed among the first 17 evaluable patients. 
PD-L1 Negative:  A PD-L1 negative cohort is included to provide evidence of objective 
response and inform subsequent drug development in patients selected or unselected for PD-
L1 status. A single-stage design with an enrollment of 15 patients will be used to compare a 
null response rate of 1% with a desirable response rate of 20%. The cohort size was selected 
to yield a very high probability of not missing a response signal if one exists. The decision 
rule is based on zero responses: the drug combination would not be considered worthy of 
further investigation if no patients respond. If the true response rate is 20%, then the 
probability that zero responses would be observed in 15 patients is 0.035 (target type II error 
of 0.05). Therefore, there would be less than 4% chance of missing a true 20% response rate 
if the alternative hypothesis is true. The type-I error for the design is 0.14. 
Concurrent with the first-stage review of efficacy in the PD-L1 expressing cohort, a detailed 
safety review will be conducted, as described in Section 11.5 and in Section 17.4. The safety 
review will also include data from patients in the secondary cohort with PD-L1 negative 
disease who are enrolled prior to the 17th evaluable patient with PD-L1 expressing disease. 
17.4. 
Safety Monitoring 
The safety review will be concurrent with the first efficacy review of objective response that 
is specified by the Simon two-stage design. This review will be based on 17 evaluable 
patients with PD-L1 expressing disease from the first stage of the two-stage design, and 
patients in the secondary cohort with PD-L1 negative disease who are enrolled prior to the 
17th patient with PD-L1 expressing disease.  Review of these safety data will be conducted 
by the trial Steering Committee (see Section 19.2) and an independent IBCSG Data and 
Safety Monitoring Committee (DSMC, see Section 19.3) and reported within one month. 
Based on the review, the DSMC may advise that the trial be suspended for additional review 
and possible dose modification; however, the final decision regarding suspension or dose 
modification will be made by the trial Steering Committee. After this initial safety 
assessment, toxicity and adverse event data will be evaluated as part of the semi-annual trial 
review by the DSMC. 
The total number of patients included in the safety review will be between 17 and 32 
patients and will depend upon the number of patients enrolled in the secondary PD-L1 
negative cohort at the time of the assessment.  The decision rules and probabilities presented 


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below are based on 17 patients with PD-L1 expressing disease; however, these will be 
adjusted based on the actual number of patients in the safety analysis to provide comparable 
operating characteristics.  
As part of the early safety monitoring, we will focus particular attention on cardiac events 
(CE) of grade 3 or higher (Section 11.5). If 3 or more of the first 17 patients experience CE, 
then the trial enrollment may be suspended. Table 10 summarizes the probability of 
observing 3 or more CE based on the first 17 patients for various underlying true CE 
probabilities. If the true probability of cardiac toxicity is 18% or higher the probability is 
greater than 60% that 3 or more patients will be observed with CE at the time of the early 
safety monitoring.  
Table 10  Operating characteristics of early cardiac monitoring 
True Incidence of Cardiac Toxicity 
Probability of Observing Three or More 
Patients with CE among First 17 
1% 
< 0.01 
3% 
0.01 
5% 
0.05 
10% 
0.24 
15% 
0.48 
18% 
0.61 
20% 
0.69 
30% 
0.92 
 
All reported AEs will also be summarized as part of this safety review. For a sample of 17 
patients, there is high probability of observing at least one event if a toxicity has an 
incidence of at least 9%. If the true incidence of an unexpected or severe toxicity is 9% or 
greater, the probability is at least 0.80 that one or more patients out of 17 will experience the 
toxicity during the early safety monitoring period. If the true incidence of unexpected or 
severe toxicity is 3% or less, the probability is 0.40 or less that at least one patient of 17 will 
experience the toxicity during the early safety monitoring period. Table 11 summarizes the 
probabilities of observing at least one patient with a severe or unexpected toxicity during the 
initial safety review for a range of true incidence rates. 
Table 11  Operating characteristics of early safety monitoring 
True Incidence of Unexpected or Severe 
Toxicity 
Probability of Observing One or More 
Patients with Toxicity among First 17 
1% 
0.16 
3% 
0.40 
5% 
0.58 
8% 
0.76 
9% 
0.80 
10% 
0.83 
15% 
0.94 


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17.5. 
Screening and Enrollment 
The total enrollment of this phase Ib/II trial will be between 6 and 61 evaluable patients. 
The minimum would occur if the combination of MK-3475 and trastuzumab proved too 
toxic at body weight-based dose levels 1 and -1 and the trial was stopped during the dose 
escalation phase. A maximum enrollment of 61 patients reflects two complete dose 
escalation levels of 6 patients each and 55 patients enrolled during phase II.  Under the 
assumption that approximately two thirds of patients will be found ineligible upon 
screening, it is estimated that about 120 patients will be screened to obtain the maximum 
sample of 61 evaluable patients.  
17.6. 
Analysis of Demographics/Baseline Characteristics 
Demographic and other baseline characteristics will be summarized for all patients by study 
population (Ib or II (PD-L1 expressing, PD-L1 negative), and by dose level for patients in 
the phase Ib study.  Demographic and baseline characteristics of patients who are replaced 
(Section 17.3) will be summarized in a separate category. Summaries of continuous 
demographic/baseline variables, including age, weight, and vital signs, will be presented as 
N, mean, standard deviation, median, quartiles, and minimum and maximum values. For 
categorical variables, such as ER status, the number and percentage of patients will be used.   
17.7. 
Efficacy Analysis (Phase II) 
Primary and secondary endpoints, and correlative objectives of the phase II portion of the 
trial will be based on the phase II population, unless otherwise stated.  Efficacy endpoints 
will be analyzed separately by PD-L1 cohort. Safety endpoints will be summarized in the 
aggregate for all 55 patients (PD-L1 expressing and PD-L1 negative).   
17.7.1. Primary Endpoint  
At the time of each restaging, patients will be classified as achieving complete response 
(CR), partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable 
for response according to RECIST (Version 1.1) criteria. Objective response will be 
determined by the best overall confirmed response designation recorded between the date of 
first dose of trial therapy and the date of objectively documented disease progression or 
cessation of trial therapy, whichever occurs first. For patients without documented 
progression or cessation of trial therapy, all available response designations will contribute 
to the objective response determination.  
 For the primary objective, the proportion of patients with PD-L1 expressing disease 
with an objective response will be presented with a two-sided 90% confidence 
interval calculated using the method of Atkinson and Brown [60], which allows for 
the two-stage design.   
 For the secondary objective, the proportion of patients with PD-L1 negative disease 
with an objective response will be presented with a two-sided 90% exact binomial 
confidence interval.  For a sample of 15 patients, the confidence interval will be no 
wider than 0.46. 


