Conditions: Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 73
Healthy volunteers: no

Brief summary:
Exploratory phase II trial of intravenous (IV) Pembrolizumab MK-3475 as second or further line with advanced Non-small cell Lung Cancer (NSCLC) who have failed to a prior treatment with anti-PDL1 drug.

Pembrolizumab 200 mg ,Q3W, IV infusion, Day 1 of each 3 week cycle will be administered until disease progression.

Detailed description:
This is a multi-center exploratory phase II trial of intravenous (IV) Pembrolizumab MK-3475 as second or further line with advanced Non-small cell Lung Cancer (NSCLC) who have failed to a prior treatment with anti-PDL1 drug.

110 patients will be enrolled in this trial to examine the efficacy and outcomes of these patients.

In addition to the usual procedures in a phase II study (evaluation of response, toxicity, etc.) special attention will be paid in this trial to the molecular assessment in biological samples.

Subjects will receive Pembrolizumab at a fixed dose of 200 mg every 3 weeks (Q3W). Subjects will be evaluated with radiographic imaging to assess response to treatment. Investigators will make all treatment-based decisions using the Immune-Related Response Criteria (irRC). However, for determination of overall response rate (ORR) and progression-free survival (PFS), the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used.

Adverse events will be monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment with Pembrolizumab will continue until documented disease progression, unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdraws consent, noncompliance with trial treatment or procedure requirements, or administrative reasons.

After the end of treatment, each subject will be followed for a minimum of 30 days for adverse event monitoring (serious adverse events will be collected for up to 90 days after the end of treatment unless the subject starts a new anticancer therapy between days 31 and 90). Subjects will have post-treatment follow-up for disease status, including initiating a non-study cancer treatment and experiencing disease progression, until death, withdrawing consent, or becoming lost to follow-up.

Participation in this trial will be dependent upon supplying tumor tissue from a newly obtained formalin-fixed specimen from locations not radiated prior to biopsy. The specimen will be evaluated at a central laboratory facility for expression status of PD-L1 in a prospective manner. Only subjects whose tumors express PD-L1 as determined by the central laboratory facility will be eligible for inclusion in this study. Also it is highly recommend to send archival tumor tissue from the patient.

Arms:
arm 1: Patients who experienced progression disease while on treatment progression disease \< 12 weeks after stopping treatment. After that the patients took chemotherapy ≥ 4 cycles and progressed again. After the last progression the patient is included in the study to be retreated with Pembrolizumab 200mg arm 2: Stop treatment and progression \> 12 weeks after stopping treatment. After the last progression the patient is included in the study to be retreated with Pembrolizumab 200mg

Interventions: intervention 1: Pembrolizumab intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: 200 mg, Q3W intervention 2: 200 mg, Q3W

Protocol document:
Prot_SAP_000.pdf: 
REPLAY (GECP 17/02)_v 3.0_14 January 2019  
 
 
“A Phase II open-label multicenter exploratory study to assess 
-
advanced non - small cell lung cancer” REPLAY
NCT03526887 
 
 
Document Dates: Summary of Protocol Amendment Version 3.0:  
14th January 2019 
 


REPLAY_GECP 17/02_v.3.0_14_Jan_2019 
 
 
 
 
 
 
 
 
A PHASE II OPEN-LABEL MULTICENTER EXPLORATORY STUDY TO 
ASSESS EFFICACY OF PEMBROLIZUMAB RE-CHALLENGE AS SECOND 
OR FURTHER LINE IN PATIENTS WITH ADVANCED NON-SMALL CELL  
LUNG CANCER 
 
 
REPLAY: Re-challenge Pembrolizumab study 
 
 
 
 
 
Study Sponsor: Fundación GECP 
EudraCT Number: 2017-003947-39 
Sponsor code: GECP 17/02 
 
Version 3.0 
 
 
 
 
 
 
 
 
Contacts 


 
2 
REPLAY_GECP17/02_v.3.0_14_Jan_2019
Trial Chairs 
Principal Investigator 
  
Coordinator 
 
 
 
 
  
Oncology Service 
Hospital 12 de Octubre 
Avda. de Córdoba s/n 
 
 
 
Safety and Regulatory Affairs 
Coordinating office of 
the Fundación GECP 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 
Tel. 93 430 20 06 
Fax. 93 419 17 68 
Email: pharmacovigilance.slcg@gecp.org 
Coordinating office of the 
Fundación GECP 
Monitoring team 
Monitor/CRA 
 
