A Multicenter Phase II Trial to Evaluate the Efficacy and Safety of Pembrolizumab and Gemcitabine in Patients With HER2-negative Advanced Breast Cancer (ABC) "PANGEA-Breast"
Phase: PHASE2
Conditions: Advanced Breast Cancer
Sponsor: Spanish Breast Cancer Research Group

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 1 of 95 
 
 
 
Protocol GEICAM/2015-04 
“A multicenter phase II trial to evaluate the efficacy and safety of 
pembrolizumab and gemcitabine in patients with HER2-negative Advanced 
Breast Cancer (ABC)” 
“PANGEA-Breast” 
 
SPONSOR:  
GEICAM (Spanish Breast Cancer Research Group Foundation) 
Avenida de los Pirineos 7, planta 1ª, oficina 1-14 
28703 San Sebastián de los Reyes (Madrid), Spain 
Phone: 0034 916 592 870 
 
Fax: 0034 916 510 406 
Email: geicam@geicam.org 
 
CHIEF INVESTIGATOR: 
Dr. Luis de la Cruz Merino, Hospital Universitario Virgen de la Macarena, Sevilla 
Sponsor Study Code: GEICAM/2015-04 
EudraCT Number: 2016-001779-54 
 
Protocol reviewed by FECMA (Spanish Federation of Breast Cancer Patients)  
 
CONFIDENTIAL 
The information and data included in this protocol contain secrets and privileged or confidential information which is the property of 
GEICAM. No one is authorized to make this information public without the written permission of GEICAM. These limitations shall 
also be applied to all the information considered to be privileged or confidential and provided in the future. This material can be 
disclosed and used by its equipment and collaborators as necessary for conducting the clinical trial. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 2 of 95 
 
Protocol Number: GEICAM/2015-04 
Protocol Tittle: A multicenter phase II trial to evaluate the efficacy and safety of 
pembrolizumab and gemcitabine in patients with HER2-negative Advanced Breast Cancer 
(ABC). “PANGEA-Breast” 
EudraCT Number: 2016-001779-54 
Version:6.0 
Version Date: 19-Mar-2018 
 
 
__________________________________________                      _____________________ 
Chief Investigator:                                                                            Date (dd/mmm/yyyy) 
Dr. Luis de la Cruz Merino 
 
__________________________________________                      _____________________ 
Scientific Department:                                                                      Date (dd/mmm/yyyy) 
Susana Bezares, Medical Monitor 
 
__________________________________________                      _____________________ 
Statistician:                                                                                       Date (dd/mmm/yyyy) 
Maria José Escudero 
 
__________________________________________                      _____________________ 
Protocol Manager:                                                                            Date (dd/mmm/yyyy) 
 Sara Benito 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 3 of 95 
 
SUMMARY OF THE STUDY PROTOCOL 
Study Title: A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab 
and gemcitabine in patients with HER2-negative Advanced Breast Cancer (ABC) 
“PANGEA-Breast” 
Sponsor Study Code: GEICAM/2015-04 
Sponsor: GEICAM (Spanish Breast Cancer Research Group Foundation)   
Indication: HER2-negative Advanced Breast Cancer (ABC) 
Countries and approximate number of sites: Spain / 10 sites 
Number of patients: 53 patients (up to a maximum of 65 patients if 12 additional patients are 
needed due to the run-in-phase). 
Study Rationale: 
Available data support the hypothesis of an immune mediated antitumor activity in breast 
carcinoma, and several lines of research are ongoing. It is critical to understand what happens in 
the tumoral microenvironment in order to design biological agents and approaches that might 
modulate the immune response towards cancer cell destruction. At this point and due to new 
knowledge emerged with immune checkpoints function at immune synapses, combinatorial 
schedules seem to be a promising strategy. In this sense, combining chemotherapy and 
immunotherapy is an interesting approach in chemo-sensitive diseases that will eventually 
synergize and reach meaningful clinical results. 
Gemcitabine is a cytotoxic drug with well-known immunostimulatory properties that include 
increasing antigen (neoantigens) threshold and cross-presentation (via APCs), with enhancement 
of T-cell response and generation of memory T cells. In addition, gemcitabine has demonstrated 
the ability to restore immune surveillance by reducing myeloid derived suppressor cells (MDSC) 
levels in murine models. Furthermore, gemcitabine-based schedules have demonstrated clinical 
activity in breast cancer. 
Programmed death 1 (PD-1) is a molecule expressed on activated T cells that plays a major role 
in maintenance of T-cell tolerance limiting effector T cell responses. There are two ligands of 
PD-1, PD-L1 and PD-L2 (or B7-H1 and B7-H2), although PD-L1 is considered the most 
important one. PD-L1 is aberrantly expressed in some tumors including breast cancer, and thus it 
can induce immune suppression through signaling PD-1. In breast cancer PD-L1 expression (in 
tumor tissue and Tumor infiltrating lymphocytes (TILs)) has been shown to be correlated with 
worse clinicopathological data like larger tumor size, histologic grade III tumors, or negative 
hormone receptors. Blocking PD-1/PD-L1 interaction might have an immunogenic effect in 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 4 of 95 
 
breast carcinoma patients. At this point, pembrolizumab is a human programmed death receptor-1 
(PD-1)-blocking antibody that has gained Food and Drug Administration (FDA) approval for the 
treatment of patients with unresectable or metastatic melanoma and disease progression following 
ipilimumab treatment. 
In our opinion, there is sufficient evidence to consider that advanced breast carcinoma may be 
sensitive to immunotherapeutic approaches. Our proposal is based on a combination strategy with 
two immunostimulatory agents: gemcitabine (immunogenic apoptosis and elimination of MDSC) 
and pembrolizumab (blocking PD1/PD-L1 interaction) in advanced breast carcinoma (ABC) that 
may synergize and induce responses with long term clinical benefit. 
At this point, there exist a set of immune biomarkers in peripheral blood as myeloid derived 
suppressor cells (MDSC), regulatory T cells (Treg), cytokines and others that can be highly 
informative with respect to the immune activation status of the host. This trial will include 
translational research that will pursue to analyze the abovementioned set of immune biomarkers 
in the clinical setting, looking at their basal level and monitoring their evolution at different time 
points during treatment with gemcitabine and pembrolizumab  
This translational research may shed light on the putative mechanisms of clinical activity of this 
combination and identify endpoints that may predict clinical activity.  
Study Drug/Medication: 
Eligible patients will be enrolled and treated with: 
 Pembrolizumab at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-
day cycle.  
in combination with 
 Gemcitabine at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be explored in 
combination with pembrolizumab in the initial exploratory run-in-phase if necessary) as 
an intravenous (IV) infusion on day 1 and 8 of each 21-day cycle. 
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, 
clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of 
consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with 
pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment 
(though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months may 
be eligible for up to one year of additional pembrolizumab treatment if they progress after 
stopping it. 
An initial exploratory run-in-phase will be performed to test the safety of the combination and 
determine the Recommended Phase II Dose (RP2D) of gemcitabine in combination with fixed 
doses of pembrolizumab. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 5 of 95 
 
Study Design and Treatment: 
This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate the 
efficacy and safety of pembrolizumab in combination with gemcitabine in patients with HER2-
negative ABC that have previously received anthracyclines and taxanes (unless clinically 
contraindicated). In hormone receptor positive patients, previous treatment with 2 or more lines 
of hormone therapy will also be required. Patients must have at least one measurable lesion that 
can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI or plan 
X-ray and a metastatic lesion accessible for biopsy. Approximately 53 patients (up to a maximum 
of 65 patients depending on the results of the run-in-phase) will be included in this trial. 
The study will include two cohorts of patients: i) Triple Negative and ii) Luminal A+B, with an 
approximate 1:1 distribution between both groups. 
A safety dose testing or “run-in-phase”, with a 6+6 design, in which toxicity will be evaluated 
within the first cycle, will be performed since pembrolizumab in combination with gemcitabine 
has not been previously tested. Initially 6 patients will be included in the study at dose level 0 
(gemcitabine at a dose of 1,250mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and 
pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle): 
• If ≤ 2 patients experience Dose Limiting Toxicity (DLT), 6 additional patients will be 
included at the current dose level. If there is a confirmation of this dose to be safe (≤ 3 
patients experiencing DLT), this will be considered the RP2D and it will be used for the 
following recruited patients. 
• If ≥ 3 patients experience DLT within the first 6 patients, or ≥ 4 within the first 12 patients 
included at dose level 0, a de-escalation to dose level -1 (gemcitabine at a dose of 
1,000mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and pembrolizumab at 
a dose of 200mg as an IV infusion on day 1 of each 21-day cycle) will be performed. In 
this case, a group of 12 additional patients will be included at dose level -1, if ≥ 4 
experience DLT, this combination will be considered too toxic and the study will be 
stopped. If ≤ 3 experience DLT with this combination, this will be considered the RP2D 
and it will be used for the following recruited patients. 
Initially 3 patients will be allowed for inclusion simultaneously. These 3 patients will be followed 
closely during the first cycle to observe the occurrence of any DLT. At the times these 3 patients 
are completing the first cycle, the next 3 patients will be included one by one, until the first cohort 
is completed. 
If none of these 6 patients have a DLT, up to 4 patients will be allowed for inclusion from the 
second cohort of 6 patients; they will follow the same procedure as in the first cohort. If one of 
these patients from the second cohort has a DLT, the inclusion will be in smaller groups (with a 
maximum number of 4 patients with DLT) and following the same procedure as in the first cohort 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 6 of 95 
 
of 6 patients. 
An internal committee will periodically review the safety data in order to take the decision to 
maintain or decrease the dose level. This internal committee will consist of the chief investigator, 
the GEICAM medical monitor and the study statistician. The meetings will be performed by 
teleconference to take these decisions as quickly as possible once the last patient finishes the first 
cycle of treatment. Other meetings will be considered ad-hoc whenever necessary (i.e when new 
DLTs appear). 
Patients included in the run-in-phase at the same dose than that in the phase II will be considered 
for the phase II analysis. 
Primary Objective: 
• Run-in-phase: To determine the Recommended Phase II Dose (RP2D) of gemcitabine in 
combination with fixed doses of pembrolizumab. 
• Phase II: To assess the efficacy of pembrolizumab in combination with gemcitabine in 
terms of Objective Response Rate (ORR) in patients with HER2-negative ABC. 
Primary End-point: 
• Run-in-phase: To determine the incidence rate of Dose Limiting Toxicity (DLT) within 
the first cycle of the combination. 
• Phase II: Objective Response Rate (ORR) is defined as Complete Response (CR) plus 
Partial Response (PR) according to Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1. 
Secondary Objectives: 
The following secondary objectives will be studied:  
• To assess other efficacy measures of the combination in patients included in the phase II 
(including those in the run-in-phase at the same dose that in the phase II). 
• To determine safety and tolerability of the combination in all patients included in the 
study.  
Secondary End-points: 
The following secondary end-points will be studied:  
• Efficacy: 
o Progression-Free Survival (PFS) assessed according to RECIST version 1.1 by the 
investigator.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 7 of 95 
 
o Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial 
Response (PR) plus Stable Disease (SD) lasting ≥ 24 weeks according to RECIST 
version 1.1. 
o Response Duration (RD) assessed according to RECIST version 1.1. 
o Overall Survival (OS). With special interest on long term responders (i.e. alive and 
without disease progression after 24 months of study treatment). 
• Safety will be assessed by standard clinical and laboratory tests (hematology, serum 
chemistry). Adverse Events (AE) grade will be defined by the NCI CTCAE (National 
Cancer Institute Common Terminology Criteria for Adverse Events) version 4.0. 
Exploratory Objectives: 
The following exploratory objectives will be studied in all patients included in the study unless 
otherwise specified: 
• To assess other efficacy measures of the combination based on immune-related (ir) 
response criteria in patients included in the phase II (including those in the run-in-phase at 
the same dose that in the phase II). 
• To search for tumor tissue and peripheral blood biomarkers of clinical activity. 
• To compare biomarkers data from cohorts of healthy volunteers (if available) with data 
from patients included in the study.  
Exploratory End-points: 
The following exploratory end-points will be studied: 
• Efficacy: 
o ORR is defined as irCR plus irPR according to irRECIST. 
o Progression-Free Survival (PFS) assessed according to irRECIST by the 
investigator. 
o Clinical Benefit Rate (CBR) defined as irCR plus irPR plus irSD lasting ≥ 24 
weeks according to irRECIST. 
o Response Duration (RD) assessed according to irRECIST.  
• A set of immune biomarkers will be analysed and correlated with evolution of the disease 
and efficacy of pembrolizumab in combination with gemcitabine (ORR and other efficacy 
end-points: PFS, CBR and RD), paying special attention to long term responders. 
• This set of immune biomarkers will be compared with those from healthy volunteers (if 
available). 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 8 of 95 
 
Study population and main inclusion and exclusion criteria: 
Patients with HER2-negative advanced breast cancer.  
Inclusion Criteria:  
Patients are eligible to be included in the study only if they meet all of the following criteria: 
1. The patient has signed and dated the informed consent document and it has been obtained 
before conducting any procedure specifically for the study. 
2. Female ≥ 18 years of age on day of signing informed consent. 
3. Histological/cytological confirmation of breast cancer with evidence of advanced disease, 
not amenable to resection or radiation therapy with curative intent. 
4. Documented luminal A, luminal B (HER2-negative) or triple negative disease by 
immunohistochemistry (IHQ) and/or in situ hybridization (FISH/CISH/SISH) based on 
local testing on the most recent tumor biopsy defined as follows: 
o Luminal A: tumor with positive estrogen receptor (ER) status (≥1% of tumor 
cells with ER expression) and HER2-negative status (IHQ score 0/1+ or negative 
by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for single probe 
assessment a HER2 copy number < 4) and high progesterone receptor (PgR) (≥ 
20% of tumor cells with PgR expression) and low Ki67 (< 14%).  
o Luminal B (HER2-negative): tumor with positive ER status (≥1% of tumor cells 
with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in 
situ hybridization defined as a HER2/CEP17 ratio < 2 or for single probe 
assessment a HER2 copy number < 4) and either low or negative PgR (< 20% of 
tumor cells with PgR expression) and/or high Ki67 (≥ 14%).  
o Triple negative: tumor with negative hormone receptor status (<1% of tumor 
cells with ER and PgR expression) and HER2-negative status (IHQ score 0/1+ or 
negative by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for single 
probe assessment a HER2 copy number < 4). 
5. Have at least one unidimensionally measurable lesion by RECIST 1.1. 
6. Patient agrees to the collection of a metastatic tumor sample (biopsy) at the time of 
inclusion and at progression (whenever possible).  
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale. 
8. Demonstrate adequate organ function as follows (all screening labs should be performed 
within 7 days of study treatment initiation): 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 9 of 95 
 
o Bone marrow: 
 Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/l) 
 Platelets ≥ 100,000/mm3 (100x109/l) 
 Hemoglobin ≥ 9g/dl or ≥ 5.6 mmol/l without transfusion or EPO 
dependency (within 7 days of assessment) 
o Hepatic: 
 Serum total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) 
 Alkaline Phosphatase ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver 
metastases or bone metastases or any non-malignant bone disease 
 AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for patients 
with liver metastases 
 Albumin ≥ 2.5 g/dl 
o Renal: 
 Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 ml/min for 
patients with creatinine levels > 1.5 x ULN 
o Coagulation: 
 International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x 
ULN unless patient is receiving anticoagulant therapy as long as PT or 
PTT is within therapeutic range of intended use of anticoagulants. 
 Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless patient 
is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants.  
9. Prior treatment with anthracyclines and taxanes (unless clinically contraindicated), two or 
more prior lines of hormone therapy in hormone receptor positive disease, and no more 
than four prior chemotherapy lines for ABC. 
10. At least 3 months life expectancy.  
11. Patient of childbearing potential should have a negative urine or serum pregnancy within 
72 hours prior to receiving the first dose of study drug/medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
12. Patients of childbearing potential (see section 4.4. for definition) must be willing to use an 
adequate method of contraception as outlined in Section 4.4. – Contraception, for the 
course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 10 of 95 
 
the subject. 
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
Exclusion Criteria:   
Patients will be excluded from the study if they meet any of the following criteria: 
1. HER2-positive disease by immunohistochemistry or in situ hybridation (FISH-SISH-
CISH). 
2. Patient is currently participating or has participated in a study of an investigational agent 
and received study therapy or used an investigational device within 4 weeks of the first 
dose of study drug/medication. 
3. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 
1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier. 
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
o Note: Patients with ≤ grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
o Note: If patient received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
6. Has received a live vaccine within 30 days of planned start of study therapy.  
o Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) 
are live attenuated vaccines, and are not allowed.  
7. Has hypersensitivity to pembrolizumab, gemcitabine or any of theirs excipients. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and all neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are not using steroids for at 
least 7 days prior to trial treatment. This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability.   
9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 11 of 95 
 
form of immunosuppressive therapy within 7 days prior to the first dose of study 
drug/medication. 
10. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
11. Has a current or prior malignancy within the previous 5 years (other than breast cancer or 
adequately treated basal cell or squamous cell carcinoma of the skin or in-situ carcinoma 
of the cervix). 
12. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
13. Has an active infection requiring systemic therapy. 
14. Has a known history of active TB (Bacillus Tuberculosis) or Human Immunodeficiency 
Virus (HIV) (HIV 1/2 antibodies) or a known active Hepatitis B (e.g., HBsAg reactive) or 
Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the patient’s participation for the full 
duration of the trial, or is not in the best interest of the patient to participate, in the opinion 
of the treating investigator.   
16. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
17. Patient is pregnant or breastfeeding, or expecting to conceive within the projected 
duration of the trial, starting with the baseline visit through 120 days after the last dose of 
trial treatment. 
Justification of Sample size determination: 
A Simon minimax two-stage design will be employed with the possibility of stopping early due to 
lack of response. Results from previous studies showed that gemcitabine produced a response rate 
of around 20%, this will be our expected H0. With the combination of pembrolizumab and 
gemcitabine, we expect to increase this rate to 35% what will be our H1 (an absolute increase of 
15%), with an alpha error of 0.05 and a statistical power of 80%, we will need to include 53 
evaluable patients in this trial. The first stage will include 31 evaluable patients, if at least 7 
present a response, recruitment will continue to include the 53 evaluable patients. The null 
hypothesis of H0=20% will be rejected if 16 or more responses are observed in 53 patients.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 12 of 95 
 