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17.7.2. Secondary Endpoints 
Safety and Tolerability:  All adverse events recorded during the trial will be summarized 
for the safety population. The incidence of events that are new or worsening from the time 
of first dose of treatment will be summarized according to system organ class and/or 
preferred term, severity (based on CTCAE grade), type of adverse event, and relation to 
study treatment. Deaths reportable as SAEs and non-fatal serious adverse events will be 
listed by patient and tabulated by primary system organ class, and type of adverse event.   
Disease Control Rate: The proportion of patients with disease control will be presented 
with two-sided 90% confidence intervals estimated using exact binomial methods. Based on 
the sample size of 40 patients with PD-L1 expressing disease, the confidence interval will 
be no wider than 0.32; for the sample of 15 patients with PD-L1 negative disease, the 
confidence interval will be no wider than 0.46.    
DoR, TTP, PFS and OS: The distributions of duration of response (DoR), time to 
progression (TTP), progression-free survival (PFS), and overall survival (OS) will each be 
summarized using the product-limit method of Kaplan-Meier. The two PD-L1 expression 
cohorts will be summarized separately. Median times for each endpoint will be presented 
with two-sided 90% confidence intervals estimated using log(-log(survival)) methodology. 
Kaplan-Meier estimates of TTP and PFS at 6 or 12 months after treatment initiation will 
also be presented with two-sided 90% confidence intervals. 
17.8. 
Correlative Objectives 
The analysis of correlative objectives will be based on the combined cohorts of evaluable 
patients with PD-L1 expressing and PD-L1 negative breast cancer enrolled in the phase II 
portion of the trial. Stratified analyses according to PD-L1 expression will also be 
conducted. 
17.8.1. Tumor-Infiltrating Lymphocytes (TILs) 
The relationship between tumor-infiltrating lymphocytes (TILs) and outcomes will be 
explored according to pre-treatment TIL percentages. It is hypothesized that higher levels of 
lymphocytic infiltration will be associated with better outcomes. Histopathologic evaluation 
of TILs will be performed independently by two pathologists and the mean value will be 
used for the analysis. Stromal lymphocytic infiltration will be defined as the percentage of 
tumor stroma containing infiltrating lymphocytes. TILs will be evaluated as previously 
described [3,4]. Bland-Altman analyses will be used to summarize agreement between 
pathologists.  
To examine responses according to levels of TILs, the population will be divided 
retrospectively according to objective response or non-response. Pre-treatment percentages 
of stromal infiltrating lymphocytes will be summarized descriptively for the two response 
groups and compared using Wilcoxon rank-sum tests. If there are 9 responses and 46 non-
responses, a Wilcoxon rank-sum test with a two-sided, 10% type I error will have 85% 
power to detect a difference in baseline lymphocyte percentage that is 1.06 times the 
common standard deviation. Visualization of the relationship between baseline TILs and the 


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distributions of TTP or PFS will employ Kaplan-Meier estimates stratified by lymphocyte-
predominant breast cancer (LPBC) phenotype or median of the distribution of intra-tumoral 
or stromal percentages. LPBC phenotype will be defined as 50% infiltration of either 
stromal or intra-tumoral lymphocytic infiltration. Medians of the time-to-event endpoints 
will be shown with two-sided 90% confidence intervals; the distributions of TTP or PFS 
will be compared across TIL strata using the log-rank test. 
Changes in TILs between baseline and progression/treatment discontinuation will be 
calculated (post-pre) for each patient and summarized descriptively. In addition, the 
correlation of TIL changes with measures of peripheral blood markers will be explored 
graphically, or by appropriate statistical methods based on data availability, to assess 
associations. 
17.8.2. PD-L1 Expression Levels 
The association between pre-treatment PD-L1 expression and outcomes will be explored. It 
is hypothesized that the upregulation of PD-L1 may allow cancers to evade the immune 
system; therefore, higher expression levels of PD-L1 would be associated with poorer 
outcomes. To assess the association of pre-treatment PD-L1 with response, the proportion of 
patients with objective response according to pre-treatment PD-L1 will be summarized with 
two-sided 90% exact, binomial confidence intervals. Visualization of the relationship 
between baseline PD-L1 expression and the distributions of TTP or PFS will employ 
Kaplan-Meier estimates stratified by PD-L1 expression. Medians of the time-to-event 
endpoints will be shown with two-sided 90% confidence intervals.  
The relationship between PD-L1 expression and TIL expression will also be explored to 
better characterize the tumor microenvironment. Pre-treatment percentages of stromal 
infiltrating lymphocytes will be summarized descriptively according to PD-L1 expression 
and compared using Wilcoxon rank-sum tests.  Descriptions of the immune repertoire of 
TILs will also be presented based on available data.  
17.8.3. Estrogen Receptor (ER) Expression 
The association between pre-treatment expression of ER and outcomes will also be explored 
as a secondary objective. Pre-treatment ER expression will be dichotomized as present 
(≥1% expression) or absent (<1%). The proportions of patients with objective response in 
each ER subgroup will be summarized with two-sided 90% exact, binomial confidence 
intervals. The distributions of TTP or PFS will be compared across the ER strata using the 
log-rank test. If the distribution of ER expression is not sparse, we will employ STEPP 
(Subpopulation Treatment Effect Pattern Plot [61]) analyses over the continuous range of 
baseline ER values to visualize the relationship between ER expression and the distributions 
of PFS or TTP. 
17.8.4. Outcome According to Quantified HER2 Level 
To examine responses according to pre-treatment levels of FISH ratio (HER2/CEP17) or 
HER2 gene copy number, the study population will be divided retrospectively according to 
objective response or non-response.  Pre-treatment FISH ratios or HER2 copy numbers will 


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be summarized descriptively for the two response groups and compared using Wilcoxon 
rank-sum tests. If there are 9 responses and 46 non-responses, a Wilcoxon rank-sum test 
with a two-sided, 10% type I error will have 85% power to detect a difference in measure 
that is 1.06 times the common standard deviation. Visualization of the relationship between 
FISH ratio or HER2 copy number and the distributions of TTP or PFS will employ Kaplan-
Meier estimates. FISH ratio or HER2 copy number data will each be divided into high/low 
groups at the medians of the respective distributions. The distributions of TTP or PFS will 
be compared across FISH ratio or HER2 copy number strata using the log-rank test; 
medians of the time-to-event endpoints will be shown with two-sided 90% confidence 
intervals. 
17.8.5. Tumor dynamics 
The pharmacodynamic effects of the combination of MK-3475 and trastuzumab on markers 
in peripheral blood and serum proteins will be assessed by summary statistics, and 
investigated graphically to explore patterns of change over time and differences according to 
treatment exposure. Associations between biomarker measures from peripheral blood or 
tumor biopsy and clinical outcomes will also be explored graphically. 
17.9. 
Exploratory Objectives 
The RECIST response category of partial response (PR) will be divided into two 
subcategories: moderate partial response (MPR: 30-59% uni-dimensional reduction) and 
very good partial response (VGPR: 60% or greater uni-dimensional reduction) to address 
the exploratory hypothesis that patients with VGPR will have longer duration of response 
than patients with MPR. Duration of response will be summarized using a conditional 
landmark analysis to address potential guarantee-time bias. The relevant landmark time will 
be established prior to any analyses of the data. Median durations of response for each 
subcategory will be presented with two-sided, 90% confidence intervals. A second analysis 
will include patients with CR as a third subcategory, if possible.  
Correlative investigations between MPR/VGPR and pre-treatment ER, PD-L1, FISH ratio 
HER2 copy number, and TILs will also be conducted to investigate if levels of these 
biomarkers differ between MPR and VGPR responders. 
18. 
Ethical aspects, regulatory approval, and patient informed consent 
The Investigator will ensure that this trial is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. 
The trial must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” ICH Tripartite Guideline (January 1997) or with local law if it affords greater 
protection to the patient. For studies conducted in the EU/EEA countries, the Investigator 
will ensure compliance with the EU Clinical Trial Directive (2001/20/EC). 