 
 
Monitor/CRA 
 
 
 
Lead CRA 
 
 
 
Project Manager 
 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 
 
 
 
 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 
 
 
 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 
Tel. 93 430 20 06ext: 206 
 
 
Eva Pereira 
Avenida Meridiana 358, 6ªplanta 
08027 Barcelona 


 
3 
REPLAY_GECP17/02_v.3.0_14_Jan_2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
4 
REPLAY_GECP17/02_v.3.0_14_Jan_2019
Protocol Signature Page 
A PHASE II OPEN-LABEL MULTICENTER EXPLORATORY STUDY TO 
ASSESS EFFICACY OF PEMBROLIZUMAB RE-CHALLENGE AS SECOND 
OR FURTHER LINE IN PATIENTS WITH ADVANCED NON-SMALL CELL 
LUNG CANCER
REPLAY: Re-challenge Pembrolizumab study
Sponsor code: GECP 17/02 
Approved by: 
 
 


 
 
5 
REPLAY_GECP17/02_v.3.0_14_Jan_2019 
Principal Investigator Protocol Signature Page 
 
Study Title: A Phase II open-label multicenter exploratory study to assess efficacy of 
Pembrolizumab re-challange as second or further line in patients with advanced non - 
small cell lung cancer   REPLAY 
Sponsor protocol code: GECP 17/02 
EudraCT Number: 2017-003947-39 
Protocol version: v 3.0, 14th January 2019 
 
As principal investigator of this site, I hereby confirm that: 
I have read the protocol and agree that it contains all necessary details for conducting this trial. I will 
conduct the trial as outlined in the following protocol and in compliance with GCP, and will apply 
due diligence to avoid protocol deviations.  
 
I will provide copies of the protocol and all drug information relating to pre-clinical and prior clinical 
experience furnished to me by the Fundación GECP, to all physicians responsible to me who 
participate in this trial. I will discuss this material with them to assure that they are fully informed 
regarding the drug and the conduct of the trial.  
 
I agree to keep accurate records on all patient information including patient's informed consent 
statement, drug shipment and return forms, and all other information collected during the trial for a 
minimum period of 25 years according to the new Royal Decree 1090/2015 approved in Spain. 
 
Name of Principal Investigator:___________________________________ 
 
 name and place:_____________________________________ 
______________ 
 
 
Signature                                                                              Date 
 
 
 
 


 
 