Statistical Analyses: 
 Demographics and Baseline Characteristics 
Standard descriptive statistics, such as the mean, median, range and proportion, will be 
used to summarize the patient sample and to estimate parameters of interest. 
 Safety Analyses 
AEs and Serious Adverse Events (SAE) will be reported in frequency tables (overall and 
by intensity). The safety analysis will be performed in the population that has received at 
least one dose of any of the study drugs/medications.  
 Efficacy Analyses 
All efficacy endpoints will be evaluated in the Efficacy and ITT populations.  
 Biomarker analysis 
The biomarker analysis will be exploratory and descriptive. For continuous variables, 
mean, standard deviation, median, minimum and maximum values will be provided. 
Categorical variables will be summarized by numbers and proportions. Biomarker 
endpoints will be evaluated in all patients enrolled in the study with available samples. 
Study Duration: 
The end date of study is date of last patient´s death or the date when there is sufficient data to 
achieve the primary and secondary objectives and all patients have ended the study treatment, 
whichever comes first.  
Performing exploratory objectives will be independent of the date of the end of the study. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 13 of 95 
 
 
Table of Contents  
Section 
Page 
1. 
Introduction .......................................................................................... 22 
1.1. 
Overview of Breast Cancer ............................................................. 22 
1.2. 
Treatment options for Advanced Breast Cancer ............................. 22 
1.3.  Immune system and tumors ............................................................ 22 
1.3.1. Immune system and Breast cancer ............................................... 23 
1.4. Overview of Pembrolizumab .............................................................. 24 
1.4.1. Efficacy of pembrolizumab in solid tumors ................................. 24 
1.4.2. Safety of pembrolizumab .............................................................. 26 
1.4.3. Rationale for Dose Selection/Regimen/Modification ................... 29 
1.5. Immunotherapy in combination with chemotherapy .......................... 30 
1.5.1.  
Gemcitabine ............................................................................ 30 
1.6.  Study Rationale ............................................................................... 30 
2. 
Objectives ............................................................................................. 32 
2.1. 
Primary Objective ........................................................................... 32 
2.2.  Primary End-point ........................................................................... 32 
2.3. 
Secondary Objectives ...................................................................... 32 
2.4.  Secondary End-points ..................................................................... 32 
2.5.  Exploratory Objectives .................................................................... 33 
2.6.  Exploratory End-points ................................................................... 33 
3. 
Investigational Plan .............................................................................. 34 
3.1. 
Study Design ................................................................................... 34 
3.1.1.  
Run-in-phase ........................................................................... 34 
3.1.2.  
Phase II cohort ........................................................................ 36 
3.1.3.  
Disease Assessments............................................................... 36 
3.1.4.  
Second Course Phase (Pembrolizumab retreatment Period) .. 37 
3.2. 
Duration of the study ....................................................................... 38 
4. 
Study Population .................................................................................. 40 
4.1. 
Inclusion Criteria ............................................................................. 40 
4.2. 
Exclusion Criteria ............................................................................ 42 
4.3. 
Discontinuations .............................................................................. 43 
4.3.1. 
Discontinuation of Study Drug/Medication ............................ 43 
4.3.2. 
Discontinuation of Pembrolizumab after CR.......................... 45 
4.3.2. 
Discontinuation of Study Sites ............................................... 45 
4.3.3. 
Discontinuation of Study ........................................................ 45 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 14 of 95 
 
4.4. 
Contraception .................................................................................. 45 
5. 
Treatment ............................................................................................. 47 
5.1. 
Treatments Administered ................................................................ 47 
5.2. 
Materials and Supplies .................................................................... 47 
5.2.1.  
Storage, preparation and administration ................................. 47 
5.2.1.1. 
Pembrolizumab ................................................................. 48 
5.2.1.2. 
Gemcitabine ...................................................................... 49 
5.2.2. 
 Accountability ........................................................................ 49 
5.3. 
Method of Assigning a Patient to a Treatment ................................ 50 
5.4. 
Special Treatment Considerations. Dose Adjustments of Study 
Drug/Medication ............................................................................. 50 
5.4.1.  
Pembrolizumab ....................................................................... 50 
5.4.2. 
Gemcitabine ............................................................................ 53 
5.4.2.1. Dose Adjustments within a Cycle ........................................... 53 
5.4.2.2. Dose Adjustments for Subsequent Cycles .............................. 53 
5.5. 
Medication Errors and Overdose .................................................... 54 
5.6. 
General Concomitant Medication and Supportive Care 
Guidelines ....................................................................................... 55 
5.6.1. 
Prohibited Medications ........................................................... 55 
5.6.2. 
Permitted Medications ............................................................ 56 
5.7. 
Treatment Compliance .................................................................... 59 
6. 
Efficacy and Safety Evaluations, Sample Collection and Testing 
(Standard Laboratory Testing) and Appropriateness of Assessments . 61 
6.1. 
Efficacy Assessments ...................................................................... 61 
6.1.1. 
Primary Efficacy Assessments................................................ 61 
6.1.2. 
Secondary Efficacy Assessments............................................ 61 
6.2. 
Safety Assessments ......................................................................... 61 
6.2.1. 
Timing of Assessments ........................................................... 62 
6.2.2. 
Definitions .............................................................................. 62 
6.2.3 
Management, Timing and Assessment of Adverse Events..... 66 
6.2.4. 
Management, Timing and Assessment of SAEs ..................... 67 
6.2.5. 
Management, Timing and Assessment of SUSARs ............... 71 
6.3. 
Other Assessments .......................................................................... 72 
6.3.1.  
Exploratory Efficacy Assessments based on immune-
related (ir) RECIST ................................................................. 72 
6.3.2. 
Biomarker Assessments .......................................................... 73 
7. 
Data Quality Assurance ........................................................................ 75 
7.1. 
Data Management and Registries File ............................................ 75 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 15 of 95 
 
8. 
Sample Size and Statistical Methods ................................................... 77 
8.1. 
Determination of Sample Size ........................................................ 77 
8.1.1. 
Sample Size determination ..................................................... 77 
8.2. 
Statistical and Analytical Plans ....................................................... 77 
8.2.1. 
General Considerations ........................................................... 77 
8.2.1.1. 
Patient Populations ............................................................ 77 
8.2.2. 
Patient Disposition .................................................................. 78 
8.2.3. 
Patient Characteristics............................................................. 78 
8.2.4. 
Concomitant Therapy ............................................................. 78 
8.2.5. 
Treatment Compliance ............................................................ 79 
8.2.6. 
Efficacy Analyses ................................................................... 79 
8.2.6.1. 
Analyses of Primary Endpoint .......................................... 79 
8.2.6.2. 
Analysis of Secondary Endpoints ..................................... 80 
8.2.6.3. 
Analysis of Exploratory Endpoints ................................... 81 
8.2.7. 
Safety Analyses....................................................................... 81 
8.2.8. 
Other Analyses ........................................................................ 82 
8.2.8.1. 
Biomarker Analysis........................................................... 82 
8.2.9. 
Subgroup Analyses ................................................................. 82 
8.2.10. 
Criteria for End of Study ........................................................ 82 
9. 
Informed Consent, Confidentiality, Responsibility Insurance and 
Regulatory Considerations ................................................................... 83 
9.1. 
Informed Consent ............................................................................ 83 
9.2. 
Respect of Confidentiality ............................................................... 83 
9.3. 
Responsibility Insurance ................................................................. 84 
9.4. 
Regulatory Considerations .............................................................. 84 
9.4.1. 
Investigator Information ......................................................... 84 
9.4.2. 
Protocol Signatures ................................................................. 84 
10. Practical Considerations ....................................................................... 85 
10.1. Monitoring, Audit and Inspections ................................................. 85 
10.2. Preservation of Study Documentation ............................................ 85 
10.3. Protocol Modification ..................................................................... 85 
10.4. Use of the Information and Publication .......................................... 85 
10.5. Ethics Committees .......................................................................... 86 
11. References ............................................................................................ 87 
Protocol Attachment 1. Study Schedule ....................................................... 90 
Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status ............................................................................... 93 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 16 of 95 
 
Protocol Attachment 3. Adverse event (AE) non defined in CTCAE .......... 94 
Protocol Attachment 4. Adverse Events / Serious Adverse Events 
Assessment Guide ................................................................................ 95 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 17 of 95 
 
Abbreviations and Definitions 
ABC 
Advanced Breast Cancer 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT/ALAT (SGPT) 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ALC 
Absolute Lymphocyte Count 
aPTT 
Activated Partial Thromboplastin Time 
AR 
Adverse Reaction 
AST/ASAT (SGOT) 
Aspartate Aminotransferase 
BC 
Breast Cancer 
CB 
Clinical Benefit 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CISH 
Chromogenic In Situ Hybridization 
Compliance 
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
CNS 
Central Nervous System 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT Scan 
Computed Tomography Scan 
DKA 
Diabetic Ketoacidosis 
DLT 
Dose Limiting Toxicity 
eCRF 
Electronic Case Report Form (sometimes referred to as Clinical Report Form). An 
electronic form for recording study participants’ data during a clinical study, as 
required by the protocol. 
ECG 
Electrocardiogram 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 18 of 95 
 
ECI 
Event of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency 
End of Study (Trial) 
The end of study (trial) is the date of the last visit or last scheduled procedure shown 
in the Study Schedule for the last active patient in the study. 
Enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned a registration number and treatment. 
Enter 
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial. Patients 
entered into a trial are those who sign the informed consent document directly or 
through their legally acceptable representatives. 
ER 
Estrogen Receptor 
ERB 
Ethical review board: A board or committee (institutional, regional, or national) 
composed of medical professional and nonmedical members whose responsibility is to 
verify that the safety, welfare, and human rights of the patients participating in a 
clinical trial are protected. 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
GCP 
Good Clinical Practice 
GEICAM 
Spanish Breast Cancer Research Group 
HER2 
Human Epidermal Growth Factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator´s Brochure 
ICD 
Informed Consent Document  
IMP 
Investigational Medicinal Product 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the responsible 
leader of the team and may be called the principal investigator. 
INR 
International Normalized Ratio 
irRC 
Immuno-related Response Criteria 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 19 of 95 
 
ITT 
Intent To Treat 
IV 
Intravenous 
Legal Representative 
An individual, judicial, or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical trial. 
MDSC 
Myeloid Derived Suppressor Cells 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
OR 
Objective Response 
ORR 
Objective Response Rate 
OS 
Overall Survival 
Patient 
A subject with a defined disease. 
PD 
Progressive Disease or Programmed Death depending on the context 
PFS 
Progression-Free Survival 
PgR 
Progesterone Receptor 
PR 
Partial Response 
PT 
Prothrombin Time 
Q2W 
Every 2 Weeks 
RD 
Response Duration 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase II Dose 
SABCS 
San Antonio Breast Cancer Symposium 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 20 of 95 
 
SISH 
Silver In Situ Hybridization 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 Diabetes Mellitus 
TIL 
T Infiltrating Lymphocyte 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 21 of 95 
 
 
 
 
A multicenter phase II trial to evaluate the efficacy and safety of 
pembrolizumab and gemcitabine in patients with HER2-negative Advanced 
Breast Cancer (ABC) 
“PANGEA-Breast” 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 22 of 95 
 
1. Introduction 
1.1. 
Overview of Breast Cancer 
Breast cancer (BC) represents one of the most frequent cancers in general population and the 
first malignant tumor in women worldwide. In Europe, there were an estimated of 464,000 new 
cases of breast cancer in 2012, with a mortality of 131.000 cases (1). Specifically in Spain, 
incidence is around 26.000 new cases per year and although a steady decrease in mortality has 
been demonstrated in the last decades, nearly 20% of the patients relapse and ultimately die of 
breast cancer, which represent a mortality of approximately 6000 women per year in Spain (2). 
1.2. 
Treatment options for Advanced Breast Cancer  
Treatment options for advanced breast cancer (ABC) are numerous and varied, however new 
and better therapies are clearly needed, especially in triple negative tumors and in hormone-
sensitive but heavily pretreated disease, a challenging situation where impact of the current 
treatments in overall survival is relatively low (3). 
1.3.  Immune system and tumors 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors (4-11). Immune edition has been recently recognized 
as a highly relevant hallmark of cancer, which may impact and contribute notably to the 
different evolution of almost all types of tumors (12,13).  
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, so playing a major role in maintenance of T-cell tolerance 
limiting effector T cell responses (14,15). 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 PD-L2, or also 
named B7-H1 and B7-H2). The structure of murine PD-1 has been resolved (16). 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 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 23 of 95 
 
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 (17). The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 (18) as both 
molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed 
on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells (19). Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells (20), as well as subsets of macrophages (21) and dendritic cells 
(22). The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced 
in a variety of cell types (15), including non-hematopoietic tissues as well as in various tumors. 
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. Based on that, PD-L1 is considered 
more important than PD-L2 in solid tumors. Although healthy organs express little (if any) PD-
L1, a variety of cancers, including breast cancer were demonstrated to aberrantly express 
abundant levels of this T-cell inhibitor (23, 24), and thus it can induce immune suppression 
through signaling PD-1 (15). PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL). This 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. 
1.3.1. Immune system and Breast cancer 
In breast cancer many evidences have emerged in the last few years highlighting the role of 
PD-L1 expression in tumor tissue and tumor infiltrating lymphocytes (TILs). In fact PD-L1 
expression and TILs have been shown to be correlated with worse clinicopathological data, like 
larger tumor size, histologic grade III tumors, or negative hormone receptors (25). It has been 
reported that high or low density of TILs infiltration may have an impact in disease free 
survival and overall survival in early breast cancer, especially for the triple negative and HER2-
positive subtypes (26). A higher TILs infiltration seems to be related to a successful immune 
response of the host, that usually translate into better long term outcomes in the adjuvant setting 
(prognostic factor), and a higher probability to obtain a pathologic complete response in the 
neoadjuvant scenario (predictive factor) (27-29). Therefore, available data support the 
hypothesis of an immune mediated antitumor activity in breast carcinoma. Blocking PD-1/PD-
L1 interaction might have an immunogenic effect in breast carcinoma patients and several lines 
of research are ongoing in this way.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 24 of 95 
 