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18.1. 
Ethical Review Board/Ethics Committee 
All protocols and the patient Informed Consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The ERB/IRB 
written, signed approval letter/form must contain approval of the designated Investigator, 
the protocol (identifying protocol title and version number), and of the patient Informed 
Consent. Documentation of Ethics Committee approval(s) must be sent to the IBCSG Data 
Management Center prior to enrollment of the first patient. The IBCSG Ethics Committee 
also approves the protocol and reviews it annually. 
Any modifications made to the protocol will be reviewed by the IBCSG Ethics Committee 
and must also be submitted to the appropriate ERB/IRB for information or approval in 
accordance with local procedures and regulatory requirements and to Health Authorities if 
required.  
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities 
(if required), the Investigator shall implement the protocol modifications. Protocol 
modifications for urgent safety matters may be directly implemented following the 
instructions of IBCSG. 
18.2. 
Regulatory approval procedures 
If applicable, in addition to the approval of the Ethics Committee according to national 
legislation, the protocol, other protocol-related documents including patient information and 
Informed Consent and other documents as required locally must be submitted to and be 
approved by the health authority. Documentation of health authority approval must be sent 
to the IBCSG Data Management Center prior to Participating Center activation. 
18.3. 
Protection of human patients 
The IBCSG has an Office for Human Research Protection (OHRP) Federal Wide Assurance 
(FWA00009439) and follows all of the policies and procedures that are part of that 
assurance. All potential patients for this trial will receive a full explanation of the trial, its 
purpose, treatments, risks, benefits, and all of the other items listed in Section 18.4. 
Additional institution-specific sections should be added to Appendix I as needed. 
The medical record must be available for review by the IBCSG audit team and regulatory 
authorities as described in Section 19.7. 
Serious Adverse Event (SAE) Reports are distributed monthly. In addition they are available 
on the IBCSG website (www.ibcsg.org) for participating Centers. 
18.4. 
Informed Consent 
Informed Consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “IBCSG Patient Information Sheet and Informed Consent" (See 
Appendix I). One signed and dated copy of the Informed Consent must be given to each 
patient and the original copy must be retained in the Investigator's trial records. The 
Informed Consent form must be available in the case of data audits. Verification of signed 
Informed Consent and the date signed are required for randomization to this trial.   


IBCSG 45-13 / BIG 4-13 PANACEA 
 
V2.1  Amendment 1   11 January 2016 
Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
The "Declaration of Helsinki"  recommends that consent be obtained from each potential 
patient in biomedical research trials after the aims, methods, anticipated benefits, and 
potential hazards of the trial, and discomfort it may entail, are explained to the individual by 
the 
physician 
(http://www.wma.net/en/30publications/10policies/b3/index.html). 
The 
potential patient should also be informed of her right to not participate or to withdraw from 
the trial at any time.  The patient should be told that material from her tumor will be stored 
and potentially used for additional studies not described in this protocol.  
If the patient is in a dependent relationship to the physician or gives consent under duress, 
the Informed Consent should be obtained by an independent physician. By signing this 
protocol, the Investigator agrees to conduct the trial in accordance with Good Clinical 
Practice and the "Declaration of Helsinki."  
The IBCSG recognizes that each institution has its own local, national, and international 
guidelines to follow with regard to Informed Consent. Therefore, we provide a template 
information sheet and Informed Consent form (Appendix I), which can be downloaded and 
edited to incorporate information specific to your institution (see www.ibcsg.org). The 
template Patient Information Sheet and Informed Consent has been written according to 
ICH guidelines, which state the Informed Consent should adhere to GCP and to the ethical 
principles that have origin in the “Declaration of Helsinki”. The final version should receive 
the Institutional Review Board/ Local Ethics Committee approval in advance of its use. 
Centers should send their locally modified PIS/IC to the IBCSG Data Management Center 
for review and approval before submitting to their Ethics Committee.  
18.5. 
Premature withdrawal 
18.5.1. Cessation of trial treatment 
Patients have the right to refuse further trial treatment at any time during the trial. Patients 
may also be withdrawn from trial treatment at any time at the discretion of the Investigator 
due to an adverse event, or based on any other relevant medical condition. Such patients will 
remain in the trial. The patient will continue to be documented according to protocol. 
18.5.2. Withdrawal of consent 
Patients have the right to withdraw consent for further trial participation at any time without 
having to specify the reason. The data recorded up to the time point of withdrawal will 
continue to be evaluated in the trial. The Investigator should ask the patient for her consent 
to continue to collect information on her disease and survival status. 
It should be documented in both the medical records and in the eCRF (Form 45-COC) 
whether it is acceptable for the patient to be contacted by telephone for survival status 
updates. For the patient’s safety, an end of treatment visit should be performed and 
documented in the eCRF. 


IBCSG 45-13 / BIG 4-13 PANACEA 
 
V2.1  Amendment 1   11 January 2016 
Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
19. 
Governance and Administrative Considerations 
19.1. 
Insurance 
IBCSG will contract the appropriate liability insurance for this trial. Patients who suffer 
injuries due to the trial should report them immediately to their physician. The local Center 
should report all alleged claims immediately to the IBCSG. 
19.2. 
Steering Committee 
A Steering Committee will be constituted for this trial. The primary responsibilities of the 
Steering Committee are twofold. First, the Steering Committee is responsible for 
maintaining the scientific integrity of the trial, for example, by recommending changes to 
the protocol in light of emerging clinical or scientific data from other trials. Second, the 
Steering Committee is responsible for the translation of recommendations of the IBCSG 
Data and Safety Monitoring Committee into decisions. Membership will include IBCSG 
officials, trial chair and co-chairs, trial statisticians, representatives from some Participating 
Centers, and representatives from MSD Pharmaceuticals. 
General partition of responsibilities: 
The Steering Committee has the authority to make and implement any final decisions, such 
as sub-studies of the trial or amendments to the trial protocol, and may recommend the 
termination/early termination of the trial. 
The IBCSG Executive Committee is responsible for the implementation of all final 
decisions taken by the Steering Committee. 
The IBCSG Foundation Council decides on the termination/early termination of the trial. 
19.3. 
Data and Safety Monitoring Committee (DSMC) 
The trial will be presented for review to the IBCSG Data and Safety Monitoring Committee 
(DSMC) at each of their semi-annual meetings. Accrual and safety will be monitored. The 
results of the first stage efficacy analysis will be discussed by the DSMC as soon as 
available. 
19.4. 
Endpoint Committee 
An Endpoint Review Committee will be appointed composed of an immunotherapy expert, 
the IBCSG medical reviewer and the trial statistician. The committee will review all 
assessments of response on a monthly basis and in real time. Analysis of the primary 
endpoint will be based on response data reviewed and confirmed by the Endpoint Review 
Committee. 
19.5. 
Publication of trial results 
IBCSG will publish the results of the trial based on the final study report. 