6 
REPLAY_GECP17/02_v.3.0_14_Jan_2019 
 
INDEX 
 
1.0 TRIAL SUMMARY ....................................................................................................................................... 9 
2.0 TRIAL DESIGN ........................................................................................................................................... 10 
2.1 TRIAL IDENTIFICATION ............................................................................................................................... 10 
2.2 PATIENT SELECTION DIAGRAM .................................................................................................................... 10 
3.1 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)PRIMARY OBJECTIVE(S) & HYPOTHESIS(ES) ....................... 12 
3.2 SECONDARY OBJECTIVE(S) &HYPOTHESIS(ES) ........................................................................................... 12 
3.3 EXPLORATORY OBJECTIVE ......................................................................................................................... 12 
3.4 TRIAL STUDY CENTERS ............................................................................................................................... 13 
3.5 TRIAL DURATION ........................................................................................................................................ 13 
3.6 SPONSOR DETAILS AND MONITOR IDENTIFICATION ..................................................................................... 13 
4.0 BACKGROUND & RATIONALE ............................................................................................................. 13 
4.1 BACKGROUND AND RATIONALE .................................................................................................................. 13 
4.2 PHARMACEUTICAL AND THERAPEUTIC BACKGROUND ............................................................................... 16 
4.3 PRECLINICAL AND CLINICAL TRIAL DATA .................................................................................................. 17 
4.4 RATIONALE FOR THE TRIAL AND SELECTED SUBJECT POPULATION ........................................................... 17 
4.5 RATIONALE FOR DOSE SELECTION/REGIMEN/MODIFICATION .................................................................... 18 
4.6 RATIONALE FOR ENDPOINTS ....................................................................................................................... 20 
4.7 EFFICACY ENDPOINTS................................................................................................................................. 20 
4.8 BIOMARKER RESEARCH .............................................................................................................................. 21 
5.0 METHODOLOGY ....................................................................................................................................... 22 
5.1 ELIGIBILITY CRITERIA ................................................................................................................................ 22 
5.1.1 Subject Inclusion Criteria .................................................................................................................. 22 
5.1.2 Subject Exclusion Criteria ................................................................................................................. 24 
5.2 TRIAL TREATMENTS ................................................................................................................................... 27 
5.3 DOSE SELECTION/MODIFICATION ............................................................................................................... 27 
5.3.1 Dose Selection .................................................................................................................................... 27 
5.3.2 Dose Modification (Escalation/Titration/Other)................................................................................ 27 
5.4 TIMING OF DOSE ADMINISTRATION AND TRIAL COMPLIANCE ..................................................................... 30 
5.5 TRIAL BLINDING/MASKING ........................................................................................................................ 30 
5.6 RANDOMIZATION OR TREATMENT ALLOCATION ........................................................................................ 31 
5.7 STRATIFICATION ......................................................................................................................................... 32 
5.8 CONCOMITANT MEDICATIONS/VACCINATIONS (ALLOWED & PROHIBITED) ................................................ 32 
5.8.1 Acceptable Concomitant Medications ................................................................................................ 32 
5.8.2 
Prohibited Concomitant Medications ........................................................................................... 32 
5.8.3 Rescue Medications & Supportive Care ............................................................................................ 33 
5.8.3.1 Supportive Care Guidelines ............................................................................................................ 33 
5.9 DIET/ACTIVITY/OTHER CONSIDERATIONS .................................................................................................. 37 
5.9.1 Diet..................................................................................................................................................... 37 
5.9.2 Contraception .................................................................................................................................... 37 
5.9.3 Use in Pregnancy ............................................................................................................................... 39 
5.9.4 Use in Nursing Women ...................................................................................................................... 40 
5.10 SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA ............................................................................. 40 
5.11 DISCONTINUATION OF STUDY THERAPY AFTER CR .................................................................................. 41 
5.12 CLINICAL CRITERIA FOR EARLY TRIAL TERMINATION ............................................................................. 41 


 
 
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REPLAY_GECP17/02_v.3.0_14_Jan_2019 
6.0 TRIAL FLOW CHART ............................................................................................................................... 42 
7.0 TRIAL PROCEDURES ............................................................................................................................... 44 
7.1 TRIAL PROCEDURES .................................................................................................................................... 44 
7.2 ADMINISTRATIVE PROCEDURES .................................................................................................................. 44 
7.2.1 Informed Consent ............................................................................................................................... 44 
7.2.2 Inclusion/Exclusion Criteria .............................................................................................................. 45 
7.2.3 Medical History ................................................................................................................................. 45 
THE INVESTIGATOR OR QUALIFIED DESIGNEE WILL OBTAIN PRIOR AND CURRENT DETAILS REGARDING DISEASE 
STATUS. ............................................................................................................................................................ 45 
7.2.4 Prior Medications .............................................................................................................................. 45 
7.2.5 Concomitant Medications .................................................................................................................. 45 
7.4 ASSIGNMENT OF SCREENING NUMBER ....................................................................................................... 45 
7.5 CLINICAL PROCEDURES/ASSESSMENTS ...................................................................................................... 46 
7.5.1 Adverse Event (AE) Monitoring ......................................................................................................... 46 
Please refer to section 7.7 for detailed information regarding the assessment and recording of AEs7.5.2 
Full Physical Exam ..................................................................................................................................... 46 
7.5.4 Vital Signs .......................................................................................................................................... 46 
7.5.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale ................................................. 46 
7.5.6 Tumor Imaging and Assessment of Disease ....................................................................................... 47 
7.5.7 Tumor Tissue Collection and Correlative Studies Blood Sampling ................................................... 47 
Detailed instructions for tissue collection, processing and shipment are provided in the Samples Manual. 
7.5.8 Laboratory Procedures/Assessments ................................................................................................. 47 
7.5.9 Blood Collection for Serum Pembrolizumab ..................................................................................... 49 
7.6 OTHER PROCEDURES .................................................................................................................................. 49 
7.6.1 Withdrawal/Discontinuation .............................................................................................................. 49 
ANY ADVERSE EVENTS WHICH ARE PRESENT AT THE TIME OF DISCONTINUATION/WITHDRAWAL SHOULD BE 
FOLLOWED IN ACCORDANCE WITH THE SAFETY REQUIREMENTS, OUTLINED IN SECTION 7.7 ASSESSING AND 
RECORDING ADVERSE EVENTS......................................................................................................................... 49 
7.6.2 VISIT REQUIREMENTS .............................................................................................................................. 49 
7.6.3 Screening ........................................................................................................................................... 49 
7.6.4 Screening Period ................................................................................................................................ 49 
7.6.5 Treatment Period ............................................................................................................................... 49 
7.6.6 Post-Treatment Visits ......................................................................................................................... 49 
7.6.7 Safety Follow-Up Visit ....................................................................................................................... 49 
7.6.8 Follow-up Visits ................................................................................................................................. 50 
7.6.9 Survival Follow-up ............................................................................................................................. 50 
7.7 ASSESSING AND RECORDING ADVERSE EVENTS ......................................................................................... 50 
7.7.1   Main adverse events related to Pembrolizumab .............................................................................. 52 
7.7.2Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor and to MSD. 
Reporting of pregnancy ............................................................................................................................... 52 
7.7.2.1Reporting of overdose ...................................................................................................................... 52 
7.7.2.2Reporting of Pregnancy and Lactation to the Sponsor and to Merck .............................................. 53 
7.8IMMEDIATE REPORTING OF ADVERSE EVENTS TO THE SPONSOR AND TO MERCK ....................................... 53 
7.8.1 
Definition of Serious Adverse Event (SAE) ................................................................................... 53 
7.8.2 Events of Clinical Interest .................................................................................................................. 55 
7.8.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting .................................................... 56 
7.9 
COMMUNICATION OF ADVERSE EVENTS ................................................................................................. 56 
REPORTING SAE AND TARGETED ADVERSE EVENTS TO THE SPONSOR (FUNDACIÓN GECP (SLCG/GECP)) ... 57 
7.10SPONSOR RESPONSIBILITY FOR REPORTING ADVERSE EVENTS ................................................................. 61 
8.0 STATISTICAL ANALYSIS PLAN ............................................................................................................ 61 
8.1 STATISTICAL ANALYSIS PLAN SUMMARY................................................................................................... 61 