1.4. Overview of Pembrolizumab 
New immunotherapeutic drugs (monoclonal antibodies like anti-CTLA4, anti-PD1, anti-PD-
L1, etc) are entering into the clinic with unexpected successful results in a broad spectrum of 
tumors that are apparently unrelated (melanoma, non-small cell lung cancer, bladder cancer and 
others) (14).  
Pembrolizumab 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.   
A summary of the most important clinical data is included in the next sections; please refer to 
the Investigator´s Brochure (IB) for preclinical information and additional clinical data (30).  
1.4.1. Efficacy of pembrolizumab in solid tumors 
Pembrolizumab dose was assessed in the phase I KEYNOTE-001 that consisted of a first-in-
human dose-finding cohort (part A) that assessed pembrolizumab given intravenously at 1 
mg/kg, 2 mg/kg, 3 mg/kg, and 10 mg/kg once every 2 weeks (Q2W) or every 3 weeks (Q3W) 
(31) and several expansion cohorts exploring the efficacy and safety v of several 
pembrolizumab doses and schedules in patients with advanced melanoma (parts B and D) and 
non-small cell lung cancer (NSCLC) (parts C and F). 
In the melanoma expansion cohorts 655 patients were included that were either ipilimumab-
pretreated or naïve were treated with 3 different pembrolizumab dose regimens (2 mg/kg Q3W, 
10 mg/kg Q3W, and 10 mg/kg Q2W) in a non-randomized (32) and a randomized fashion  (33-
35).  
The overall response rate of pembrolizumab in patients from the non-randomized cohorts 
(n=135) were 38% as per RECIST criteria and 37% by immune-related response criteria (irRC) 
without any difference found between the ipilimumab-pretreated or naïve patients. Numerical 
differences in ORR were seen between doses and schedules, although the 95% confidence 
intervals (CIs) largely overlapped; ORR was 52% (95 % CI: 38–66) at 10 mg/kg Q2W, 27% 
(95 % CI: 15–42) at 10 mg/kg Q3W, and 25% (95 % CI: 9–49) at 2 mg/kg Q3W. 
One of the randomized cohorts of KEYNOTE-001 included 173 ipilimumab-refractory patients 
who were randomly assigned to pembrolizumab 2 mg/kg Q3W or 10 mg/kg Q3W (33). ORR at 
both doses was 26% as per RECIST criteria. In the ipilimumab-naive randomized cohort, 103 
patients were randomly assigned to receive pembrolizumab 2 mg/kg or 10 mg/kg Q3W (34). 
ORR per RECIST v1.1 was 33% in the 2-mg/kg group and 40% in the 10-mg/kg group (P = 
0.48). The final randomized melanoma cohort of KEYNOTE-001 included 244 patients with 
ipilimumab-naive or ipilimumab-treated disease who were randomly assigned to 
pembrolizumab 10 mg/kg Q2W or Q3W to further explore response and outcome at these 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 25 of 95 
 
schedules (35). ORR was 31% in the Q3W arm and 35% in the Q2W arm, indicating no 
difference in ORR between schedules (P = 0.5052). 
All this data together compared favorably to historical response rates for available treatments 
for melanoma. For example, the largest randomized clinical trial in previously treated advanced 
melanoma patients, in which carboplatin and paclitaxel were used in the control arm, and 
sorafenib plus carboplatin and paclitaxel in the experimental arm, produced a response rate of 
11% and 12%, respectively (36). This data shows significant activity regardless of prior 
ipilimumab treatment (although those ipilimumab naïve appear to have higher response rates). 
Of importance is the fact that the studies did not show a statistically significant difference in 
activity between doses and schedules. 
In the phase II randomized KEYNOTE-002 study, 540 patients previously treated with 
ipilimumab or BRAF/MEK inhibitors (if BRAF positive) were randomize to receive 
pembrolizumab (two arms with two schedules of 2 or 10 mg/kg Q3W, respectively) or 
chemotherapy (best dealers choice) (37). PFS was improved in patients assigned to 
pembrolizumab 2 mg/kg (HR 0.57, 95%CI 0.45-0.73; p<0.0001) and pembrolizumab 10 mg/kg 
(0.50, 95%CI 0.39-0.64; p<0.0001) compared with those assigned to chemotherapy. 6-month 
progression-free survival was 34% (95%CI 27-41) in the pembrolizumab 2 mg/kg group, 38% 
(95%CI 31-45) in the 10 mg/kg group, and 16% (95%CI 10-22) in the chemotherapy group. 
Treatment with pembrolizumab lead to an ORR that was >4 fold higher (21.1%; 95%CI 15.4, 
27.8 and 25.4%; 95%CI:19.2,32.4, for the 2 and 10 mg/Kg respectively) than the response rate 
of the chemotherapy control arm (4.5%; 95%CI 1.9,8.6). This difference was highly 
statistically significant, with a one sided p-value of <0.0001. 
Based on this data, KeytrudaTM (pembrolizumab) at a dose of 2 mg/kg Q3W has been 
approved by the FDA and EMA for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following ipilumumab and, if BRAF V600 mutation 
positive, a BRAF inhibitor. 
Very recently, the results from the KEYNOTE-006 trial in melanoma patients that have not 
been previously pretreated with ipilimumab, have also been reported (38). This is a 
randomized, controlled, phase III study, in which 834 patients with advanced melanoma were 
randomized in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg/Kg) every 2 weeks or 
every 3 weeks or four doses of ipilimumab (at 3 mg/Kg) every 3 weeks. The estimated 6-month 
progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for 
pembrolizumab every 3 weeks, and 26.5% for ipilimumab (HR for disease progression, 0.58; 
P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 
0.46 to 0.72 and 0.47 to 0.72, respectively). The estimated 12-month survival rates were 74.1%, 
68.4%, and 58.2%, respectively (HR for death for pembrolizumab every 2 weeks, 0.63; 95% 
CI, 0.47 to 0.83; P=0.0005; HR for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; 
P=0.0036). The ORR was improved with pembrolizumab administered every 2 weeks (33.7%) 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 26 of 95 
 
and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both 
comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, 
after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab 
groups.  
Pembrolizumab has also shown activity in non-small cell lung cancer in 495 patients (394 
previosuly treated and 101 treatment naïve) included in the KEYNOTE-001 study receiving 
two different doses of either 2 or 10 mg/Kg every 3 weeks or 10 mg/Kg every 2 weeks (39). 
The response rate was 19.4%, in all patients, with and ORR of 24.8% (95% CI: 16.7–34.3) in 
treatment-naive patients and 18.0% (95% CI: 14.4–22.2) in previously treated patients. 
Pembrolizumab demonstrated an ORR of 33.3% (95% CI: 4.3–77.7) at 2 mg/kg Q3W, 19.2% 
(95% CI: 14.8–24.2) at 10 mg/kg Q3W, and 19.3% (95% CI: 14.1–25.4) at 10 mg/kg Q2W. 
Other efficacy variables showed a median duration of response of 12.5 months (10.4 months in 
previously treated patients and 23.3 months in treatment naïve patients), a median PFS of 3.7 
months (3 months in previously treated patients and 6 months in treatment naïve patients) and a 
median overall survival of 12.0 months (9.3 months in previously treated patients and 16.2 
months in treatment naïve patients. PD-L1 expression was assessed in a set of these patients 
(training set of 182 patients) and a cut-off of at least 50% of tumor cells was selected. Among 
patients with a proportion score of at least 50% in the validation group (n=313), the response 
rate was 45.2%, the median progression-free survival was 6.3 months and the median overall 
survival was not reached (better than those with <50% of tumor cells expressing PD-L1).  
First data with pembrolizumab in breast cancer were communicated in December 2014 at the 
San Antonio Breast Cancer Symposium (SABCS 2014) in a population of heavily pretreated (≥ 
2 treatments for metastatic disease in 65.7% of the cases) ABC women with triple negative and 
PD-L1+ tumors. Pembrolizumab was administered at 10 mg/kg every 2 weeks to a total of 32 
included patients. An overall response rate of 18.5% (5/27 evaluable patients) and clinical 
benefit rate of 44.4% (including 7 patients with SD) and PFS of 1.9 months were reported. 
Anti-PD1 treatment was safe; adverse events of any grade were observed in 56% of patients; 
grade 3 events were observed in 12.5% and grade 4 in 3.1%. Three patients (9.4%) had a 
serious adverse event, one of which resulted in death due to disseminated intravascular 
coagulation (40). These data have served as a proof of principle of activity for anti-PD1 
therapies in breast cancer. 
1.4.2. Safety of pembrolizumab  
Toxicity reported to date, primarily in melanoma patients, has been manageable and not 
treatment limiting in the majority of patients. The most common AEs have been fatigue, rash, 
pruritus, arthralgia, amylase elevation, and diarrhea. AEs are generally immune-related but 
manageable following the guidelines drawn from previous experience with ipilimumab, mainly 
with corticosteroids and dose interruptions.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 27 of 95 
 
Common AEs of any grade and Grade 3 or above AEs detected in patients enrolled in 
KEYNOTE-001 are described in Tables 1 and 2 respectively. The incidence of grade ≥3 AEs 
was 14% in the nonrandomized melanoma cohorts and 12% in the randomly assigned 
ipilimumab-refractory patients, the most prevalent were pneumonitis, diarrhea, hepatitis, and 
endocrine-related AEs such as hyper- or hypothyroidism. 
Table 1. Adverse events with incidence ≥5 % observed in patients from KEYNOTE-001 
and KEYNOTE-006 trials. 
 
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 28 of 95 
 
Table 2. Incidence of grade ≥ 3 AEs in patients from KEYNOTE-001 and KEYNOTE-006 
 
In KEYNOTE-006 the pembrolizumab arms had less toxicity compared with ipilimumab; 
incidence of grade ≥3 toxicity was 13.3%, 10.1%, and 19.9% for the 10 mg/kg Q2W vs 10 
mg/kg Q3W doses of pembrolizumab and ipilimumab, respectively. The rate of drug 
discontinuation secondary to AEs for these groups was 4.0%, 6.9%, and 9.4%, respectively. 
Common AEs observed with pembrolizumab were fatigue, diarrhea, hyperthyroidism, 
hypothyroidism, rash, and pruritus; grade ≥3 diarrhea occurred in >1 % of patients (2.5 % and 
1.1%, respectively, for Q2W vs Q3W schedules). Grade ≥3 colitis occurred in 1.4% and 2.5% 
and grade ≥3 hepatitis in 1.1% and 1.8% at the Q2W and Q3W schedules, respectively, detailed 
in Tables 2 and 3. 
Lung patients treated on KEYNOTE-001 had a similar safety profile to that observed in 
patients with melanoma. The incidence of AEs of grade ≥3 was 9.5%, with pneumonitis 
(1.8%), dyspnea (3.8%), decreased appetite (1%), and asthenia (1%) having the highest 
frequencies. Pneumonitis of any grade occurred in 3.6% of patients. To date, no specific 
associations in patients with NSCLC have been reported between the risk of pneumonitis and 
previous or subsequent radiotherapy after progression on an anti-PD-1/PD-L1 agent. There was 
1 treatment-related death (pneumonitis). Median follow-up duration in all reported and 
published trial cohorts has been short, and mature data on long-term toxicity are awaited. The 
kinetics of toxicity will be important in managing patients on pembrolizumab, especially in 
patients undergoing continued treatment within the context of durable CR or PR. Important 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 29 of 95 
 
issues for future investigation include how the profile of AEs will alter with combinatorial 
immune or multimodality therapies, such as vaccines and radiation therapy. 
1.4.3. Rationale for Dose Selection/Regimen/Modification 
The dose escalation portion of KEYNOTE-001 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, as a 
consequence no MTD was identified. This first in human study of pembrolizumab 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) (31). Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
PK data analysis of pembrolizumab 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.   
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 pembrolizumab 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 fixed 
dose across all body weights. Pembrolizumab has been found to have a wide therapeutic range 
based on the melanoma indication. The differences in exposure for a 200mg fixed 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 for pembrolizumab 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 pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab 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 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 30 of 95 
 
The choice of the 200mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200mg 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 fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in 
the logistical chain at treatment facilities and reduce wastage. 
1.5. Immunotherapy in combination with chemotherapy 
At this point and due to the new knowledge generated with immune checkpoints function at 
immune synapses, combination schedules seem to be a promissory strategy, so that “non-
inflamed” tumors in a basal state may switch to an “inflamed” condition, triggering the danger 
signal to activate the immune system of the host (41,42). Especially in chemo-sensitive 
diseases, the combination of chemotherapy and immunotherapy seems to be an interesting 
approach that will eventually synergize and reach meaningful clinical results (43). 
1.5.1.  
Gemcitabine 
Gemcitabine is a cytotoxic drug with well-known immunostimulatory properties that include 
increasing antigen (neoantigens) threshold and cross-presentation (via APCs), with 
enhancement of T-cell response and generation of memory T cells (44). In addition, 
gemcitabine has demonstrated the ability to restore immune surveillance by reducing myeloid 
derived suppressor cells (MDSC) levels in murine models (45).  
Furthermore, gemcitabine-based schedules have demonstrated clinical activity in breast cancer 
(46-48) achieving response rates of around 16 to 29%. 
1.6.  Study Rationale 
At the present time there is enough preclinical and clinical evidence to consider that ABC may 
be sensitive to immunotherapeutic approaches. This trial is based on a combination strategy 
with two immunostimulatory agents: gemcitabine (immunogenic apoptosis and elimination of 
MDSC) and pembrolizumab (blocking PD1/PD-L1 interaction) in ABC in the search of a 
synergism that may induce responses with long term clinical benefit. Gemcitabine and 
pembrolizumab as single therapies are safe with very a very low rate of serious adverse events 
(SAE), therefore combination of both drugs might be warranted on efficacy and toxicity 
grounds. Nevertheless, we propose to perform a safety dose testing phase or run-in-phase since 
pembrolizumab in combination with gemcitabine has not been previously tested.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 31 of 95 
 
This trial includes a translational sub-study that will pursue to analyze a set of immune 
biomarkers in peripheral blood, looking at their basal level and monitoring their evolution at 
different time points during treatment with gemcitabine and pembrolizumab. In ABC, immune 
response assessment in tissue is challenging as biopsies are at many times not easily accessible 
or/and risky for the patients. At this point, there exist a set of immune biomarkers in peripheral 
blood as myeloid derived suppressor cells (MDSC), regulatory T cells (Treg), cytokines and 
others that can be highly informative with respect to the immune activation status of the host 
(49,50). This translational research may shed light on the putative mechanisms of the eventual 
efficacy of this combination and ultimately identify immune biomarkers that may predict 
clinical activity. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 32 of 95 
 
2. Objectives 
2.1. 
Primary Objective 
• Run-in-phase: To determine the Recommended Phase II Dose (RP2D) of gemcitabine 
in combination with fixed doses of pembrolizumab. 
• Phase II: To assess the efficacy of pembrolizumab in combination with gemcitabine in 
terms of Objective Response Rate (ORR) in patients with HER2-negative ABC. 
2.2.  Primary End-point 
• Run-in-phase: To determine the incidence rate of Dose Limiting Toxicity (DLT) within 
the first cycle of the combination. 
• Phase II: Objective Response Rate (ORR) is defined as Complete Response (CR) plus 
Partial Response (PR) according to Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1. 
2.3. 
Secondary Objectives 
The following secondary objectives will be studied: 
• To assess other efficacy measures of the combination in patients included in the phase II 
(including those in the run-in-phase at the same dose that in the phase II). 
• To determine safety and tolerability of the combination in all patients included in the 
study. 
2.4.  Secondary End-points 
The following secondary end-points will be studied: 
• Efficacy: 
o Progression-Free Survival (PFS) assessed according to RECIST version 1.1 by 
the investigator.  
o Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial 
Response (PR) plus Stable Disease (SD) lasting ≥ 24 weeks according to 
RECIST version 1.1. 
o Response Duration (RD) assessed according to RECIST version 1.1. 
o Overall Survival (OS). With special interest on long term responders (i.e. alive 
and without disease progression after 24 months of study treatment). 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 33 of 95 
 
• Safety will be assessed by standard clinical and laboratory tests (hematology, serum 
chemistry). Adverse Events (AE) grade will be defined by the NCI CTCAE (National 
Cancer Institute Common Terminology Criteria for Adverse Events) version 4.0. 
2.5.  Exploratory Objectives 
The following exploratory objectives will be studied in all patients included in the study unless 
otherwise specified: 
• To assess other efficacy measures of the combination based on immune-related (ir) 
response criteria in patients included in the phase II (including those in the run-in-phase 
at the same dose that in the phase II). 
• To search for tumor tissue and peripheral blood biomarkers of clinical activity. 
• To compare biomarkers data from cohorts of healthy volunteers (if available) with data 
from patients included in the study. 
2.6.  Exploratory End-points 
The following exploratory end-points will be studied: 
• Efficacy: 
o ORR is defined as irCR plus irPR according to irRECIST. 
o Progression-Free Survival (PFS) assessed according to irRECIST by the 
investigator. 
o Clinical Benefit Rate (CBR) defined as irCR plus irPR plus irSD lasting ≥ 24 
weeks according to irRECIST. 
o Response Duration (RD) assessed according to irRECIST.  
• A set of immune biomarkers will be analysed and correlated with evolution of the 
disease and efficacy of pembrolizumab in combination with gemcitabine (ORR and 
other efficacy end-points: PFS, CBR and RD), paying special attention to long term 
responders. 
• This set of immune biomarkers will be compared with those from healthy volunteers (if 
available). 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 34 of 95 
 
3. 
Investigational Plan 
3.1. 
Study Design 
This is a multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab in 
combination with gemcitabine in patients with HER2-negative ABC that have previously 
received anthracyclines and taxanes (unless clinically contraindicated). In hormone receptor 
positive patients, previous treatment with 2 or more lines of hormone therapy will also be 
required. Patients must have at least one measurable lesion that can be accurately assessed at 
baseline and is suitable for repeated assessment by CT, MRI or plan X-ray and a metastatic 
lesion accessible for biopsy.  
The study will include two cohorts of patients: i) Triple Negative and ii) Luminal A+B, with an 
approximate 1:1 distribution between both groups. 
An initial exploratory run-in-phase will be performed to test the safety of the combination and 
determine the RP2D of gemcitabine in combination with fixed doses of pembrolizumab.  
Approximately 53 patients (up to a maximum of 65 patients depending on the results of the 
run-in-phase) will be included in this trial. 
3.1.1.  
Run-in-phase 
A safety dose testing or “run-in-phase”, with a 6+6 design, in which toxicity will be evaluated 
within the first cycle, will be performed. Initially 6 patients will be included in the study at dose 
level 0 (gemcitabine at a dose of 1,250mg/m2 as an IV infusion on day 1 and 8 of each 21-day 
cycle and pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle): 
• If ≤ 2 patients experience Dose Limiting Toxicity (DLT), 6 additional patients will be 
included at the current dose level. If there is a confirmation of this dose to be safe (≤ 3 
patients experiencing DLT), this will be considered as RP2D and it will be used for the 
following recruited patients. 
• If ≥ 3 patients experience DLT within the first 6 patients, or ≥ 4 within the first 12 
patients included at dose level 0, a de-escalation to dose level -1 (gemcitabine at a dose 
of 1,000mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and 
pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle) 
will be performed. In this case, a group of 12 additional patients will be included at dose 
level -1, if ≥ 4 experience DLT this combination will be considered too toxic and the 
study will be stopped. If ≤ 3 experience DLT with this combination, this will be 
considered the RP2D and it will be used for the following recruited patients. 
Initially 3 patients will be allowed for inclusion simultaneously. These 3 patients will be 
followed closely during the first cycle to observe the occurrence of any DLT. At the times 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 35 of 95 
 
these 3 patients are completing the first cycle, the next 3 patients will be included one by 
one, until the first cohort is completed. 
If none of these 6 patients have a DLT, up to 4 patients will be allowed for inclusion from the 
second cohort of 6 patients; they will follow the same procedure as in the first cohort. If one of 
these patients from the second cohort has a DLT, the inclusion will be in smaller groups (with a 
maximum number of 4 patients with DLT) and following the same procedure as in the first 
cohort of 6 patients. 
An internal committee will periodically review the safety data in order to take the decision to 
maintain or decrease the dose level. This internal committee will consist of the chief 
investigator, the GEICAM medical monitor and the study statistician. The meetings will be 
performed by teleconference to take these decisions as quickly as possible once the last patient 
finishes the first cycle of treatment. Other meetings will be considered ad-hoc whenever 
necessary (i.e when new DLTs appear). 
 