IBCSG 45-13 / BIG 4-13 PANACEA 
 
V2.1  Amendment 1   11 January 2016 
Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
19.6. 
Premature discontinuation of the trial 
The trial may be discontinued early in parts or completely if the information on the trial 
treatment leads to doubt as to the benefit/risk ratio. 
The trial can be terminated at any time if the authorization and approval to conduct the 
Study is withdrawn by ethics committee or regulatory authority decision, insufficient 
accrual, emerging new data impacting the scientific value of the trial or ethical grounds. 
19.7. 
Quality Assurance 
The IBCSG conducts trials according to the ICH Good Clinical Practice (GCP) guidelines. 
The Trial IBCSG Data Manager reviews each CRF. In addition, the IBCSG Medical 
Reviewer reviews each case at specific timepoints. The IBCSG conducts periodic audit 
visits to ensure proper trial conduct, verify compliance with GCP, and perform source data 
verification. 
The Investigator should ensure that source documents are made available to appropriately 
qualified personnel from IBCSG or its designees, or to health authority inspectors after 
appropriate notification. 
MSD-designated staff and quality assurance auditors may audit the conduct of any site and 
shall be granted reasonable access to facilities during normal business hours. Such auditors 
shall not be entitled to access, make copies of the source documents and/or to take them 
away. 
At regular intervals during the clinical trial, the Center will be contacted, through 
monitoring visits, letters or telephone calls, by a representative of the Monitoring Team to 
review trial progress, Investigator and patient compliance with clinical trial protocol 
requirements and any emergent problems. These monitoring visits will include but not be 
limited to review of the following aspects: patient Informed Consent, patient recruitment 
and follow-up, SAE documentation and reporting, AEs with pre-specified monitoring 
documentation and reporting, AE documentation, trial treatment administration, patient 
compliance with the regimens, drug accountability, concomitant therapy use and quality of 
data. 
19.8. 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact IBCSG or personnel monitoring the trial to 
request approval of a protocol deviation, as no deviations are permitted. The Investigator 
should document and explain any deviations from the approved protocol and promptly 
report them to IBCSG and to the EC concerned in accordance with the applicable EC 
policies and procedures. If the Investigator feels a protocol deviation would improve the 
conduct of the trial this must be considered a protocol amendment, and unless such an 
amendment is developed and activated by IBCSG and approved by the IRB/IEC/REB it 
cannot be implemented. All protocol deviations will be documented. 


IBCSG 45-13 / BIG 4-13 PANACEA 
 
V2.1  Amendment 1   11 January 2016 
Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
19.9. 
Data protection 
A unique Patient Identification Number (ID) will be assigned by the IBCSG Registration/ 
Randomization System to each patient registered into the trial. The names of the patients 
will not be disclosed to the IBCSG.  
Only the Patient ID will be used to identify a patient on the eCRF. Identification of patients 
must be guaranteed at the Participating Center. In order to avoid identification errors, 
Centers should keep a Patient Identification Log containing the patients’ name, year of birth, 
hospital number and the Patient ID allocated by IBCSG. 
Regulatory authorities and the pertinent Ethics Committee (ERB/IRB) may have access to 
patient data on-site. IBCSG audit or monitoring personnel will also have access to such data 
on-site. 
19.10. Record Retention 
The Center must retain all essential documents according to ICH GCP. This includes copies 
of the patient trial records, which are considered as source data, patient Informed Consent 
statement, laboratory printouts, drug inventory and destruction logs, and all other 
information collected during the trial. These documents are to be stored until at least 15 
years after the termination of the trial. IBCSG guarantees access and availability of the data 
entered into iDataFax for at least 15 years after the termination of the trial. 
Longer retention may be required for Participating Centers according to national 
regulations. 
In the event that the Principal Investigator retires or changes employment, custody of the 
records may be transferred to another competent person who will accept responsibility for 
those records. Written notice of such transfer has to be given to IBCSG and the local Ethics 
Committee at least one month in advance. 
20. 
Confidentiality 
The protocol, CRFs and other protocol-related documents are confidential and are the 
property of the IBCSG. 
21. 
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Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
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Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
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Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
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IBCSG 45-13 / BIG 4-13 PANACEA 
 
V2.1  Amendment 1   11 January 2016 
Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
INTERNATIONAL BREAST CANCER 
STUDY GROUP 
IBCSG 45-13/BIG 4-13 
 
 
 
PANACEA 
 
 
 
 
 
 
A phase Ib/II trial evaluating the efficacy of MK-3475 
(pembrolizumab) and trastuzumab in patients with trastuzumab-
resistant, HER2-positive metastatic breast cancers 
 
 
Statistical Analysis Plan 
 
NCT02129556 
 
August 11, 2015 
 
 
 
 
Study Statistician:  Anita Giobbie-Hurder 
 
 


 
2 
 
Table of Contents 
1 
Study Overview ....................................................................................................................... 3 
1.1 
Synopsis ............................................................................................................................ 3 
1.2 
Schema ............................................................................................................................. 3 
1.3 
Statistical design assumptions and sample size considerations ...................................... 4 
1.4 
Screening and Enrollment ................................................................................................ 5 
2 
Overview of Data Analysis Software and Settings .................................................................. 5 
3 
Phase Ib ................................................................................................................................... 6 
3.1 
Analysis Population .......................................................................................................... 6 
3.2 
Primary Objective ............................................................................................................. 6 
3.3 
Primary Endpoint.............................................................................................................. 6 
4 
Phase II .................................................................................................................................... 7 
4.1 
Analysis Population .......................................................................................................... 7 
4.2 
Primary Objective ............................................................................................................. 7 
4.3 
Primary Endpoint.............................................................................................................. 7 
4.4 
Secondary Endpoints and Definitions .............................................................................. 8 
4.4.1 
Safety and Tolerability .............................................................................................. 9 
4.4.2 
Disease Control Rate ............................................................................................... 11 
4.4.3 
Time-To-Event Endpoints ........................................................................................ 12 
5 
Additional Presentations and Analyses ................................................................................ 15 
5.1 
Accrual ............................................................................................................................ 15 
5.2 
Study Sample .................................................................................................................. 15 
5.3 
Patient Demographics and Baseline Disease and Prior Treatment ............................... 15 
5.4 
Patterns of Response ..................................................................................................... 16 
5.5 
Correlatives .................................................................................................................... 16 
5.5.1 
Tumor-Infiltrating Lymphocytes (TILs) .................................................................... 16 
5.5.2 
Estrogen Receptor Expression ................................................................................ 16 
5.5.3 
Outcome According to Quantified HER2 Level ....................................................... 17 
 
 
 


 
3 
 
1 Study Overview   
1.1 Synopsis 
This is a phase Ib/II clinical trial to evaluate the hypothesis that the combination of an 
immune re-activation approach and anti-HER2 therapy can reverse trastuzumab resistance 
and improve clinical outcomes in HER2-positive breast cancer.   The primary objectives of 
this phase Ib/II study are to determine the recommended dose of the anti-PD-1 monoclonal 
antibody (mAb), MK-3475 (pembrolizumab), in combination with standard dose 
trastuzumab, and to evaluate the efficacy and safety profile of the drug combination in 
patients with PD-L1 expressing, HER2-positive unresectable loco-regional or metastatic 
breast cancer who have experienced progression during prior trastuzumab-based therapy.  
As part of Amendment #1 (QIII 2015), a second, parallel cohort of 15 patients with PD-L1 
negative, HER2-positive, unresectable loco-regional or metastatic breast cancer will be 
enrolled in the phase II trial and evaluated for efficacy. 
 