Definition of the Dose Limiting Toxicity (DLT): 
DLT is defined as the occurrence of any of the following adverse events or abnormal laboratory 
value (graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0), assessed as possibly, probably or definitively related to study 
drug/medication, occurring within the first cycle of study treatment: 
Hematologic toxicities: 
• Any Grade 4 thrombocytopenia or neutropenia lasting > 7 days. 
Non-hematologic toxicities: 
• Episcleritis, uveitis, or iritis of Grade 2 or higher. 
• Any Grade 4 toxicity. 
• Any Grade 3 toxicity EXCLUDING: 
o Nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours. 
o Grade 3 rash in the absence of desquamation, no mucosal involvement, does not 
require steroids, and resolves to Grade 1 by the next scheduled dose of 
pembrolizumab. 
o Transient Grade 3 Aspartate Transaminase (AST/SGOT) or Alanine Transaminase 
(ALT/SGPT) elevation, defined as no more than 3 days with or without steroid use. 
• Discontinuation or delay of more than 2 weeks of any study drug/medication due to 
treatment-related AE. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 36 of 95 
 
Patients will continue to receive the study treatment until objective disease progression, clinical 
progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, 
whichever occurs first, this is the active treatment phase. Patients discontinuing the study 
treatment will enter the follow-up phase. Patients completing 24 months of uninterrupted 
treatment with pembrolizumab or 35 administrations of study medication will stop 
pembrolizumab treatment (though may continue with gemcitabine).  
Note: 24 months of study medication is calculated from the date of first dose. Subjects who stop 
pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab 
treatment if they progress after stopping it provided they meet the requirements detailed in 
Section 3.1.4 
3.1.2.  
Phase II cohort 
Eligible patients will be enrolled and treated with pembrolizumab in combination with 
gemcitabine at the RP2D. Patients included in the run-in-phase at the same dose that the phase 
II will be considered for the phase II analysis. 
Patients will continue to receive the study treatment until objective disease progression, clinical 
progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, 
whichever occurs first, this is the active treatment phase. Patients discontinuing the study 
treatment will enter the follow-up phase. Patients completing 24 months of uninterrupted 
treatment with pembrolizumab or 35 administrations of study medication will stop 
pembrolizumab treatment (though may continue with gemcitabine). 
Note: 24 months of study medication is calculated from the date of first dose. Subjects who stop 
pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab 
treatment if they progress after stopping it provided they meet the requirements detailed in 
Section 3.1.4 
3.1.3.  
Disease Assessments 
Disease assessments will be performed at baseline and every 9 weeks (± 1 week) from the start 
of study treatment. All lesion measurements must be recorded in the eCRF. Disease assessment 
for all patients at baseline will include: 
 CT scan or MRI of the chest, abdomen and pelvis (CAP). 
 Bone scan is mandatory if the patient has bone disease or if there is any suspicious of 
bone metastases. Any suspicious abnormalities (i.e., hotspots) identified on the bone 
scans at baseline must be confirmed by X-ray, CT scan with bone windows or MRI.   
 Brain CT scan or MRI is mandatory if the patient has any suspicious of central nervous 
system (CNS) metastases.   
 CT scan or MRI of any other site of disease as clinically indicated. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 37 of 95 
 
 Clinical assessment of superficial disease which will include photographs of all 
superficial metastatic lesions.   
The method chosen to confirm the bone metastases at baseline (X-ray, CT scan with bone 
windows or MRI) must follow the same assessment schedule as for measurable lesions, every 9 
weeks (± 1 week) from the start of study treatment. Patients with bone lesions identified at 
baseline will repeat the bone scans as clinically indicated (i.e., patient describes new or 
worsening bone pain, or has increasing alkaline phosphatase level, or other signs and symptoms 
of new/progressing bone metastases) and to confirm a complete response. 
Each assessment will be performed as scheduled according to the calendar regardless of any 
dosing delay to prevent the introduction of bias into the assessment of efficacy. Failure to 
perform any of the required disease assessments will result in the inability to determine disease 
status for that time point. Tumor assessments will be performed until radiographically and/or 
clinically (i.e., for photographed or palpable lesions) documented Progressive Disease (PD) as 
per RECIST v.1.1 or irRECIST v.1.0 (if PD is not clear, an internal committee will review the 
case) or initiation of new anticancer therapy or discontinuation of patient from overall study 
participation (e.g., death, patient's request, lost to follow up), whichever occurs first.  
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as primary data source. 
Patients discontinuing the tumor assessments for the primary endpoint will enter a follow up 
period during which survival and new anticancer therapy information will be collected every 6 
months from the last tumor assessment. At the time of the OS survival analysis all patients 
should have updated information in the eCRF with a maximum time window of 12 weeks to the 
cut-off date. The follow up period will conclude at the time of the final OS analysis.  
3.1.4.  
Second Course Phase (Pembrolizumab retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment. This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
o Was treated for at least 24 weeks with pembrolizumab before discontinuing therapy 
o Received at least two cycles with pembrolizumab beyond the date when the initial 
CR was declared 
• OR 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 38 of 95 
 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab (except 
for the continuation of gemcitabine) 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Inclusion criteria number 8 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential (see section 4.4. for definition) must be willing 
to use an adequate method of contraception as outlined in Section 4.4. – Contraception, 
for the course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation in this second course 
phase or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when they 
last received pembrolizumab. Treatment will be administered for up to one additional year. 
3.2. 
Duration of the study  
It is estimated that the accrual will be completed approximately in 18 months.  
All patients included will receive study therapy until objective disease progression, clinical 
progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, 
whichever occurs first, this is the active treatment phase. Patients discontinuing the study 
treatment will enter the follow-up phase. Patients completing 24 months of uninterrupted 
treatment with pembrolizumab or 35 administrations of study medication will stop 
pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop 
pembrolizumab after 24 months may be eligible for up to one year of additional 
pembrolizumab treatment if they progress after stopping it. 
For safety reasons all patients will have a visit 30 (+/-5) days after finishing treatment with the 
study drug/medication.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 39 of 95 
 
The end date of study is date of last patient´s death or the date when there is sufficient data to 
achieve the primary and secondary objectives and all patients have ended the study treatment, 
whichever comes first.  
Performing exploratory objectives will be independent of the date of the end of the study. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 40 of 95 
 
4. 
Study Population 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
1. The patient has signed and dated the informed consent document and it has been 
obtained before conducting any procedure specifically for the study. 
2. Female ≥ 18 years of age on day of signing informed consent. 
3. Histological/cytological confirmation of breast cancer with evidence of advanced 
disease, not amenable to resection or radiation therapy with curative intent. 
4. Documented luminal A, luminal B (HER2-negative) or triple negative disease by 
immunohistochemistry (IHQ) and/or in situ hybridization (FISH/CISH/SISH) based on 
local testing on the most recent tumor biopsy defined as follows: 
o Luminal A: tumor with positive estrogen receptor (ER) status (≥1% of tumor 
cells with ER expression) and HER2-negative status (IHQ score 0/1+ or 
negative by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for 
single probe assessment a HER2 copy number < 4) and high progesterone 
receptor (PgR) (≥ 20% of tumor cells with PgR expression) and low Ki67 (< 
14%).  
o Luminal B (HER2-negative): tumor with positive ER status (≥1% of tumor 
cells with ER expression) and HER2-negative status (IHQ score 0/1+ or 
negative by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for 
single probe assessment a HER2 copy number < 4) and either low or negative 
PgR (< 20% of tumor cells with PgR expression) and/or high Ki67 (≥ 14%).  
o Triple negative: tumor with negative hormone receptor status (<1% of tumor 
cells with ER and PgR expression) and HER2-negative status (IHQ score 0/1+ 
or negative by in situ hybridization defined as a HER2/CEP17 ratio < 2 or for 
single probe assessment a HER2 copy number < 4). 
5. Have at least one unidimensionally measurable lesion by RECIST 1.1. 
6. Patient agrees to the collection of a metastatic tumor sample (biopsy) at the time of 
inclusion and at progression (whenever possible).  
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale. 
8. Demonstrate adequate organ function as follows (all screening labs should be 
performed within 7 days of study treatment initiation): 
o Bone marrow: 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 41 of 95 
 
 Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/l) 
 Platelets ≥ 100,000/mm3 (100x109/l) 
 Hemoglobin ≥ 9g/dl or ≥ 5.6 mmol/l without transfusion or EPO 
dependency (within 7 days of assessment) 
o Hepatic: 
 Serum total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) 
 Alkaline Phosphatase ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver 
metastases or bone metastases or any non-malignant bone disease 
 AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN for patients 
with liver metastases 
 Albumin ≥ 2.5 g/dl 
o Renal: 
 Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 ml/min for 
patients with creatinine levels > 1.5 x ULN 
o Coagulation: 
 International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x 
ULN unless patient is receiving anticoagulant therapy as long as PT or 
PTT is within therapeutic range of intended use of anticoagulants. 
 Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless 
patient is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants.  
9. Prior treatment with anthracyclines and taxanes (unless clinically contraindicated), two 
or more prior lines of hormone therapy in hormone receptor positive disease, and no 
more than four prior chemotherapy lines for ABC.  
10. At least 3 months life expectancy.  
11. Patient of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study drug/medication. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.   
12. Patients of childbearing potential (see section 4.4. for definition) must be willing to use 
an adequate method of contraception as outlined in Section 4.4. – Contraception, for the 
course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 42 of 95 
 
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. HER2-positive disease by immunohistochemistry or in situ hybridation (FISH-SISH-
CISH). 
2. Patient is currently participating or has participated in a study of an investigational 
agent and received study therapy or used an investigational device within 4 weeks of the 
first dose of study drug/medication. 
3. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
o Note: Patients with ≤ grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
o Note: If patient received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
6. Has received a live vaccine within 30 days of planned start of study therapy.  
o Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed.  
7. Has hypersensitivity to pembrolizumab, gemcitabine or any of theirs excipients. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Patients with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and all neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 43 of 95 
 
9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of study 
drug/medication. 
10. Has an active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
11. Has a current or prior malignancy within the previous 5 years (other than breast cancer 
or adequately treated basal cell or squamous cell carcinoma of the skin or in-situ 
carcinoma of the cervix). 
12. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
13. Has an active infection requiring systemic therapy. 
14. Has a known history of active TB (Bacillus Tuberculosis) or Human Immunodeficiency 
Virus (HIV) (HIV 1/2 antibodies) or a known active Hepatitis B (e.g., HBsAg reactive) 
or Hepatitis C (e.g., HCV RNA [qualitative] is detected).  
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the patient’s participation for 
the full duration of the trial, or is not in the best interest of the patient to participate, in 
the opinion of the treating investigator.   
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
17. Patient is pregnant or breastfeeding, or expecting to conceive within the projected 
duration of the trial, starting with the baseline visit through 120 days after the last dose 
of trial treatment. 
4.3. 
Discontinuations 
4.3.1. 
Discontinuation of Study Drug/Medication 
The criteria for enrollment must be followed explicitly. If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient should be discontinued from the study 
drug/medication, but can be allowed to continue in the study in order to provide the follow-up 
data needed for the analysis of the entire population. An exception may be granted if the 
patient, in the opinion of the investigator, is having benefit from the study drug/medication. In 
these rare cases, the investigator must obtain documented approval from GEICAM to allow the 
patient to continue to receive the study drug/medication. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 44 of 95 
 
Patients can be discontinued from the study therapy in the following circumstances: 
• 
Patient’s own request. 
• 
Unacceptable toxicity as defined in the protocol. 
• 
Tumor progression/recurrence as defined in the protocol. 
• 
Any clinical AE, laboratory abnormality or inter-current illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of 
the patient. 
• 
Pregnancy: 
o Instruct to contact the investigator or study staff immediately if they suspect 
they might be pregnant. 
o The investigator must immediately notify GEICAM if a study patient becomes 
pregnant. 
• 
Termination of the study by GEICAM. 
• 
Physician’s decision, including need of other anti-cancer therapy, not specified in the 
protocol.  
• 
If the patient is non-compliant with study procedures.  
• 
Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (e.g. infectious disease) 
illness. 
• 
All patients will be discontinued from the active treatment phase and entered into the follow 
up phase in case of a delay of more than 12 weeks or permanent discontinuation of both 
study treatments. 
• 
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations 
of study medication, whichever is later. In this case, the investigator may decide to continue 
the treatment with gemcitabine if considers this is in the benefit for the patient, in this case 
the patient will be maintained in the active treatment phase. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects who 
stop pembrolizumab after 24 months may be eligible for up to one year of additional 
pembrolizumab treatment if they progress after stopping it provided they meet the 
requirements detailed in Section 3.1.4 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the study treatment. 
All permanent treatment discontinuation should be recorded by the investigator in the eCRF 
when considered as confirmed. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 45 of 95 
 
4.3.2. 
Discontinuation of Pembrolizumab after CR  
Discontinuation of pembrolizumab may be considered for subjects who have attained a 
confirmed CR that have been treated for at least 24 weeks with this therapy and had at least two 
cycles with pembrolizumab beyond the date when the initial CR was declared. Subjects who 
then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of the 
investigator if no cancer treatment was administered since the last dose of pembrolizumab 
(except for the continuation of gemcitabine), the subject meets the safety parameters listed in 
the Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at the same 
dose and schedule at the time of initial discontinuation.  Additional details are provided in 
Section 3.1.4  
4.3.2. 
Discontinuation of Study Sites 
Study site participation may be discontinued if GEICAM, the investigator or the Ethical 
Review Board (ERB) of the study site judges it necessary for any reason.  
4.3.3. 
Discontinuation of Study 
The study may be discontinued by GEICAM if this is medically reasonable and consistent with 
applicable regulations of Good Clinical Practice (GCP). Stopping the study for medical reasons 
may be required if patients experience adverse reactions under the treatment with the study 
drug/medication or if new information about the safety or effectiveness of the study 
drug/medication justifies it. 
4.4. 
Contraception 
Patients will not be considered of childbearing potential if they are either:  
• postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
• have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
• has a congenital or acquired condition that prevents childbearing. 
 
Patients of childbearing potential must agree to avoid becoming pregnant while receiving study 
drug and for 120 days after the last dose of study drug by complying with one of the following:   

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 46 of 95 
 
• practice abstinence from heterosexual activity (can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, 
etc.) and withdrawal are not acceptable methods of contraception);  
OR  
• use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are: 
o Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
o Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
 
In order to participate in the study subjects of childbearing potential must adhere to the 
contraception requirement (described above) from the day of study medication initiation (or 14 
days prior to the initiation of study medication for oral contraception) throughout the study 
period up to 120 days after the last dose of trial therapy.  If there is any question that a subject 
of childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 47 of 95 
 
5. Treatment 
5.1. 
Treatments Administered 
Patients will receive the following treatment: 
 Pembrolizumab at a dose of 200mg as an intravenous (IV) 30 minutes infusion on day 1 
of each 21-day cycle.  
in combination with 
 Gemcitabine at a dose of 1,250mg/m2 as an intravenous (IV) 30 minutes infusion on 
day 1 and 8 of each 21-day cycle. 
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, 
clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of 
consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with 
pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment 
(though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months 
may be eligible for up to one year of additional pembrolizumab treatment if they progress after 
stopping it. 
A lower dose of gemcitabine at 1,000mg/m2 will be explored in combination with 
pembrolizumab if necessary based on the safety and tolerability of the combination as assessed 
in the run-in phase.  
Prophylactic antiemetic therapy will be administered under site criteria.  
5.2. 
Materials and Supplies 
For this study, the term “study drug” (Investigational Medicinal Product [IMP]) refers to 
pembrolizumab.  
Gemcitabine is “study medication” that is administered in accordance with its local prescribing 
information; this drug is not regarded as IMP. It is considered standard of care.  
GEICAM will provide the study sites with pembrolizumab for the purpose of this study. Since 
gemcitabine is a marketed product approved for this indication and is administered according to 
the label it will not be provided by GEICAM.  
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 study 
drug/medication in accordance with the protocol and any applicable laws and regulations. 
5.2.1.  
Storage, preparation and administration 
Investigators and site staff are reminded to continuously monitor storage temperatures and 
ensure that thermometers are working correctly as required for proper storage of study 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 48 of 95 
 
drug/medication. These include thermometers for both the room storage and refrigerator 
storage.  
Any temperature excursions related to the study drug must be reported immediately to 
GEICAM and documented. Once a deviation is identified, the study drug MUST be 
quarantined and not used until GEICAM provides documentation of permission to use the 
investigational product.  
Study drug should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements. Returned medication should be stored separately from 
medication that needs to be dispensed. 
Refer to the Standard Operating Procedure (SOP) at each study site for study medication 
storage.  
5.2.1.1. 
Pembrolizumab  
GEICAM will provide the study sites with pembrolizumab for the purpose of this study as 
summarized in Table 3.  
Table 3. Product Descriptions 
Product Name 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Infusion 
 
Pembrolizumab should be stored at controlled refrigerator (2°C-8°C) in their original container.  
Preparation and administration: 
• Pembrolizumab infusion solution should be prepared in 0.9% sodium chloride (preferred 
diluent) or 5% dextrose and the final concentration of pembrolizumab in the infusion 
solution should be between 1 mg/mL and 10 mg/mL.  
• Pembrolizumab solution may be stored at room temperature for a cumulative time of up to 4 
hours. The 4 hour countdown begins when the vial is pierced, and includes room 
temperature storage of admixture solutions in the IV bags and the duration of infusion. In 
addition, IV bags may be stored under refrigeration at 2 °C to 8 °C for up to 20 hours. If 
refrigerated, allow the IV bags to come to room temperature prior to use.   
• Add the required pembrolizumab into the infusion IV bag containing normal saline and 
gently invert the bag 10-15 times to mix the solution. 
• Parenteral drug product should be inspected visually for particulate matter and discoloration 
prior to administration. Discard the drug product vial if visible particles are observed. 
• Do not shake or freeze the vials or the infusion solution. Caution: Do not shake the 
vials/bags otherwise this may result in formation of foam. If foam is noticed in either vial or 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 49 of 95 
 
bag, the drug product will need to be discarded. A new preparation should be made, taking 
care not to shake or agitate the product. 
• Administer the infusion solution intravenously using a sterile, non-pyrogenic, low-protein 
binding 0.2 to 5 μm in-line or add-on filter. 
• Do not co-administer other medicinal products through the same infusion line. 
• Pembrolizumab is for single use only. Discard any unused portion left in the vial. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
Pembrolizumab 200mg will be administered as a 30 minute IV infusion every 3 weeks. 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). 
Drug preparation and administration will be performed at the site by a physician, registered 
nurse or other qualified health care provider. 
5.2.1.2. 
Gemcitabine 
Refer to the Summary of Product Characteristics (SmPC) for gemcitabine for instructions and 
steps necessary for drug storage, preparation and administration. Drug preparation and 
administration will be performed at the site by a physician, registered nurse or other qualified 
health care provider. 
5.2.2. 
 Accountability 
It is the responsibility of the investigator to ensure that a current record of pembrolizumab and 
gemcitabine disposition is maintained at each study site where study drug/medication are 
inventoried and disposed. Records or logs must comply with applicable regulations and 
guidelines. 
GEICAM will provide forms to facilitate inventory control if the staff at the investigational site 
does not have an established system that meets these requirements.  
Upon completion or termination of the study, all unused and/or partially used study drug will 
be destroyed at the site per institutional policy. It is the investigator´s responsibility to arrange 
for disposal of all empty containers, provided that procedures for proper disposal have been 
established according to applicable local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 50 of 95 
 
5.3. 
Method of Assigning a Patient to a Treatment 
All patients who meet all criteria for enrollment will be registered to receive pembrolizumab in 
combination with gemcitabine.  
All patients will be screened by one of the investigators prior to study entry. An explanation of 
the study and discussion of the expected side effects and presentation of the informed consent 
document will take place. Eligible and consenting patients (entered) will be enrolled into the 
study.  
No patients can receive protocol treatment until enrollment has been performed. All eligibility 
criteria must be met at the time of enrollment. There will be no exceptions. Any question 
should be addressed with GEICAM prior to enrollment. The eligibility checklist must be 
completed and signed by the investigator prior to enrollment and it must be included into 
medical history of each patient.  
The study personnel at the site will enroll to patient through the eCRF and the system will send 
the number of the patient registration to the site.   
All eligible patients enrolled in the study will be entered in a patient registration log maintained 
by the GEICAM central office.  
Trial treatment must be administered within 7 days from enrollment.  
5.4. 
Special Treatment Considerations. Dose Adjustments of Study 
Drug/Medication 
All dose modifications should be based on the worst preceding toxicity.  
Every effort should be made to administer study treatment at the planned dose and schedule. 
However, in the event of significant treatment-related toxicity, administration of study 
drug/medication may need to be adjusted as described in the following sections. Depending on 
the nature of the toxicity observed, dose adjustments may be required for one or more study 
drug/medication in the combination.  
All dose modifications/adjustments must be clearly documented in the patient's source notes 
and the appropriate section of the eCRF. 
5.4.1.  
Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 4 below. See Section 5.6.2 for 
supportive care guidelines, including use of corticosteroids. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 51 of 95 
 
Table 4. Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab 
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 
weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for signs and 
symptoms of enterocolitis (i.e. 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis.  
• 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returned to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 52 of 95 
 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• Initiate insulin 
replacement therapy for 
participants with T1DM  
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
• 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• 
Administer 
corticosteroids and 
initiate hormonal 
replacements as clinically 
indicated.   
 
• 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism 
Grade 2 
Continue  
• Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• 
Administer 
corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2
Withhold 
• 
Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 
2 
Withhold 
• 
Based on type and 
severity of AE administer 
corticosteroids  
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be 
resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of 
T1DM).  
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 53 of 95 
 
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 study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with GEICAM. The reason for interruption 
should be documented in the patient's study record. 
5.4.2. 
Gemcitabine 
Treatment can be delayed up to 12 weeks if the patient has not recovered from toxicity prior to 
the start of a new cycle. Treatment should be resumed if neutrophil count is > 1,500 and 
platelets > 100,000. In addition, for non-hematologic toxicities (with the exception of alopecia, 
vomiting and neurotoxicity), treatment should be delayed until resolution to Grade 1 or to the 
patient’s baseline value before proceeding. If a patient has not recovered after 12 weeks she 
will be discontinued from gemcitabine (patients permanently discontinuing gemcitabine for a 
reason different than progression can continue with pembrolizumab). 
5.4.2.1. Dose Adjustments within a Cycle 
Table 5. Hematological Toxicity Day 8 
Neutrophils 
(x 109/L) 
 
Platelets 
(x 109/L) 
% of total 
gemcitabine dose 
>1.5 
Y 
>100 
100 
1-1.5 
Y 
>100 
75 
> 1.5 
Y 
75-100 
75 
1-1.5 
Y 
75-100 
50 
<1 
Y/O
<75 
0 
 
Table 6. Non-hematological Toxicity Day 8 
NCI CTCAE Grade 
Total dose of 
gemcitabine 
0-2 (and grade 3 nausea/vomiting) 
100% 
3-4 (except grade 3 nausea/vomiting) 
50% or interrupteda
a This decision will depend on the toxicity observed and the investigator’s criterion 
If a day 8 dose is omitted for any reason it should not be subsequently administered. Doses 
reduced due to toxicity shall be administered as full doses in subsequent cycles unless they 
meet one of the criteria described in section 5.4.2.2. 
5.4.2.2. Dose Adjustments for Subsequent Cycles 
They will be based on the most severe toxicity experienced in the previous cycle: 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 54 of 95 
 
Hematological Toxicity: The total dose of gemcitabine will be administered unless the patient 
has experienced one of the following in the previous cycle: 
• Neutropenic fever, 
• Prolonged Grade 4 neutropenia (more than 7 days duration), 
• Thrombocytopenia with hemorrhage, 
• Delay or omission of day 8 dose of the previous cycle as a result of hematologic 
toxicity, in which case gemcitabine will be administered at 75% of the initial dose level 
in subsequent cycles. 
Non-hematological Toxicity: doses will be adjusted according to the following table:  
Table 7. Non-hematological Toxicity 
NCI CTCAE Grade 
% of total dose of gemcitabine 
0-2 (and grade 3 nausea/vomiting) 
100 
3 (except nausea/vomiting) 
75 
4 
50 or discontinued from the studya
aThis decision will depend on the type of toxicity observed and the investigator’s criterion. 
5.5. 
Medication Errors and Overdose 
Medication errors may result in this study from the administration or consumption of the wrong 
drug, by the wrong patient, at the wrong time or at the wrong dosage strength. Such medication 
errors occurring to a study participant are to be captured on the AE page of the eCRFs and on 
the SAE form when appropriate. In the event of medication dosing error, GEICAM should be 
notified immediately.  
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
o Medication errors involving patient exposure to the product; 
o Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating patient. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated AE(s) is captured on an AE 
eCRF page (refer to Management, Timing and Assessment of Adverse Events section for 
further details). 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 55 of 95 
 
5.6. 
General Concomitant Medication and Supportive Care Guidelines 
Patients must be instructed not to take any additional medication (over-the-counter or other 
products) during the study without prior consultation with the investigator. Any medications 
including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior to 
the start of study treatment and up to 30 days following the last dose of investigational product 
and the reason for their administration must be recorded on the eCRF.  
Routine postoperative care, such as dressing changes, suture removal, drain removal, or venous 
access (central or peripheral), does not need to be recorded. Anesthetics used for any surgical 
procedures performed during the patient’s participation in the study can be recorded as 
“unspecified anesthesia” on the concomitant treatment records; it is not necessary to list the 
specific anesthetics. Palliative and supportive care for cancer-related symptoms will be offered 
to all patients in this study. 
5.6.1. 
Prohibited Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from study treatment or 
vaccination may be required. The investigator should discuss any questions regarding this with 
GEICAM. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the patient's primary physician. 
Patients are prohibited from receiving the following therapies during the Baseline and 
Treatment Phase of this trial: 
• Antineoplastic systemic chemotherapy (other than gemcitabine), biological or targeted 
therapy or endocrine therapy. 
• Immunotherapy not specified in this protocol. 
• Investigational agents other than pembrolizumab and gemcitabine. 
• Radiation therapy  
o Note: Radiation therapy to a symptomatic solitary lesion may be allowed at the 
investigator’s discretion.   
• Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), 
hormonal 
contraception, 
megestrol 
acetate, 
and 
selective 
estrogen-receptor modulators used with prophylactic intent are prohibited.  If the patient 
is receiving these at the moment of entering the study, treatment should be discontinued 
before enrollment, or 14 days prior to enrollment in the case of oral contraception.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 56 of 95 
 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of higher doses 
than physiologic doses of corticosteroids (e.g. more than oral prednisone 10 mg daily) 
may be approved after consultation with GEICAM except for that used for a limited 
time in order to prevent nausea/vomiting. 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Patients 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6.2. 
Permitted Medications 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 
5.4.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 57 of 95 
 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
• Diarrhea/Colitis:  
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
o All patients who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Type 1 diabetes mellitus [T1DM] (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA): 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism:  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 58 of 95 
 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism and Grade 2-4 hypothyroidism events: 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) 
are suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids. 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• Management of Infusion Reactions: signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 8 below shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of pembrolizumab. 
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 59 of 95 
 
Table 8. Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate (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. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further pembrolizumab 
treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (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: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further 
pembrolizumab 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. 
 
5.7. 
Treatment Compliance 
As all study treatments will be administered on an outpatient basis, it is the responsibility of the 
investigator to ensure that a current record of pembrolizumab and gemcitabine disposition is 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 60 of 95 
 
maintained at each study site where study drug/medication are inventoried and disposed. 
Records or logs must comply with applicable regulations and guidelines. 
GEICAM will provide forms to facilitate inventory control if the staff at the investigational site 
does not have an established system that meets these requirements. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 61 of 95 
 
6. 
Efficacy and Safety Evaluations, Sample Collection and Testing 
(Standard Laboratory Testing) and Appropriateness of Assessments 
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule, Protocol Attachment 1. 
6.1. 
Efficacy Assessments 
All assessments to be performed at baseline and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
6.1.1. 
Primary Efficacy Assessments 
The primary efficacy variable is Objective Response Rate (ORR).  
Tumor response will be assessed using RECIST 1.1 criteria. Tumor assessment will be 
performed at baseline; the same method of measurement used at baseline will be used for 
further evaluations that will be conducted every 9 weeks. The best response across treatment 
will be recorded. ORR is defined as the percentage of patients with a complete or partial 
response out of the Efficacy population. 
6.1.2. 
Secondary Efficacy Assessments 
The secondary efficacy variables are: 
 Clinical Benefit Rate (CBR) is defined as complete response (CR), partial response 
(PR), or stable disease (SD) ≥ 24 weeks according to the RECIST version 1.1. 
 Response Duration (RD) is defined as the time from the first documentation of 
objective tumor response (CR or PR) to the first documented progressive disease using 
RECIST version 1.1, or to death due to any cause, whichever occurs first.   
 Progression Free Survival (PFS) is defined as the time from enrollment to the first 
documented progressive disease, using RECIST version 1.1, or death from any cause, 
whichever occurs first. 
 Overall Survival (OS) is defined as the time from the date of enrollment to the date of 
death from any cause. 
6.2. 
Safety Assessments  
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting GEICAM of any event that seems unusual. 
The investigator is responsible for appropriate medical care of patients during the study. 
The investigator remains responsible for following, through an appropriate health-care option, 
adverse events that are serious or that caused the patient to discontinue before completing the 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 62 of 95 
 
study. The patient should be followed until the event is resolved or explained. Frequency of 
follow-up evaluation is left to the discretion of the investigator. 
During the course of the study, all patients entering the trial must be evaluated according to the 
schedule outlined in the flow charts and described below. The results of the evaluation will be 
recorded in the eCRF pages until the patients are not followed anymore. 
6.2.1. 
Timing of Assessments 
All assessments to be performed at baseline and during the study are specified in the Study 
Schedule, Protocol Attachment 1.  
Vital signs assessments will include blood pressure, pulse and body temperature. A baseline 
standard 12-lead ECG is mandatory; on the other visits it will be only performed if clinically 
indicated. 
The following safety laboratory assessments will be performed by the local laboratories, at the 
times specified in the Study Schedule: 
• Hematology: hemoglobin, platelet count, White Blood Cell (WBC), Absolute 
Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC). 
• Biochemistry: albumin, alkaline phosphatase, ALT, AST, total bilirubin, serum 
creatinine, creatinine clearance (for patients with creatinine levels > 1.5 x ULN), 
glucose and urea. 
• INR/PT and aPTT. 
• T3 or FT3 (Total or Free triiodothyronine), FT4 and TSH 
• Urinalysis 
All AEs (and their relatedness to the study drug/medication) occurring during the study will be 
documented in the eCRF. AEs will be graded according to NCI-CTCAE version 4.0. 
6.2.2. 
Definitions 
The safety definitions are described in the table 7. 
Table 9: Safety definitions  
Concept 
Definition 
Adverse Event  (AE) 
Any new untoward medical occurrence or worsening of a pre-
existing medical condition in a patient or clinical investigation 
subject administered an investigational (medicinal) product and 
that does not necessarily have a causal relationship with this 
treatment.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 63 of 95 
 