1.2 Schema 
 
 
Screening: unresectable locoregional or metastatic breast cancer overexpressing HER2
Submit an FFPE block from core biopsy for central testing
Central Testing:
HER2 by IHC
Phase Ib: dose finding for MK-3475 in 3+3 design  ─  Phase II at RP2D
Treatment in 3 week cycles:
1
2
3
4
5  etc………..… PD
T : trastuzumab  6mg/kg
T
T
T
T
T
M : MK-3475      at RP2D
M
M
M
M
M
HER2 neg:
not eligible
HER2 pos:
Central PD-L1 testing
PD-L1 neg:
not eligible
PD-L1 positive: enroll
Blood samples:
whole blood
plasma prior to cycles 1, 3, 5 and then every 3 cycles, 
30 days and 6 months after end of tx
Tissue
at enrollment:
re-biopsy at PD *:
Samples:
FFPE block
FFPE Block
Fresh frozen block *
Fresh frozen block
* if feasible
* if feasible


 
4 
 
1.3 Statistical design assumptions and sample size considerations 
It is expected that a maximum of 67 evaluable patients will be enrolled.  The phase Ib trial will 
use a standard 3+3 dose-escalation design to determine the recommended phase-II dose 
(RP2D) of the anti-PD-1 mAb, MK-3475, in combination with standard dose trastuzumab using 3 
possible dose levels (trastuzumab 6 mg/kg and MK-3475 at 2 mg/kg, 10 mg/kg, or a fall-back 
dose of 1 mg/kg). The RP2D, or a fixed dose of 200 mg MK-3475 will then be carried forward to 
the phase II trial. Each patient will receive combination trastuzumab and MK-3475 until disease 
progression, lack of tolerability, completion of 24 months of treatment with MK-3475, or until 
the patient declines further protocol treatment.  In the phase II trial, 40 patients will be 
enrolled in the cohort of patients with PD-L1 expressing disease, and 15 patients in the cohort 
of PD-L1 negative disease. 
 
Each patient’s disease must be centrally assessed for expression of PD-L1 in a core biopsy taken 
from an unresectable loco-regional or metastatic lesion using Merck CLIA-certified IHC test in a 
designated lab. HER2 status of the tumor will also be centrally confirmed at the same time. A 
patient whose disease is both PD-L1 expressing and HER2-overexpressing (IHC 3+ or 
FISH/chromogenic in situ hybridization [CISH] positive) will be eligible for enrollment into the 
phase Ib or into the cohort of patients with PD-L1 expressing disease in the phase II.  Patients 
with HER2-overexpressing and PD-L1 negative disease will be eligible for enrollment into the 
parallel phase II cohort.  
 
Phase Ib: The sample size for the phase Ib trial will be between 6 and 12 enrolled patients and 
will depend on the number of dose cohorts needed to determine the RP2D.  A patient in the 
phase Ib portion of the trial will be replaced if determination of dose-limiting toxicity (DLT; 
(defined in Protocol Section 10.2.1) cannot be adequately assessed because of rapid disease 
progression during the first cycle of therapy, or if treatment and/or follow-up is stopped during 
the first cycle of therapy for reasons other than toxicity.  Patients who do not receive 
trastuzumab in the first cycle of therapy due to an infusion reaction to MK-3475 will also be 
replaced and will not be counted as having a DLT. 
 
The following table summarizes the probability that the dose will be escalated (i.e., that 0 in 3 
patients or 1 in 6 patients experiences DLT) given the true but unknown rate of DLT in cycle 1. 
 
True, but Unknown, DLT Rate 
Probability of Dose Escalation 
10% 
91% 
20% 
71% 
30% 
49% 
40% 
31% 
50% 
17% 
60% 
8% 
 
Phase II:  
PD-L1 Expressing: The phase II trial in the cohort of patients with PD-L1 expressing breast 
cancer employs Simon’s optimal two-stage design, with a total target sample size of 40 


 
5 
 
evaluable patients.  The null hypothesis of a true objective response rate (ORR) of 7% will be 
tested against a one-sided alternative objective response rate of 22%.  Seventeen (17) 
evaluable patients will be enrolled in the first stage, and if one or fewer objective responses are 
observed in 17 patients, then enrollment will stop. If there are two or more objective 
responses, then an additional 23 patients will be enrolled, for a total of 40 evaluable patients. 
The null hypothesis will be rejected if a total of six or more objective responses are observed in 
40 evaluable patients. This design yields a type I error rate of 0.05 (target type I error of 0.05) 
and power of 85% (target type II error of 0.15) when the true objective response rate is 22%. If 
the null hypothesis is true, the probability is 0.66 that enrollment will stop at the end of the first 
stage.   
 
Enrollment will pause at the end of the first stage to allow for two, concurrent analyses of the 
data. One analysis will focus on the assessment of ORR using the criteria described above. The 
second analysis will be a detailed safety review, described in Protocol Section 11.5 and in 
Protocol Section 17.4. The enrollment pause will last until responses have been confirmed in 
the first 17 patients and safety has been evaluated carefully as described in Protocol Section 
17.4. 
 
PD-L1 Negative:  The PD-L1 negative cohort is designed to provide evidence of response and 
inform subsequent drug development.  A single-stage design with an enrollment of 15 patients 
will be used to compare a null response rate of 1% with a desirable response rate of 20%.  The 
cohort size was selected to yield a very high probability of not missing a response signal if one 
exists.  The decision rule is based on zero responses: the drug combination would not be 
considered worthy of further investigation if no patients respond.  If the true response rate is 
20%, then the probability that zero responses would be observed in 15 patients is 0.035.  
Therefore, there would be less than 4% chance of missing a true 20% response rate if the 
alternative hypothesis is true. 
1.4 Screening and Enrollment  
The total enrollment of this phase Ib/II trial will be between 6 and 67 evaluable patients. The 
minimum would occur if the combination of MK-3475 and trastuzumab proved too toxic at MK-
3475 doses of 2 mg/kg and 1 mg/kg and the trial was stopped during the dose escalation phase. 
A maximum enrollment of 67 patients reflects two complete dose escalation levels of 6 patients 
each, and 55 patients (40 PD-L1-expressing and 15 PD-L1-negative) in the phase II.  Under the 
assumption that approximately 50% of patients will be found ineligible upon screening, it is 
estimated that between 85 and 95 patients will be screened to obtain the maximum sample of 
67 evaluable patients.  
2 Overview of Data Analysis Software and Settings 
Unless otherwise noted, all data manipulation and analyses will be performed using SAS.  
Categorical tables will be generated using PROC TABULATE with percentages calculated within 
column (COLPCTN).  Fisher’s exact testing will be based on two-sided exact probabilities 
produced using PROC FREQ with the EXACT option in the TABLE statement.   


 
6 
 
 
Tables of data measured on a continuous scale will be generated using PROC TABULATE and will 
include N, N missing, mean, standard deviation, minimum, median, and maximum for data 
summaries.  Wilcoxon rank-sum testing will be conducted using PROC NPAR1WAY.  Exact two-
sided p-values will be used, whenever possible, which are generated using the EXACT 
WILCOXON statement. 
 
Distributions of time-to-event outcomes will be calculated using Kaplan-Meier estimation from 
PROC LIFETEST.  Confidence intervals will be estimated using the procedure default of log(-
log(endpoint)).  Numbers at risk will be shown (PLOTS=SURVIVAL (ATRISK)).  The x-axis of these 
plots will be in months after start of therapy and the y-axis will be proportions. 
3 Phase Ib 
3.1 Analysis Population 
All patients receiving one or more doses of MK-3475 and trastuzumab will be included in the 
assessment of DLT. 
3.2 Primary Objective 
To determine the recommended dose of MK-3475 in combination with standard dose 
trastuzumab. 
3.3 Primary Endpoint 
The incidence of dose-limiting toxicity of MK-3475 in combination with standard dose 
trastuzumab. 
 