An AE can therefore be any unfavorable and unintended sign, 
symptom or disease temporally associated with the use of 
investigational product, whether or not considered related to the 
investigational product.  
Laboratory abnormalities should be reported as AE only in case 
they lead to an action on study treatment or if they are serious.  
Adverse Reaction (AR) 
All untoward and unintended responses to a medicinal product 
related to any dose administered.  
All expected ARs are listed in the Investigator's Brochure (IB) 
in case of not authorized investigational product or Summary of 
Product Characteristics [SmPC] in case of an authorized 
investigational product. If the nature or the severity of an 
adverse reaction is not consistent with the applicable product 
information, the AR is defined as unexpected. The basis for the 
decision is the current version of the corresponding reference 
document that has been submitted and approved by the 
competent authority and the ethics committees. 
Accountability criteria 
The sponsor will classify the adverse event, based in their 
causation relation with the investigational product, following 
the Karch y Lasagna (1977) algorithm, as: 
o Final: there is reasonable temporal sequence between 
the drug administration and the existence of the adverse 
event. This event matches with the adverse reaction 
described for the investigational product, improves with 
the omission and reappears after its re-administration 
and can’t be explained by other causes. 
o Probable: there is reasonable temporal sequence 
between the investigational product administration and 
the appearance of the adverse event. This event matches 
with the adverse reaction described for the drug, 
improves with the omission and can’t be explained by 
other causes. 
o Possible: there is reasonable temporal sequence between 
the investigational product administration and the 
appearance of the adverse event. This event matches 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 64 of 95 
 
with the adverse reaction described for the drug but can 
be explained by other causes. 
o Conditional or improbable: there is reasonable temporal 
sequence 
between 
the 
investigational 
product 
administration and the appearance of the adverse event. 
This event does not matches with the adverse reaction 
described for the drug and can be explained by other 
causes. 
o Not related: there is no reasonable temporal sequence 
between the investigational product administration and 
the appearance of the adverse event. This event does not 
matches with the adverse reaction described for the drug 
and can be explained by other causes. 
For expedited reporting purposes it is considered as related the 
categories: final, probable and possible from Karch y Lasagna 
(1977) algorithm and as not related the category conditional or 
improbable of that algorithm.  
The determination of the possible relation with the study 
treatment is responsibility of the principal investigator of the 
site or the person designated by him.  
Serious Adverse Event 
(SAE) and Serious 
Adverse Reaction (SAR) 
Any  adverse event or adverse reaction that, at any dose: 
o is fatal (results in death), 
o initial or prolonged inpatient hospitalization, 
o a life-threatening experience (that is, immediate risk of 
dying, defined as an event in which the patient was at 
risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death 
if it were more severe), 
o persistent or significant disability/incapacity, 
o congenital anomaly/birth defect or 
o an important medical event, defined as a medical event 
that may not be immediately life-threatening or result in 
death or hospitalization but, based on appropriate 
medical and scientific judgment, may jeopardize the 
patient or may require intervention (eg. medical, 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 65 of 95 
 
surgical) to prevent one of the other serious outcomes 
listed above.  
Do not confuse the concept “serious”, described before, with 
“severe” which refers to the intensity of the AE or AR 
(minor/mild/severe). 
The following events will be considered as AEs of Special 
Interest (AESIs) and they have to be documented as a SAE and 
notified to the Pharmacovigilance Department of GEICAM 
immediately: pembrolizumab and/or gemcitabine overdose, 
misuse, abuse, medication error and cancer.   
Any temporary increase in the severity of a symptom or 
previous sickness that happens after baseline is also considered 
an adverse event.  
Pregnancies and lactations that occur from the day of study 
medication initiation throughout the study period up to 120 
days after the last dose of trial therapy, or 30 days after the last 
dose of trial therapy if the subject initiates new anticancer 
therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes 
of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
Any serious adverse reaction whose nature, intensity or 
consequences do not correspond with the reference information 
for the investigational product (example, Investigator Brochure 
[IB] in case of not authorized investigational product or 
Summary of Product Characteristics [SmPC] in case of an 
authorized investigational product).  
The unexpected nature of an adverse reaction is based in the 
fact of not being observed previously and not in what could be 
advanced based on the pharmacological properties of the drug.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 66 of 95 
 
 
6.2.3 Management, Timing and Assessment of Adverse Events 
AE Classification  
 
Adverse events should be classified following version 4.0 of 
the Common Terminology Criteria for Adverse Events 
(CTCAE) of the National Cancer Institute (NCI).  A copy can 
be 
downloaded 
in 
the 
NCI 
web 
site: 
http://evs.nci.nih.gov/ftp1/CTCAE. The investigators team 
must have access to the CTCAE-NCI version 4.0.  
The AE not included in the CTCAE will be classified as 
described on Protocol Attachment 3. 
The causal relation between the investigational product and the 
AE will be assessed by the investigator using the Karch y 
Lasagna (1977) algorithm. 
Procedure to notify an 
AE to GEICAM 
The site must notify to GEICAM, through eCRF, the following 
events: 
o All adverse events that occur after enrollment.  
o Preexisting conditions that get worse during the study.  
o The evaluation of the possible relationship of each 
adverse event to the study drug/medication or protocol 
procedure.  
o The circumstances and data that causes the suspension 
of the treatment of a patient due to an adverse event. 
o The events leading to the clinical outcome of death from 
disease progression will be included in the efficacy 
analysis and are not recorded as adverse events, unless 
the investigator believes they could  have been caused 
by the study drug/medication.  
Timing and assessment 
of AE (see Protocol 
Attachment 4) 
The site staff will report on the eCRF the information of the AE 
in the following  periods: 
• Baseline (after 
ICD 
and 
before 
study 
drug/medications): study site personnel will note the 
occurrence and nature of each patient´s medical 
condition(s) 
and 
preexisting 
conditions 
in 
the 
appropriate section of the eCRF. If a patient never 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 67 of 95 
 
receives study drug/medication but experiences an 
adverse event after the ICD is signed, ONLY events the 
investigator believes may have been caused by a 
protocol procedure will be reported to GEICAM via 
eCRF. 
• During treatment with the study drug/medications: 
during the study, site personnel will record any change 
in the condition(s) and the occurrence and nature of any 
adverse events. A CTCAE grade rating will be assigned 
before each cycle for any adverse event experienced 
during the previous cycle.  
• 30-day post- treatment follow-up period: each patient 
will have a 30-day post- treatment follow-up evaluation 
approximately 30 days following the discontinuation of 
study treatment. Patients should be closely followed for 
study treatment adverse events in order to detect 
delayed toxicity. If drug-related toxicity is present 
beyond 30 days post-discontinuation, patients must be 
followed until the toxicity resolves or improved to 
baseline, the relationship is reassessed as unrelated, the 
investigator confirms that no further improvement can 
be expected, another therapy is initiated, or death.  
• Long-Term Follow-up Period (after the 30-day post- 
treatment): only new and ongoing SAEs thought to be 
related to study drug/medication or protocol procedures 
should be documented on the eCRF and immediately 
reported to GEICAM via the designated transmission 
method, even if the study has been closed.  
6.2.4. 
Management, Timing and Assessment of SAEs 
Timing of  SAEs (see 
Protocol Attachment 4) 
All the SAEs (either spontaneously or during the trial visits) 
will be collected since the patient signs the Informed Consent 
Document (ICD). 
All the SAEs must be documented in the medical record of the 
patient and in the eCRF. A follow up of all the SAEs should be 
done until they are solved or until the toxicity is considered 
irreversible.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 68 of 95 
 
SAEs which do not need 
to be notified to the 
Pharmacovigilance 
Department of GEICAM 
The following events are not considered SAEs: 
o A visit to the emergency room or other hospital 
department lasting less than 24 hours that does not 
result in admission (unless considered an “important 
medical event” or a life-threatening event). 
o Elective surgery planned before signing consent. 
o Hospitalization which is due solely to a planned study 
visit and without prolongation. 
o Routine health assessment requiring admission for 
baseline/trending 
of 
health 
status 
(e.g. 
routine 
colonoscopy). 
o Medical/surgical admission for purpose other than 
remedying ill health state that was planned before study 
entry. Appropriate documentation is required in these 
cases. 
o Admission encountered for another life circumstance 
that carries no bearing on health status and requires no 
medical/surgical intervention (e.g. lack of housing, 
economic 
inadequacy, 
caregiver 
respite, 
family 
circumstances, administrative). 
o Progression of the malignancy during study (including 
signs and symptoms of progression), unless the outcome 
is fatal and death occurred before end of treatment. 
Thereafter death due to disease progression has not to 
be reported as SAE.  
o Hospitalization due to signs and symptoms of disease 
progression. 
o An overnight stay in the hospital that is only due to 
transportation, 
organization 
or 
accommodation 
problems and without medical background.  
They will be reported in the eCRF and in the patient record. 
The rest of SAEs must be notified as described as follows. 
Procedure to notify a  
SAE to the  
Pharmacovigilance 
The SAEs must be notified to the Pharmacovigilance 
Department of GEICAM. A member of the investigator team 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 69 of 95 
 
Department of GEICAM must complete and sign the GEICAM SAE notification form 
which will be sent by fax/mail, immediately and always during 
the 24 hours following knowledge of the SAE: 
Pharmacovigilance Department of GEICAM  
Fax: +34 917 371 619 
farmacovigilancia@geicam.org  
GEICAM will review the received form and, if necessary, will 
ask more information to the investigator. 
When additional information is obtained about the SAEs, or 
this is solved or is improbable it will change, a follow-up report 
must be also completed and sent by fax/mail, immediately and 
always 
during 
the 
following 
the 
24 
hours 
to 
the 
Pharmacovigilance Department of GEICAM. 
If GEICAM suspects that the SAE could be a SUSAR, the 
investigator should give the follow up information requested. 
All SAEs/AESIs from the time the patient have the first dose of 
the study drug/medication through 30 days following the last 
administration of study drug/medications must be reported 
according to the procedure described above. All SAE 
regardless of timing must be reported, if considered related to 
study drug/medication. 
Likewise, progression of a patient's underlying condition 
leading to one of the above should also not be reported as a 
SAE, but documented as primary study endpoint. 
GEICAM will report all SAEs and AESIs immediately to the 
Chief Investigator.  
All SAEs and AESIs will be followed-up by the investigator 
until satisfactory resolution. Annually all SARs will be reported 
as the DSUR to the Competent Authorities and the leading 
ethics committee, including all SUSARs.  
Withdrawal from further treatment shall be at the discretion of 
the investigator. 
Events of Clinical 
Interest (ECI)  
ECI must be reported within 24 hours from the time the 
investigator team is aware of such an occurrence, regardless of 
whether or not the investigator considers the event to be related 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 70 of 95 
 
to study drug/medication. 
Events of clinical interest for this trial include: 
• an overdose of Pembrolizumab product, defined as any 
dose of 1,000 mg or greater (≥5 times the indicated 
dose), that is not associated with clinical symptoms or 
abnormal laboratory results.  
• an overdose of Gemcitabine product is defined as any 
dose that is 10% higher than the theoretical dose.  
• an AST or ALT > 3 x ULN and an total bilirubin > 2 x 
ULN and, at the same time, an alkaline phosphatase < 2 
x ULN. 
In addition, these ECI require additional detailed information to 
be collected and entered in the study database. 
ECI may be identified through spontaneous patient report and / 
or upon review of subject data. Adverse events that are both an 
SAE and an ECI should be reported one time as an SAE only, 
however the event must be appropriately identified as an ECI as 
well in in the database. 
Death on Study 
Any death occurring during the active treatment part of the 
study and within 30 days following the last treatment must be 
reported to GEICAM as the sponsor within 24 hours, regardless 
of the relation to study drug/medication, and has to be reported 
on the death report form section of the eCRF.  
The cause of death should be documented (cancer-related, 
treatment-related, cancer- and treatment-unrelated). Autopsy 
reports should be collected whenever possible and sent to the 
GEICAM.  
Deaths that occur due to tumor progression do not have to be 
reported as a SAE unless they occurred before end of treatment. 
Deaths after the end of study which are considered to be related 
to study treatment have to be reported as SAEs.  
To the extent feasible sufficient information including relevant 
laboratory values, ECG, scan, biopsy or autopsy results must be 
provided by the investigator in the SAE narrative (even if 
investigator determines the SAE is not related) so as to permit 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 71 of 95 
 
an independent causality assessment by a Competent Authority.
6.2.5. 
Management, Timing and Assessment of SUSARs 
Expedited Notification of  
SUSAR to the Competent 
Authorities/ERB 
The Pharmacovigilance Department of GEICAM is responsible 
to notify to each of the Competent Authorities and ERBs of the 
participating countries, all the SUSARs collected in the study, 
following the procedures shown in the current legislation.   
Timing of notification  
The deadline for reporting a SUSAR shall be 15 calendar days 
from when GEICAM becomes aware of it. When suspected 
SUSAR caused the death of the patient or endangered her life, 
GEICAM will send the information within 7 calendar days from 
the date on which it becomes aware. This information must be 
completed, if possible, in the next 8 days. 
Expedited reporting of 
other relevant safety 
information 
GEICAM will also notify, expeditiously, all the information 
that could modify the balance benefit/risk of the investigational 
product, or determine changes in its administration pattern or in 
the study performance, such as: 
o A qualitative change or an increase in the percentage of 
occurrence of the SAR expected, which are considered 
clinically significant. 
o The SUSAR occurring after completion of the study and 
are reported by the investigator to the sponsor.  
o New events related to the conduct of a trial or the 
development of an IMP likely to affect the safety of 
patients, such as: 
 SAE that could be related with the study 
procedure and could modify the conduct of the 
trial. 
 A significant risk to patients such as lack of 
efficacy in a drug used to treat a life-threatening 
illness. 
 A major safety finding from a newly completed 
animal study (such as carcinogenicity). 
 A temporary halt of a trial for safety reasons if 
the 
trial 
is 
conducted 
with 
the 
same 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 72 of 95 
 
investigational medicinal products in another 
country and if this information is known by 
GEICAM. 
This relevant information shall be notified as soon as possible 
and no later than 15 days after GEICAM becomes aware of it. 
Additional information will also be notified as quickly as 
possible.  
Annual Safety Reports 
The annual safety reports that include the SAEs, SARs and 
SUSARs collected during the study will be sent by GEICAM to 
the Competent Authorities and ERBs at the time established by 
the current legislation. 
Notification to  
investigators 
GEICAM will communicate to the investigators any safety 
information that may affect the safety of trial patients, as soon 
as possible.  
Information on SUSAR occurred during the study will be sent 
quarterly, in aggregate, in a list along with a brief analysis of 
the data provided.  
They will be informed also, throughout the entire study, of any 
safety aspect that impacts the performance on the clinical trial 
or in the product development, including the interruption or 
modification in the development program of the protocol 
safety-related.  
6.3. 
Other Assessments  
6.3.1.  
Exploratory Efficacy Assessments based on immune-related (ir) RECIST  
The exploratory efficacy assessments are: 
 Objective Response Rate (ORR) is defined as the percentage of patients with an irCR or 
irPR based on irRECIST. 
 Progression Free Survival (PFS) is defined as the time from enrollment to the first 
documented progressive disease, using irRECIST version 1.0 or death from any cause, 
whichever occurs first. 
 Clinical Benefit Rate (CBR) is defined as irCR, irPR or irSD ≥ 24 weeks according to 
the irRECIST version 1.0. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 73 of 95 
 
 Response Duration (RD) is defined as the time from the first documentation of 
objective tumor response (irCR or irPR) to the first documented progressive disease 
using irRECIST version 1.0, or to death due to any cause, whichever occurs first.   
6.3.2. 
Biomarker Assessments 
Detailed instructions for the collection, handling and shipment of samples are outlined in the 
Sample Management Manual.  
This trial will analyze a set of immune biomarkers in tissue and peripheral blood, in order to 
monitor clinical responses and correlate them with evolution of the disease and the efficacy of 
pembrolizumab in combination with gemcitabine, paying special attention to long term 
responders. This data will be compared with those from healthy volunteers (if available). An 
exploratory search of an immune score will be performed. 
Tissue: 
Time points for metastatic tumor sample collection will be at baseline, at cycle 3 (whenever 
possible) and at progression (whenever possible). The following biomarker analyses (included 
but not limited) will be performed: 
* Density of intratumoral and stroma cells: TILs and subtypes (Treg, CD8+), tumor-associated 
macrophage (TAM) and MDSC.  
* Gene expression and molecular profiling of tumors.  
* Comprehensive analysis of the tumor microenvironment including: 
1. RNA-seq profiling to semi-quantitatively measure transcript levels of immune 
related genes  
2. Full exon sequencing of cancer related to genes to estimate mutational burden  
3. Fluorescent in situ hybridization (FISH) to detect copy number gain of PD-L1 
and PD-L2 
4. PD-L1 protein expression. 
5. Immunohistochemistry (IHC) for CD3 and CD8 to evaluate pattern of 
infiltration 
Peripheral blood: 
Time points for the blood assessments will be at baseline, cycle 3, and at cycle 6 or at post 
treatment visit, whatever occurs first. In order to analyze the immunophenotype and the 
expression of immune biomarkers along treatment, the following assessments will be of interest 
(included but not limited to the following biomarkers): 
• T-cell repertoire using RNA-seq that include (but not limited to) CDR1, CDR2, and 
CDR3 as well as all V-D-J junctions. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 74 of 95 
 
• Analysis of the phenotype of peripheral blood mononuclear cells (PBMC) (e.g. CD45, 
CD11b, CD33, HLA-DR, CD14, CD15). 
• Analysis of the cytokine profile (cytokines, interleukines and chemokines, e.g. IFN-
gamma, TNF-alfa, IL2, IL4, IL6, IL7, IL8, IL10, IL13, IL17, IL21, IL23). 
• Analysis of tryptophan metabolites and activity of immune checkpoints (e.g. IDO). 
• Tregs Cells (e.g. lymphocytes FoxP3 positive, CD25 high, marked with CD3, CD4, 
CD127).  
• Analysis of surface antigens (modulators of CD4+ and CD8+ lymphocytes T activity): 
A) Co-suppressors expression: e.g. CTLA4 and PD1 (labelled with CD3, CD4 and 
CD8).  
B) Co-stimulators expression: e.g. CD28, OX40 y HLA-DR (labelled with CD3, CD4 
and CD8).  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 75 of 95 
 