Dose escalation will employ a standard ‘3+3’ approach, beginning in dose level 1, with rules for 
escalation and de-escalation described in the table, below. The RP2D is defined as the highest 
dose level at which less than 33% of patients (0 of three patients, or 0 or 1 of six patients) have 
experienced a DLT in cycle 1. Once dose escalation for MK-3475 reaches a dose of 10 mg/kg, no 
further escalation will occur.  Intra-patient dose escalation is not permitted. Patients enrolled in 
the phase Ib part of the trial should be treated on the assigned dose level as long as tolerable, 
for up to 24 months of MK-3475.  
 
Dose Escalation Rules 
Number of patients with DLT at a 
given dose level 
Dose Escalation Rule 
0 out of 3 
Proceed to the next dose level and enroll 3 patients 
1 out of 3 
Enroll and treat 3 additional patients at this dose level. 
≥2 out of 3 
Dose escalation will be stopped. The RP2D will be one dose below this 
dose level.   
1 out of 6 
Proceed to the next dose level. 
≥2 out of 6 
Dose escalation will be stopped. The RP2D will be one dose below this 
dose level.  
If ≥2/3 or ≥2/6 patients at dose level 1 experience DLTs, dose level -1 will be used.  If dose level -1 proves too 
toxic, the trial will stop. 


 
7 
 
 
Data Sources 
Purpose 
CRF 
Variable 
Dose cohort 
A2 
ph1dl 
No DLT 
DLT 
ndtox 
DLT occurred 
DLT 
dltae1 
Stopped during cycle 1 for 
reasons other than DLT 
EoT 
Fmno, msts 
Other AEs for comparison 
AE log 
Assorted variables 
 
DLT data are analyzed manually by the Medical Reviewer, Trial Biostatistician, and Data 
Management Center (DMC) team leaders.  DLT results for each dose cohort are presented and 
discussed on scheduled conference calls.  Reports regarding the observed toxicities, DLTs, and 
decisions about dose escalation are generated by the Biostatistician; distributed to the study 
PIs, DMC, and Coordinating Center; and stored in the study binder.   
 
Presentation: Patient listing for all patients enrolled in phase Ib 
 
Phase Ib 
Cohort 
Patient ID 
Enrolling Center 
Screening Date 
Enrollment 
Date 
DLTs Documented 
Other Cycle 
1 Adverse 
Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 Phase II 
4.1 Analysis Population 
The phase II study population will be comprised of evaluable patients enrolled in the phase II 
trial.  The PD-L1-expressing and PD-L1-negative cohorts will be evaluated separately. 
4.2 Primary Objective 
To evaluate the efficacy and safety profile of the drug combination in patients with HER2-
positive, unresectable loco-regional or metastatic breast cancer who have experienced 
progression during prior trastuzumab-based therapy.  Efficacy and safety will be assessed 
separately for the two PD-L1 expression cohorts. 
4.3 Primary Endpoint 
Objective response (confirmed CR or PR as best overall response) according to RECIST criteria 
(Version 1.1) as defined in protocol section 17.7.1. 
 
At the time of each restaging, patients will be classified as achieving complete response (CR), 
partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable for 
response according to RECIST (Version 1.1) criteria. Objective response will be determined by 


 
8 
 
the best overall confirmed response designation recorded between the date of first dose of trial 
therapy and the date of objectively documented disease progression or cessation of trial 
therapy, whichever occurs first. For patients without documented progression or cessation of 
trial therapy, all available response designations will contribute to the objective response 
determination. The proportion of patients with an objective response will be presented with a 
two-sided 90% confidence interval calculated using the method of Atkinson and Brown, which 
allows for the two-stage design.  The response rate in the PD-L1 negative cohort will be 
estimated and presented with a 90% exact, binomial confidence interval. 
 
Data Sources 
Purpose 
CRF 
Variable Name 
Dose cohort 
A2 
ph1dl 
 
A2 
ph2 
Best Overall Response (BOR) 
IR 
? 
Never started treatment 
IR 
? 
No DLT 
DLT 
ndtox 
DLT occurred 
DLT 
dltae1 
Stopped during cycle 1 for 
reasons other than DLT 
EoT 
Fmno, msts 
 
Analysis Steps: 
 
1 – Identify patients who are enrolled in phase II; 
 
2 – Separate into cohorts defined by PD-L1 expression; 
 
3 – Document and remove any patients who never began treatment; 
 
4 – Use BOR variable to classify response into responders vs. non-
 
responders/unevaluable; 
 
5 – Count responses or tabulate response rate, as appropriate for stage of analysis; 
 
6 – Once trial complete use BCB “TWOCON” routine to calculate 90% two-stage 
 
confidence interval (Atkinson and Brown) in PD-L1-expressing cohort.  Exact binomial 
 
90% confidence interval for PD-L1 negative cohort will be estimated using the “CONFIN” 
 
procedure. 
 
4.4 Secondary Endpoints and Definitions 
There are several secondary endpoints for the trial, listed below.  All efficacy analyses will be 
based on the phase II efficacy population, separate by PD-L1 cohorts; the safety analyses will be 
based on all patients receiving at least one dose of MK-3475. 
 
1.   Safety and tolerability according to NCI CTCAE version 4.0; 
2.  Disease control (DC): Best overall response of confirmed CR, PR, or SD lasting for 24 
weeks or longer, measured from the start of trial treatment until first documentation of 
progressive disease; 
3.  Duration of response (DoR): Among patients with objective response (confirmed CR 
or PR as best overall response) as the interval between dates of first documentation of 


 
9 
 
objective response and first documentation of progressive disease. In the absence of 
documented progressive disease, follow-up will be censored at date of last disease assessment;  
4.  Time to progression (TTP): The interval between the dates of the start of trial 
treatment and first documentation of progressive disease.  In the absence of documented 
progressive disease, follow-up will be censored at date of last disease assessment; 
5.  Progression-free survival (PFS): Time from start of trial treatment until documented 
disease progression or death, whichever occurs first.  Patients with new non-breast cancer 
malignancy must continue to be followed for progression of the original breast cancer. For 
patients without progression, follow-up will be censored at the date of last disease assessment 
without progression, unless death occurs within 12 weeks following the date last known 
progression-free, in which case the death will be counted as a PFS event.  Patients who 
discontinue or initiate non-protocol treatment prior to documented disease progression will be 
followed for disease progression;  
6.  Overall Survival (OS): Time from start of trial treatment to death from any cause. For 
patients who are lost to follow-up or who have no documentation of death at the time of final 
analysis, follow-up will be censored at the date of last assessment of vital status. 
 
4.4.1 Safety and Tolerability 
4.4.1.1 Early Safety Review (may be modified slightly pending Amendment) 
An early safety review will be concurrent with the first efficacy review of ORR that is specified 
by the Simon two-stage design in the PD-L1 expressing cohort. Details regarding this early 
safety review are presented in detail in Protocol Sections 11.5 and 17.4.  Data from the initial 17 
patients receiving the combination of MK-3475 and trastuzumab in the phase II study will be 
evaluated for safety in the first 4 cycles of therapy.  After this initial safety assessment, toxicity 
and adverse event data will be evaluated as part of the semi-annual trial review by the DSMC. 
 
As part of the early safety monitoring, we will focus particular attention on cardiac events (CE) 
of grade 3 or higher (Protocol Section 11.5). The incidence of the following cardiac events will 
be analyzed: 
• 
Cardiac death 
• 
Heart failure manifested by dyspnea with normal activity or at rest 
• 
Decline in LVEF of more than 10 percentage points from baseline to a value less than 50 
 
percent.  
 
If three or more of the first 17 patients experience CE, then the trial enrollment may be 
suspended.  If the true probability of cardiac toxicity is 18% or higher, the probability is greater 
than 60% that three or more patients will be observed with CE at the time of the early safety 
monitoring. 
 
All reported AEs will also be summarized as part of this safety review. For a sample of 17 
patients, there is high probability of observing at least one event if a toxicity has an incidence of 
at least 9%. If the true incidence of an unexpected or severe toxicity is 9% or greater, the 


 
10 
 
probability is at least 0.80 that one or more patients out of 17 will experience the toxicity 
during the early safety monitoring period. If the true incidence of unexpected or severe toxicity 
is 3% or less, the probability is 0.40 or less that at least one patient of 17 will experience the 
toxicity during the early safety monitoring period. 
 
Analysis Steps for Early Safety Review: 
 
1 – Identify patients in the appropriate phase II cohort and that are evaluable, having 
received at least one dose of study therapy; 
 
2 – Restrict and examine AE and SAE/ECI CRF data for first four cycles of therapy 
 
Cardiac Event Assessment: 
 
3 – AE CRF CTCAE v4 codes (others may be added):  
 
 
Cardiac death – CA108 
 
 
Heart failure – CA111, CA112, CA125, CA126 
 
 
LVEF dysfunction – CA113 
 
 
Other cardiac grade 3 or higher – CTCAE code beginning with “CA” 
 
4 – Examine SAE/ECI data for first four cycles of therapy, specifically for cardiac events 
 
 
Reason for seriousness = “Constitutes Important Event”, or 
 
 
“Event is an ECI” 
 
All Other Reported Adverse Events: 
5 – Determine highest grade of each CTCAE code reported during the first four cycles of 
therapy 
6 – Compare with baseline AEs (BAE CRF) and remove those that have continued since 
baseline without worsening grade 
7 – Examine SAE/ECI data and cross-check with events reported on AE CRF.  Remove 
 
duplicates 
8 – Summarize according to worst grade reported for each patient 
 
  
Presentation: 
 
1 – Cardiac Event Assessment 
a.  Table of cardiac events (by CTCAE term) according to worst grade reported 
and relationship to therapy 
b. Identify if ECI or SAE 
c. Provide patient listings separately by worst grade for grades 3, 4, and 5 with 
action taken 
d. Calculate number of patients with one or more grade 3 or higher cardiac 
events and present with 90% exact confidence interval. 
 
 
2 – All Other Reported Adverse Events 
a.  Table of CTCAE terms according to worst grade reported and relationship to 
therapy 


 
11 
 
b.  Identify if classified as SAE or ECI 
c. Provide patient listings by worst grade for each event of grade 3, 4, or 5 with 
action taken 
d. Calculate number of patients with one or more grade 3 or higher non-cardiac 
events and present with 90% exact confidence interval. 
 
4.4.1.2 Subsequent Reviews of Safety 
Toxicity and adverse event data will be evaluated semi-annually for review by the DSMC.  Any 
patient who received one or more doses of the study therapy will be included in the evaluation 
of safety.  Processing of data and methods of summary will be comparable to those described 
for the Early Safety Review with adverse events and toxicities identified via CTCAE code and 
summarized according to the worst grade reported for each event type per patient.  Separate 
tables will be presented according to cohort (Phase Ib, Phase II PD-L1 expressing, Phase II PD-L1 
negative), and, where applicable, by dose.  If deemed appropriate by PIs and Medical Reviewer, 
safety data for the PD-L1 expressing and negative cohorts may be combined and presented 
together for the Phase II trial. 
 
4.4.2 Disease Control Rate 
The rate of disease control is the proportion of patients in the Phase II trial with a best overall 
confirmed response of CR or PR, or SD lasting for at least 24 weeks.  All times are measured 
from the first dose of study therapy.  Duration of SD will be determined by the first 
documentation of confirmed progressive disease.  Patients who are unevaluable for response 
are included in the analysis and are counted in the rate denominator.  Disease control rates will 
be summarized by PD-L1 cohort. 
 
Data Sources 
Purpose 
CRF 
Variable Name 
Dose cohort 
A2 
ph1dl 
Best Overall Response (BOR) 
IR 
? 
Never started treatment 
IR 
? 
Stable Disease ≥ 24 wks 
IR 
? 
 
Analysis Steps:   
 
1 – Identify patients in Phase II cohort who had at least one dose of study therapy 
 
2 – Verify BOR against Tumor Evaluation Forms (TEV) to confirm response over time and 
 
duration of SD 
 
3 – Use BOR and SD variables to classify patients into disease control vs. no disease 
 
control 
 
4 – Calculate disease control rate and present with exact 90% binomial confidence 
 
interval 
 


 
12 
 
4.4.3 Time-To-Event Endpoints 
There are four secondary, time-to-event endpoints: duration of response, time to progression, 
progression-free survival, and overall survival.  The timing of the last three begins at the first 
dose of study therapy.  Duration of response is based on a subset of patients and is timed from 
the first date of confirmed CR/PR.  All times will be expressed in months.  Summaries will be 
presented by PD-L1 cohort. 
 
4.4.3.1 Duration of Response 
 
Data Sources 
Purpose 
CRF 
Variable Name 
Dose cohort 
A2 
ph1dl 
Best Overall Response (BOR) 
IR 
? 
Never started treatment 
IR 
? 
Stable Disease ≥ 24 wks 
IR 
? 
Date CR/PR first observed 
IR 
? 
Criteria for PD? 
IR 
? 
Date PD observed 
IR 
? 
Date last adequate disease 
assessment 
IR 
? 
 
Calculation Steps 
 
1 – Identify patients in Phase II cohort who had at least one dose of study therapy 
 
2 – Restrict sample to patients with CR or PR as best response to therapy 
 
3 - Patients with PR followed by CR will use the date of PR as the reference date 
 
4 – For patients with subsequent PD,  
DoR = (date progression – date CR/PR)/30.4375.    
 
 
These patients will be classified as having an event (censor = 1) 
 
5 – For patients without subsequent PD,  
DoR = (date last adequate assessment – date CR/PR)/30.4375.   
The follow-up of these patients will be censored (censor = 0). 
 
 


 
13 
 
4.4.3.2 Time to Progression 
 
Data Sources 
Purpose 
CRF 
Variable Name 
Dose cohort 
A2 
ph1dl 
Treatment start date 
IR 
? 
Never started treatment 
IR 
? 
Criteria for PD? 
IR 
? 
Date PD observed 
IR 
? 
Date last adequate disease 
assessment 
IR 
? 
 
 
Calculation Steps 
 
1 – Identify patients in Phase II cohort who had at least one dose of study therapy 
 
3 – For patients with subsequent PD,  
TTP = (date progression – date treatment start)/30.4375.    
 
 
These patients will be classified as having an event (censor = 1) 
 
4 – For patients without subsequent PD,  
TTP = (date last adequate assessment – date treatment start)/30.4375.   
The follow-up of these patients will be censored (censor = 0). 
 