7. 
Data Quality Assurance 
To ensure accurate, complete and reliable data, GEICAM will do the following: 
 Provide instructional material to the study sites, as appropriate, 
 sponsor a start-up training session to instruct the investigators and study 
coordinators. This session will give instructions on the protocol, the completion 
of the eCRFs, and study procedures, 
 make periodic visits to the study site to review study progress, investigator and 
patient compliance with the clinical trial protocol requirements and any 
emergent problems, 
 be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax, 
 review and evaluate eCRF data and use standard computer edits to detect errors 
in data collection, 
 conduct a quality review of the database, and  
   verify the quality of the data. 
To ensure the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study. If requested, the 
investigator will provide GEICAM, applicable regulatory agencies, and applicable ethical 
review boards with direct access to original source documents. 
7.1. 
Data Management and Registries File 
Data for this study will be recorded via an electronic data capture system using eCRFs. Data will 
be transcribed by the site from the paper source documents onto the eCRF. In no case the eCRF is 
to be considered as source data for this trial. The eCRFs must be completed in an electronic Data 
Base. That electronic Data Base carries out with the regulatory authorities requirements. It is the 
responsibility of the Investigator to maintain adequate and accurate eCRFs (according to the 
technology used) designed by GEICAM to record (according to GEICAM instructions) all 
observations and other data pertinent to the clinical investigation. All eCRFs should be 
completed in their entirety in a neat, to ensure accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to GEICAM as soon as they are entered in the eCRF. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 76 of 95 
 
The computerized handling of the data by GEICAM when available in the eCRF may generate 
additional requests to which the Investigator is obliged to respond by confirming or modifying 
the data questioned. The requests with their responses will be managed through the eCRF. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 77 of 95 
 
8. Sample Size and Statistical Methods 
8.1. 
Determination of Sample Size 
8.1.1. 
Sample Size determination  
A Simon minimax two-stage design will be employed with the possibility of stopping early due 
to lack of response. Results from previous studies showed that gemcitabine produced a 
response rate of around 20% (46-48), this will be our expected H0. With the combination of 
pembrolizumab and gemcitabine, we expect to increase this rate to 35% what will be our H1 
(an absolute increase of 15%), with an alpha error of 0.05 and a statistical power of 80%, we 
will need to include 53 evaluable patients in this trial. The first stage will include 31 evaluable 
patients, if at least 7 present a response, recruitment will continue to include the 53 evaluable 
patients. The null hypothesis of H0=20% will be rejected if 16 or more responses are observed 
in 53 patients. 
8.2. 
Statistical and Analytical Plans 
8.2.1. 
General Considerations 
Statistical analysis of this study will be the responsibility of GEICAM. The interpretation of 
study results will be the responsibility of the chief investigator of the study.   
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained by 
GEICAM. This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment. 
All analysis will be performed using the SAS Enterprise Guide 5.1 version. 
8.2.1.1. 
Patient Populations 
Intent to treat population (ITT): The ITT population will include all patients who are 
enrolled.   
Efficacy population: Is a subset of the ITT population that have measurable disease, have 
received at least one dose of study treatment and have at least one tumor response assessment 
according to RECIST v.1.1 criteria (unless a progression or death or unacceptable toxicity is 
seen before the first tumor response assessment) and without certain major protocol deviations 
according to the protocol deviation manual.  
The Efficacy population will be the primary population for the efficacy analysis. It will be 
performed a sensitivity analysis using the ITT population. 
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 78 of 95 
 
Safety population: The Safety population will include all patients who are enrolled and have 
received at least one dose of the study treatment.   
The Safety population will be the primary population for the safety analysis. 
Biomarker population: a subset of enrolled patients with available samples. 
8.2.2. 
Patient Disposition 
A detailed description of patient disposition will be provided. It will include: 
• Summary of patients entered and by site. 
• Total number of patients entered. 
• Total number of patients enrolled. 
• Summary of reasons for patients entered, but not enrolled. 
• Total number of patients treated. 
• Summary of reasons for patients enrolled, but not treated. 
A detailed summary of reasons for patient discontinuation from study treatment will be 
provided. 
A summary of all identified important protocol violations will be provided. 
8.2.3. 
Patient Characteristics 
Patient characteristics will include a summary of the following:  
• Patient demographics. 
• Baseline disease characteristics. 
• Preexisting conditions/secondary conditions. 
• Prior therapy. 
Other patient characteristics will be summarized as deemed appropriate. 
Standard descriptive statistics, such as the mean, median, range and proportion, will be used to 
summarize the patient sample and to estimate parameters of interest. Ninety-five percent 
confidence intervals will be provided for estimates of interest where possible.  
8.2.4. 
Concomitant Therapy  
A summary of concomitant therapies will be generated in the safety population.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 79 of 95 
 
8.2.5. 
Treatment Compliance  
Treatment information will be collected at each dose administration. The estimate of percent 
compliance will be given by: 
    Percent Compliance =       Actual dose administered per week 
    x   100 
 
 
 
 
     Dose expected to be administered per week 
No minimal level of compliance will be defined for patient inclusion in efficacy analyses. To 
be considered compliant patients should have received at least 80% of the planned number of 
doses. Exploratory analysis of the impact of compliance on selected efficacy endpoints may be 
performed if deemed necessary. 
8.2.6. 
Efficacy Analyses 
All efficacy definitions are described in section 6.1. 
All efficacy analysis will be based on the Efficacy population. Additional efficacy analyses 
will be performed on the ITT population.  
All primary and secondary endpoints based on radiological (and photographical where 
applicable) assessments of tumor burden (PFS, ORR, CBR and RD) will be derived using the 
local radiologist’s/investigator’s assessment.   
8.2.6.1. 
Analyses of Primary Endpoint 
The primary endpoint is ORR. 
Objective Response Rate (ORR): A patient will be considered to have achieved an objective 
response (OR) if the patient has a sustained complete response (CR) or partial response (PR) 
according to RECIST v.1.1 definitions. Otherwise, the patient will be considered as 
non-responders in the ORR analysis. ORR will be estimated by dividing the number of patients 
with objective response (CR or PR) by the Efficacy population (“response rate”).  
 
Objective Response Rate =                       Number of CRs + PRs                       
                    Efficacy population 
 
The ORR will be reported, including a 95% confidence interval using the Clopper-Pearson 
method. 
These analyses will be conducted at a two-sided 0.05 level of significance.  
Additional sensitivity analyses will be outlined in the SAP. For the analysis in the ITT 
population, patients with inadequate data for tumor assessment (e.g., no baseline assessment or 
no follow-up assessments) will be considered as non-responders in the OR rate analysis.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 80 of 95 
 
 
In addition, the best objective response for each patient will be summarized.  
8.2.6.2. 
Analysis of Secondary Endpoints 
The secondary efficacy endpoints are: 
Progression-Free survival (PFS): PFS data will be censored on the date of the last tumor 
assessment on study for patients who do not have objective tumor progression and who have 
not died due to any cause while on study. Additionally, patients who start a new anti-cancer 
therapy prior to documented PD will be censored at the date of the last tumor assessment prior 
to the start of the new therapy.  
The primary analyses of PFS will be performed in the Efficacy population. Additionally a 
similar analysis will be also performed in the ITT population. 
Overall Survival (OS): OS data will be censored on the last date the patient is known to be 
alive.  
OS will be analyzed in the Efficacy population. Additionally a similar analysis will be also 
performed in the ITT population. 
Response Duration (RD): RD data will be censored on the date of the last tumor assessment 
on study for patients who do not have objective tumor progression and who have not died due 
to any cause while on study. Additionally, patients who start a new anti-cancer therapy prior to 
documented PD will be censored at the date of the last tumor assessment prior to the start of the 
new therapy.  
RD will only be calculated for the subgroup of patients with an objective response.  
Clinical Benefit Rate (CBR): A patient will be considered to have clinical benefit (CB) if the 
patient has a sustained complete response (CR) or partial response (PR), or stable disease (SD) 
≥ 24 weeks according to RECIST v.1.1 definitions. Otherwise, the patient will be considered as 
not achieving CB in the CBR analysis. CBR on study treatment will be estimated by dividing 
the number of patients with CR, PR, or SD ≥ 24 weeks by the Efficacy population by treatment 
arm. 
Clinical Benefit Rate =  
     Number of CRs + PRs + SDs ≥ 24 weeks__                       
                   Efficacy population  
The CBR will be reported, including a 95% confidence interval using the Clopper-Pearson 
method.   
All of the above secondary analyses will be conducted at a two-sided 0.05 level of significance.  

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 81 of 95 
 
For the CBR analysis in the ITT population, patients with inadequate data for tumor assessment 
(e.g., no baseline assessment or no follow-up assessments) will be considered as not achieving 
CB in the CBR analysis. 
Additional sensitivity analyses will be outlined in the SAP.  
Patients without post enrollment assessments will be censored at the date of enrollment + 1 day 
in all time to event analyses.   
8.2.6.3. 
Analysis of Exploratory Endpoints 
The exploratory efficacy assessments are: 
Objective Response Rate (ORR): A patient will be considered to have achieved an objective 
response (OR) if the patient has a sustained irCR or irPR according to irRECIST definitions. 
Otherwise, the patient will be considered as non-responders in the ORR analysis. 
Progression-Free survival (PFS): Progression-Free Survival (PFS) assessed according to 
irRECIST by the investigator. 
Clinical Benefit Rate (CBR): A patient will be considered to have CB if the patient has a 
sustained irCR or irPR, or irSD ≥ 24 weeks (+/- 2 weeks) according to irRECIST definitions. 
Otherwise, the patient will be considered as not achieving CB in the CBR analysis  
Response Duration (RD): Response Duration (RD) assessed according to irRECIST. 
8.2.7. 
Safety Analyses 
The toxicity and tolerability of study drug/medication will be evaluated in the safety 
population. Safety analyses will include summaries of the incidence of adverse events by 
maximum CTCAE grade (v4.0; NCI 2010) that occur during the study treatment period or 
within 30 days of the last dose of study treatment, regardless of causality and according to the 
relationship to study drug/medication as assessed by the investigator. Additionally, the 
following safety-related outcomes will be summarized: 
• Study treatment discontinuations due to adverse events. 
• Deaths. 
• SAEs. 
• Hospitalizations and transfusions. 
• Use of key concomitant medications or growth factors. 
Analyses for data with discrete dates, for example, deaths, transfusions, and concomitant 
medications, will be done through 30 days after each patient’s last dose of study treatment.  
Adverse events will also be analyzed in this timeframe; that is, if an event starts within 30 days 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 82 of 95 
 
of discontinuation from study treatment, but after 30 days after the last dose of study treatment, 
it will not be included. 
AEs data and SAEs will be presented in frequency tables by grade. Hematological and clinical 
biochemistry toxicities will be assessed from laboratory test parameters. The safety analysis 
will be performed in the safety population.  
8.2.8. 
Other Analyses 
8.2.8.1. 
Biomarker Analysis 
The biomarker analysis of the present study will be exploratory and primarily make use of 
descriptive statistical methods. For continuous variables, descriptive statistics including the 
mean, standard deviation, median, minimum and maximum values will be provided. 
Categorical variables will be summarized by numbers and proportions (if possible, the 95% 
confidence intervals will be calculated).  
Appropriate statistical methods will be used to investigate any possible relationship of 
biomarker levels with the efficacy end-points and outcome and to compare with data from 
healthy volunteers (if available). Any additional sensitivity analyses will be outlined in the 
specific statistical analysis plan. 
8.2.9. 
Subgroup Analyses  
Exploratory subgroup analysis may be performed if deemed appropriate. 
8.2.10. Criteria for End of Study 
This study will be considered complete following the data cut-off date and datalock for the 
final analysis. The data cut-off date for the final analysis will occur after all enrolled patients 
have died or withdraw of the informed consent, or there is sufficient data to achieve the 
primary and secondary objectives, whatever occurs first.   
If further data are collected that are not included as part of the final locked database, the 
postlock data will eventually be combined with the locked database and stored in a data library 
separate from the locked database.   
The end date of study is date of last patient´s death or the date when there is sufficient data to 
achieve the primary and secondary objectives and all patients have ended the study treatment, 
whichever comes first.  
Performing exploratory objectives will be independent of the date of the end of the study. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 83 of 95 
 
9. 
Informed Consent, Confidentiality, Responsibility Insurance and 
Regulatory Considerations 
9.1. 
Informed Consent 
The investigator is responsible for ensuring that the patient understands the risks and benefits of 
participating in the study, including answering any questions the patient may have throughout 
the study and sharing any new information that may be relevant to the patient's willingness to 
continue his or her participation in the trial in a timely manner. 
The informed consent document will be used to explain the risks and benefits of study 
participation to the patient in simple terms before the patient is entered into the study, and to 
document that the patient is satisfied with his or her understanding of the risks and benefits of 
participating in the study and desires to participate in the study. 
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative. This includes obtaining the appropriate signatures and dates on the 
informed consent document prior to the performance of any protocol procedures and prior to 
the administration of study drug/medication.   
As used in this protocol, the term "informed consent" includes all consent and assent given by 
patients or their legal representatives. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated if necessary. All patients (including those 
already being treated) should be informed of the new information, given a copy of the revised 
form and give their consent to continue in the study.  
9.2. 
Respect of Confidentiality 
The investigator will be responsible for preserving the suitable information about each patient 
(for example, name, address, telephone number, social security number and study identification) 
so that the competent authorities can have access to said information if necessary. These records 
must be confidentially preserved for the time indicated by the legislation. 
The investigators and GEICAM will maintain the confidentiality of all patients participating in 
the study, according to Good Clinical Practice (GCP) and local legislation. 
This clinical trial will be held in accordance and in compliance with local current legislation. 
Any treatment of personal data that is held within the clinical trial, for Sponsor, principal 
investigator, center and/or any other participant in the clinical trial, especially as far as 
informed consent, shall conform to the provisions of Organic Law 15/1999, of December 13, 
Protection of Personal Data and Royal Decree 1720/2007 of 21 December, approving the 
Regulations implementing the approved law 15/1999, of December 13, protection of personal 
Data, and any other rules in the matter. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 84 of 95 
 
9.3. 
Responsibility Insurance 
GEICAM has signed an insurance policy to cover the responsibilities of the investigator and 
those of other parties participating in the study. 
9.4. 
Regulatory Considerations 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with good clinical practices and the 
applicable laws and regulations. The investigator, head of the medical institution, or designee 
will promptly submit the protocol to applicable ERB(s). 
9.4.1. 
Investigator Information 
Physicians with a specialty in medical oncology will participate as investigators in this clinical 
trial. 
If investigators are added after the study has been approved by GEICAM, an ERB, or a 
regulatory agency, these additions will not be considered changes to the protocol. 
9.4.2. 
Protocol Signatures 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to GEICAM. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 85 of 95 
 
10. Practical Considerations 
10.1. Monitoring, Audit and Inspections 
The study will be monitored by means of regular visits of the patients. During the visits to the 
center, the monitor must review the original records of the patients, the records of medication 
stocks and document preservation. The monitor must also evaluate the study procedures and 
discuss the possible problems with the investigator. During the course of the study, audit visits 
can be carried out in the participating centers. The investigator will allow direct access to the 
source documents/data for the tasks of monitoring, audit, reviewed by the ERB and the inspection 
by the Competent Authorities. 
10.2. Preservation of Study Documentation 
The copies of all the relevant information will be preserved by the investigator for a period of at 
least 25 years after the end of the study, according to current legislation. 
10.3. Protocol Modification 
Once it has been authorized by the ERB and the Competent Authority any protocol 
modification must be documented by writing, in the form of an amendment. 
The amendments must be duly identified, by its chronological order number, dated and signed 
by GEICAM and the Chief Investigator. 
All the protocol amendments must be notified to the ERBs involved in the trial and to the 
Competent Authority. If the modifications are relevant, the authorization of the involved ERBs 
and/or the Competent Authority will be necessary before their application. 
After reading the protocol amendment, each principal investigator will sign the protocol 
amendment signature page and send a copy of the signed page to GEICAM. 
10.4. Use of the Information and Publication 
All the information concerning the study treatment provided by GEICAM in relation to this 
study, and not previously published, is considered to be confidential information with property 
right of GEICAM. This information comprises the basic information about the product, the 
clinical protocol, the work forms where appropriate, the eCRFs, the assessment methods, the 
technical methodology and the basic scientific data. This confidential information will be 
property of GEICAM, it must not be disclosed to third parties without the prior written consent of 
GEICAM and it must not be used other than for the purposes of the study. 
The information developed during the practice of this clinical study is also considered to be 
confidential. This information can be disclosed to the extent considered necessary by GEICAM.  
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 86 of 95 
 
To allow the use of the information derived from this study and to ensure the compliance with the 
current rules, the investigator is obliged to provide GEICAM with all the results of examinations 
and all the data developed in this study. Except in that required by law, the information obtained 
during the study can only be provided to the doctors and to the Competent Authorities by 
GEICAM. 
GEICAM commits to comply with current legislation relating to studies, which establishes the 
obligation to publish the results, both positive and negative, in conferences and journals, with 
reference to ERB that approved the study, and its funding source. The list of authors will be 
developed in accordance with the GEICAM SOPs. The different disclosures will be decided by 
the Chief Investigator. By signing this protocol, the Chief Investigator and Principal 
Investigators accept the terms of the GEICAM publications SOP and commit to respect them. 
10.5. Ethics Committees 
The protocol and the informed consent document will be reviewed by the involved ERBs. The 
single decision of the ERBs referring to the development of the study will be provided in writing 
to GEICAM. 
GEICAM will submit the required reports of the progress of the study to the ERB and will 
communicate the possible SAE, the life-threatening adverse events and deaths. At the end of the 
study, GEICAM must inform the ERB of trial closure. 
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 87 of 95 
 