4.4.3.3 Progression-Free Survival 
 
Data Sources 
Purpose 
CRF 
Variable Name 
Dose cohort 
A2 
ph1dl 
Treatment start date 
IR 
? 
Never started treatment 
IR 
? 
Criteria for PD? 
IR 
? 
Date PD observed 
IR 
? 
Date last adequate disease 
assessment 
IR 
? 
Date death 
IR 
? 
 
Calculation Steps 
 
1 – Identify patients in Phase II cohort who had at least one dose of study therapy 
 
2 – For patients with subsequent PD,  
PFS = (date progression – date treatment start)/30.4375.    
 
 
These patients will be classified as having an event (censor = 1) 
 
3 – For patients without subsequent PD and last-known alive,  
PFS = (date last adequate assessment – date treatment start)/30.4375.   
The follow-up of these patients will be censored (censor = 0). 
4 – For patients without subsequent PD and who died:   


 
14 
 
a.  If (date death – date last assessment)/7 ≤ 12, 
PFS = (date death – date treatment start)/30.4375. 
These patients will be classified as having an event (censor = 1). 
b.  If (date death – date last assessment)/7 > 12, 
PFS = (date last assessment – date treatment start)/30.4375. 
The follow-up of these patients will be censored (censor = 0). 
 
4.4.3.4 Overall Survival 
 
Data Sources 
Purpose 
CRF 
Variable Name 
Dose cohort 
A2 
ph1dl 
Treatment start date 
IR 
? 
Never started treatment 
IR 
? 
Date death 
IR 
? 
Date last adequate disease 
assessment 
IR 
? 
Date last contact with patient 
E 
source 
 
Calculation Steps 
 
1 – Identify patients in Phase II cohort who had at least one dose of study therapy 
 
2 – For patients alive at last follow-up, 
          OS = (max(date last adequate assessment, source) – date treatment start)/30.4375 
 
 
The follow-up of these patients will be censored (censor = 0). 
 
3 – For patients who died, 
OS = (date death – date treatment start)/30.4375 
 
 
These patients will be classified as having an event (censor = 1). 
 
Presentation of Time-To-Event Results 
The distributions of duration of response, time to progression, progression-free survival, and 
overall survival will each be summarized using the product-limit method of Kaplan-Meier. 
Median times for each endpoint will be presented with two-sided 90% confidence intervals 
estimated using log(-log(endpoint)) methodology. Kaplan-Meier estimates of TTP and PFS at 6 
or 12 months after treatment initiation will also be presented with two-sided 90% confidence 
intervals. 
 
 


 
15 
 
5 Additional Presentations and Analyses 
 
5.1 Accrual 
 
Graphics: 
1. Number of patients screened and enrolled by month 
2. Cumulative number of patients screened and enrolled by month 
3. Numbers of patients screened and enrolled by center 
 
Tables:  Overall and by Cohort 
1.  Reasons for ineligibility/non-participation 
 
5.2 Study Sample 
 
Table:  Overall and by Cohort 
1. Patient status including attrition before measurement of primary outcome 
2. Reasons for attrition 
3. Numbers of deaths, causes of death 
4. Changes in consent  
5. Number of cycles of study therapy (MK-3475, trastuzumab) 
6. Reasons for stopping therapy  
7. Receipt of non-protocol, systemic, anti-tumor treatment prior to progression 
5.3 Patient Demographics and Baseline Disease and Prior Treatment 
 
Tables:  Overall and by Cohort 
1. Age at enrollment 
2. Race 
3. ECOG performance status 
4. Menopausal status 
5. Time (months) between enrollment and  
a. Diagnosis of advanced breast cancer 
b. Diagnosis of most-recent disease progression 
c. Diagnosis of primary tumor 
6. Trastuzumab and anti-HER2 therapies prior to enrollment 
7. Prior endocrine therapy for metastatic disease 
8. Prior radiotherapy for metastatic disease 
9. Prior chemotherapy 
10. Histologic type (ductal, lobular, not determinable) 
11.  Baseline tumor burden (sum diameters of all target lesions) 
12. ER status (percent expression), PgR status (percent), Ki-67 (percent) 
13. Tumor-infiltrating lymphocytes (percent) 


 
16 
 
14. If detail available, percent PD-L1 espression 
 
5.4 Patterns of Response 
 
Graphics: 
1. Spider (spaghetti) plot of tumor responses over time based on the sum of diameters 
of target lesions.  Will include annotations of new tumors and pseudo-progressions.  
Plots will be separated by cohort. 
2. Waterfall plot of best overall tumor response.  Cohorts will be color coded. 
 
5.5 Correlatives 
Proposed correlative data analyses are based on patients enrolled in the PD-L1-expressing 
cohort of the Phase II trial.  Comparable analyses may be performed in the cohort of patients 
with PD-L1 negative disease.  If deemed appropriate by the PIs and Medical Reviewer, the two 
samples may be combined in additional correlative analyses. 
 
5.5.1 Tumor-Infiltrating Lymphocytes (TILs) 
To examine responses according to pre-treatment levels of TILs, the population will be divided 
retrospectively according to objective response (CR/PR) or non-response. Pre-treatment 
percentages of stromal infiltrating lymphocytes will be summarized descriptively for the two 
response groups and compared using Wilcoxon rank-sum tests. Based on a sample of 40 
patients, if there are 6 responses and 34 non-responses, a Wilcoxon rank-sum test with a two-
sided, 10% type I error will have 85% power to detect a difference in baseline lymphocyte 
percentage that is 1.2 times the common standard deviation.  
 
Visualization of the relationship between baseline TILs and the distributions of TTP or PFS will 
be based on Kaplan-Meier estimates stratified by lymphocyte-predominant breast cancer 
(LPBC) phenotype or median of the distribution of intratumoral or stromal percentages. LPBC 
phenotype will be defined as 50% infiltration of either stromal or intratumoral lymphocytic 
infiltration. Medians of the time-to-event endpoints will be shown with two-sided 90% 
confidence intervals; the distributions of TTP or PFS will be compared across TIL strata using the 
log-rank test. 
 
Changes in TILs between baseline and progression/treatment discontinuation will be calculated 
(post-pre) for each patient and summarized descriptively. 
 
5.5.2 Estrogen Receptor Expression 
Pre-treatment ER expression will be dichotomized as present (≥1% expression) or absent (<1%). 
The proportions of patients with objective response (CR/PR) in each ER subgroup will be 
summarized with two-sided 90% exact, binomial confidence intervals. The distributions of TTP 


 
17 
 
or PFS will be summarized using Kaplan-Meier estimates and compared across the ER strata 
using the log-rank test. 
 
5.5.3 Outcome According to Quantified HER2 Level 
The study population will be divided retrospectively according to objective response or non-
response.  Pre-treatment FISH ratios or HER2 copy numbers will be summarized descriptively 
for the two response groups and compared using Wilcoxon rank-sum tests. If there are 6 
responses and 34 non-responses, a Wilcoxon rank-sum test with a two-sided, 10% type I error 
will have 85% power to detect a difference in measure that is 1.2 times the common standard 
deviation.  
 
Visualization of the relationship between FISH ratio or HER2 copy number and the distributions 
of TTP or PFS will employ Kaplan-Meier estimates. FISH ratio or HER2 copy number data will 
each be divided into high/low groups at the medians of the respective distributions. The 
distributions of TTP or PFS will be compared across FISH ratio or HER2 copy number strata using 
the log-rank test; medians of the time-to-event endpoints will be shown with two-sided 90% 
confidence intervals.