11. References 
1 Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in 
Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013 Apr;49(6):1374-403 
2 Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality 
Worldwide: IARC 
3 Llombart Cussac A, de la Haba Rodríguez J, Ruiz Simón A, et al. SEOM clinical guidelines for the 
management of metastatic breast cancer 2013. Clin Transl Oncol. 2013 Dec;15(12):1004-10 
4 Nosho, K., et al., Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and 
prognosis: cohort study and literature review. J Pathol, 2010. 222(4): p. 350-66. 
5 Chang, W.J., et al., Inflammation-related factors predicting prognosis of gastric cancer. World J 
Gastroenterol, 2014. 20(16): p. 4586-96. 
6 Preston, C.C., et al., The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and FOXP3- T cells 
correlate with poor clinical outcome in human serous ovarian cancer. PLoS One, 2013. 8(11): p. 
e80063. 
7 Yoon, H.H., et al., Prognostic impact of FoxP3+ regulatory T cells in relation to CD8+ T lymphocyte 
density in human colon carcinomas. PLoS One, 2012. 7(8): p. e42274. 
8 Kim, S.T., et al., Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in patients with 
early breast cancer. Am J Clin Oncol, 2013. 36(3): p. 224-31. 
9 Mathai, A.M., et al., Role of Foxp3-positive tumor-infiltrating lymphocytes in the histologic features 
and clinical outcomes of hepatocellular carcinoma. Am J Surg Pathol, 2012. 36(7): p. 980-6. 
10 Liu, F., et al., CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in relation to breast 
cancer survival and molecular subtypes. Breast Cancer Res Treat, 2011. 130(2): p. 645-55. 
11 Kirk, R., Risk factors. CD8+:FOXP3+ cell ratio is a novel survival marker for colorectal cancer. Nat 
Rev Clin Oncol, 2010. 7(6): p. 299. 
12 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74 
13 D. Ruttinger, H.Winter, N. K. Van Den Engel et al. Immunotherapy of cancer: key findings and 
commentary on the third tegernsee conference. Oncologist. 2010. vol. 15,no. 1, pp. 112–118, 2010 
14 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med. 2012; 366(26): 2443–2454 
15 Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol. 2008; 26: 677–704 
16 Zhang, X., et al., Structural and functional analysis of the costimulatory receptor programmed death-
1. Immunity, 2004. 20(3): p. 337-47. 
17 Sheppard, K.A., et al., PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to PKCtheta. FEBS Lett, 2004. 574(1-3): p. 37-41. 
18 Ott, P.A., F.S. Hodi, and C. Robert, CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic 
modalities with durable clinical benefit in melanoma patients. Clin Cancer Res, 2013. 19(19): p. 5300-9. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 88 of 95 
 
19 Yao, S. and L. Chen, PD-1 as an immune modulatory receptor. Cancer J, 2014. 20(4): p. 262-4. 
20 Nishimura, H., et al., Developmentally regulated expression of the PD-1 protein on the surface of 
double-negative (CD4-CD8-) thymocytes. Int Immunol, 1996. 8(5): p. 773-80. 
21 Huang, X., et al., PD-1 expression by macrophages plays a pathologic role in altering microbial 
clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A, 2009. 106(15): p. 
6303-8. 
22 Pena-Cruz, V., et al., PD-1 on immature and PD-1 ligands on migratory human Langerhans cells 
regulate antigen-presenting cell activity. J Invest Dermatol, 2010. 130(9): p. 2222-30. 
23 Karim, R., et al., Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and 
survival of patients with cervical carcinoma. Clin Cancer Res, 2009. 15(20): p. 6341-7. 
24 Taube, J.M., et al., Colocalization of inflammatory response with B7-h1 expression in human 
melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med, 
2012. 4(127): p. 127ra37. 
25 H. Ghebeh, S.Mohammed, A. Al-Omair et al. The B7-H1 (PDL1) T lymphocyte-inhibitory molecule 
is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-
risk prognostic factors. Neoplasia. 2006; vol. 8, no. 3, pp. 190–198 
26 S.M.A.Mahmoud, E.C.Paish, D.G.Powe et al. Tumor infiltrating CD8+ lymphocytes predict clinical 
outcome in breast cancer. Journal of Clinical Oncology, 2011. vol.29,no.15,pp.1949–1955 
27 Ali HR, Provenzano E, Dawson SJ et al. Association between CD8+ T-cell infiltration and breast 
cancer survival in 12,439 patients. Ann Oncol. 2014 Aug;25(8):1536-43 
28 C.Denkert, S.Loibl, A.Noskeetal, et al. Tumor-associated lymphocytes as an independent predictor of 
response to neoadjuvant chemotherapy in breast cancer. Journal of Clinical Oncology, 2010. 
vol.28,no.1, pp.105–113 
29 Issa-Nummer Y, Darb-Esfahani S, Loibl S et al. Prospective validation of immunological infiltrate for 
prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer--a substudy of the 
neoadjuvant GeparQuinto trial. PLoS One. 2013 Dec 2;8(12):e79775 
30 
Keytruda 
(pembrolizumab) 
prescribing 
information. 
Whitehouse 
Station, 
NJ: 
Merck 
(http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi. pdf) 
31 Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, et al. Phase I study of 
pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. 
Clin Cancer Res. 2015 May 14. pii: clincanres.2607.2014. [Epub ahead of print]. 
32 Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with 
lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44. 
33 Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with 
pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of 
a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. 
34 Hamid O, Robert C, Ribas A, Wolchok F, Hodi S, Kefford R, et al. Randomized comparison of two 
doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory (IPI-R) and IPI-naive 
(IPI-N) melanoma (MEL). J Clin Oncol. 2014;32(Suppl):3000. 
35 Robert C, Joshua AM, Weber JS, Ribas A, Hodi FS, Kefford RF, et al. Pembrolizumab (pembro; MK-
3475) for advanced melanoma (MEL): randomized comparison of two dosing schedules. Ann Oncol. 
2014;25:1–41. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 89 of 95 
 
36 Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled 
study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in subjects 
with unresectable stage III or stage IV melanoma. J Clin Oncol 2009;27(17):2823-30. 
37 Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for 
ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet 
Oncol. 2015 Aug;16(8):908-18. 
38 Robert C, Schachter J, Long GV, et al Pembrolizumab versus Ipilimumab in Advanced Melanoma. N 
Engl J Med. 2015 Jun 25;372(26):2521-32 
39 Garon EB1, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N 
Engl J Med. 2015 May 21;372(21):2018-28. 
40 Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with 
advanced triple-negative breast cancer. Presented at 2014 San Antonio Breast Cancer Symposium; 
December 9-13, 2014; San Antonio, Texas. Abstract S1-09 
41 De la Cruz-Merino L, Barco-Sánchez A, Henao Carrasco F, et al. New insights into the role of the 
immune microenvironment in breast carcinoma. Clin Dev Immunol. 2013;2013:785317 
42 Matzinger P. The evolution of the danger theory. Expert Rev Clin Immunol. 2012 May;8(4):311-7 
43 R. A. Lake and B. W. S. Robinson. Immunotherapy and chemotherapy-a practical partnership. Nature 
Reviews Cancer, 2005.vol. 5, pp. 397–405 
44 Suzuki E, Kapoor V, Jassar AS, et al. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ 
myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin 
Cancer Res. 2005 Sep 15;11(18):6713-21 
45 Nowak AK, Robinson BW, Lake RA, et al. Gemcitabine exerts a selective effect on the 
humoral immune response: implications for combination chemo-immunotherapy.  Cancer Res. 2002 
Apr 15;62(8):2353-8 
46 Spielmann M, Llombart-Cussac A, Kalla S, et al. Single-Agent Gemcitabine in active in previously 
treated metastatic breast cancer. Oncology 2001;60:303-307 
47 Sun Y R, Moon Y H, Jeung HC, et al. Gemcitabine monotherapy as salvage chemotherapy in heavily 
pretreated metastatic breast cancer. Breast cancer Res 2005;90:215-221 
48 Brodowicz T, Kostler WJ, Möslinger R, et al. Single agent gemcitabine as second-and third line 
treatment in metastatic breast cancer. The breast 2000;9:338-342 
49 Martin F, Apetoh L, Ghiringhelli F. Role of myeloid-derived suppressor cells in tumor 
immunotherapy. Immunotherapy. 2012 Jan;4(1):43-57 
50 Ding ZC, Lu X, Yu M. Immunosuppressive myeloid cells induced by chemotherapy attenuate 
antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res. 2014 Jul 1;74(13):3441-53 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 90 of 95 
 
Protocol Attachment 1. Study Schedule 
Study Schedule of Events and Timelines. 
GEICAM/2015-04 (PANGEA-Breast) 
During Study Treatmentq 
(All visits +/-3 days of scheduled treatment 
day) 
Post-treatmentr 30 
days (+/-5 days) 
from the last study 
drug/medication 
dose 
After study treatment 
terminations 
Cycle 
Baseline 
 
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles 
PFS  
Follow-up 
Period every 
9 weeks 
(+/-7 days) 
OS 
Follow-up 
Period 
every 6 
months 
(+/-7 days)
Day of cycle 
1 
8 
1 
8 
1 
8 
1 
8 
Procedure/Laboratory/  
Diagnostic Test 
Within 28 days 
ENROLLMENT 
 
 
 
 
 
 
 
 
 
 
 
ICD for Entry (before any 
study specific tests)a 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
and demographicsb 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematologyd 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Biochemistryf 
X 
Xe 
 
X 
 
X 
 
X 
 
X 
 
 
INR/PT and aPTT 
X 
Xe 
 
X 
 
X 
 
X 
 
X 
 
 
T3 or FT3, FT4 and TSH 
X 
Xe 
 
 
 
X 
 
Xh 
 
X 
 
 
Urinalysisg 
X 
Xe 
 
 
 
X 
 
Xh 
 
X 
 
 
Pregnancy test 
Xi 
 
 
 
 
 
 
 
 
 
 
 
Standard 12-lead ECG 
X 
If clinically indicated 
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 91 of 95 
 
Study Schedule of Events and Timelines. 
GEICAM/2015-04 (PANGEA-Breast) 
During Study Treatmentq 
(All visits +/-3 days of scheduled treatment 
day) 
Post-treatmentr 30 
days (+/-5 days) 
from the last study 
drug/medication 
dose 
After study treatment 
terminations 
Cycle 
Baseline 
 
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles 
PFS  
Follow-up 
Period every 
9 weeks 
(+/-7 days) 
OS 
Follow-up 
Period 
every 6 
months 
(+/-7 days)
Day of cycle 
1 
8 
1 
8 
1 
8 
1 
8 
Concomitant medications 
X 
X 
X 
AEs and SAESj  
X 
X 
Pembrolizumab dosing 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Gemcitabine dosing  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor Assessment 
Xk 
Every 9 weeks from the start of treatment.  
 
Xl 
 
Date of death  
 
 
 
 
 
 
 
 
 
 
 
Xm 
Biomarker assessment 
 
 
 
 
Tumor tissue 
Xn
 
 
 
 
Xn
 
 
 
 
Xn
 
Peripheral blood  
 
 
Xo 
 
 
 
Xp
 
Xp
 
Xp 
 
 
 
Study Schedule of Events and Timelines. Protocol GEICAM/2015-04 (PANGEA-Breast) 
a 
Signed, written informed consent (approved by ERB) obtained prior to any study specific procedure. 
b 
Includes local laboratory ER/PgR/HER2/Ki67 expression levels and methods used to assess them, previous treatments. Sex, Race and Age. 
c 
Physical examination includes measurements of height (baseline only), weight, area surface body (baseline only unless patient experience a body weight 
variation greater than 10% during the treatment period with gemcitabine), blood pressure, pulse rate and body temperature. 
d 
Hemoglobin, platelet count, White Blood Cell (WBC), Absolute Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC). 
e 
If baseline Hematology, Biochemistry, INR/PT and aPTT, T3 or FT3, FT4 and TSH and Urinalysis is performed within 7 days prior to the first dose of 
study treatment, there is no need to repeat those tests on Day 1 Cycle 1. 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 92 of 95 
 
f 
Albumin, alkaline phosphatase, ALT, AST, total bilirubin serum creatinine, creatinine clearance (for patients with creatinine levels > 1.5 x ULN) glucose 
and urea. If necessary, creatinine clearance should be calculated per institutional standard. 
g 
Blood, glucose, protein, specific gravity and microscopic exam (if abnormal). Dipstick is not permitted. 
h 
T3 or FT3, FT4 and TSH and Urinalysis to be performed every odd cycle day 1. 
i 
All patients of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to first dose of study treatment. If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
j 
After informed consent form signature, but prior to initiation of study medications, only SAEs caused by a protocol-mandated intervention will be collected. 
Adverse events to be monitored continuously during the treatment period. All AEs occurring during the study and until the post-treatment visit 30 days after 
the last study medication to be recorded with grading according to NCI-CTCAE, thereafter all study drug/medication-related SAEs should continue to be 
collected.  
k 
Disease assessment for all patients at baseline will include: CT or MRI scan of the chest, abdomen and pelvis (CAP); bone scans mandatory if the patient 
has bone disease or if there is any suspicious of bone metastases, any suspicious abnormalities (i.e., hotspots) identified on the bone scans at baseline must 
be confirmed by X-ray, CT scan with bone windows or MRI, bone lesions identified at baseline will follow the same assessment schedule as for measurable 
lesions; brain CT or MRI scan is mandatory if there is any suspicious of CNS metastases; CT or MRI scan of any other sites of disease as clinically 
indicated; clinical assessment of superficial disease which will include photographs of all superficial metastatic lesions.   
All lesion measurements must be recorded in the eCRF. To be performed every 9 weeks from the start of treatment ± 1 week. 
l 
Only to be performed post-study treatment if disease progression has not yet been confirmed and patients has not begun a new therapy. The tumor 
assessment will be performed every 9 weeks from the last tumor assessment.   
m
The patients will be followed for survival until death, loss to follow-up, withdrawal of consent or study termination by GEICAM. After progression, the 
tumor assessment will be performed according to the standard medical practice. The date of death and all treatments received by the patient after progression 
(according to the standard medical practice) will be collected in the eCRF.  
n Time points for metastatic tumor sample collection will be at baseline, at cycle 3 (whenever possible) and at progression (whenever possible). 
o The sample has to be collected pre-dose or within 7 days prior to the first dose of treatment. 
p Peripheral blood assessments will be performed at cycle 3 and 6 or at post treatment visit (in case of pembrolizumab discontinuation), whatever occurs first. 
q Pembrolizumab will continue until patients complete 24 months of uninterrupted treatment or 35 administrations of it (whichever is later) and may continue 
with gemcitabine.  
r Subjects who are eligible for retreatment with pembrolizumab (as described in Section 3.1.4) may have up to two safety follow-up visits, one after the initial 
pembrolizumab discontinuation (if gemcitabine is also discontinued) and one after the Second Course Phase. 
s Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria in Section 3.1.4 will move from the follow-up phase to the 
Second Course Phase when they experience disease progression.  
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 93 of 95 
 
Protocol Attachment 2. Eastern Cooperative Oncology Group 
Performance Status 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light housework, office work 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours 
 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
 
5 
Dead 
 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
5(6):649-65 
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 94 of 95 
 
Protocol Attachment 3. Adverse event (AE) non defined in CTCAE 
CTC Grade 
Equivalent to:
Definition 
Grade 1 
Mild 
Discomfort noticed but no disruption of normal daily activity. 
Grade 2 
Moderate 
Discomfort sufficient to reduce or affect daily activity; no treatment 
or medical intervention is indicated although this could improve the 
overall well-being or symptoms of the patient. 
Grade 3 
Severe 
Inability to work or perform normal daily activity; treatment or 
medical intervention is indicated in treatment or medical intervention 
is indicated in order to improve the overall well-being or symptoms; 
delaying the onset of treatment is not putting the survival of the 
patient at direct risk. 
Grade 4 
Life-
threatening / 
disabling 
An immediate threat to life or leading to a permanent mental or 
physical conditions that prevents work or performing daily activities; 
treatment or medical intervention is required in order to maintain 
survival.  
Grade 5 
Death 
AE resulting in death. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

GEICAM/2015-04 (PANGEA-Breast)                                                       EudraCT number: 2016-001779-54  
 
Protocol Version 6.0 of 19-Mar-2018 
 
Confidential                                                                    Page 95 of 95 
 
Protocol Attachment 4. Adverse Events / Serious Adverse Events 
Assessment Guide 
Time 
After ICD 
Before Drug 
During Therapy 
30-Day  
Post- treatment 
Follow-up Period 
Long-Term  
Follow-up Period 
Events to 
Collect  
AE/SAEs 
 
New/Ongoing AE/SAEs 
 
New/Ongoing SAEs 
 
 
Related to 
Procedures 
Regardless of Relatedness to 
Study Treatment or Procedures 
Related to Study 
Treatment or Procedures 
Abbreviations:  AE = adverse event, ICD = informed consent document, SAE = serious adverse event.