 
 
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REPLAY_GECP17/02_v.3.0_14_Jan_2019 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ........................ 62 
9.1 INVESTIGATIONAL PRODUCT ...................................................................................................................... 62 
9.2 PACKAGING AND LABELING INFORMATION ................................................................................................ 62 
9.3 CLINICAL SUPPLIES DISCLOSURE ............................................................................................................... 62 
9.4 STORAGE AND HANDLING REQUIREMENTS ................................................................................................. 62 
9.5 RETURNS AND RECONCILIATION................................................................................................................. 62 
10.0 ETHICAL ASPECTS AND REGULATORY DETAILS ....................................................................... 63 
10.1 GENERAL CONSIDERATIONS ..................................................................................................................... 63 
10.2 PROTOCOL APPROVAL BY ETHIC COMMITTEE AND HEALTH AUTHORITY ................................................. 63 
10.3 CONFIDENTIALITY AND DATA PROTECTION .............................................................................................. 63 
10.4 COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS POSTING REQUIREMENTS ................................. 64 
10.5 INSURANCE POLICY ................................................................................................................................... 64 
10.6 STUDY MONITORING ................................................................................................................................. 64 
10.7 PUBLICATION POLICY ............................................................................................................................... 64 
11.0 APPENDICES............................................................................................................................................. 65 
11.1 ECOG PERFORMANCE STATUS ................................................................................................................. 65 
11.2 COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.0 (CTCAE) ............................................ 65 
11.3 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 CRITERIA FOR EVALUATING 
RESPONSE IN SOLID TUMORS ........................................................................................................................... 65 
11.4 SAE FORM AND PREGNANCY FORM .......................................................................................................... 66 
REFERENCES ................................................................................................................................................... 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
9 
REPLAY_GECP17/02_v.3.0_14_Jan_2019
1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab(MK-3475) re-challenge as second or further line
in patients with advanced non - small cell lung cancer 
Trial Phase 
Phase II 
Clinical Indication 
 Second or further line treatment in advanced NSCLC patients 
Trial Type 
 Exploratory study 
Trial Identification 
 Sponsor Code: GECP 17/02; Short name: REPLAY; MSD code: 345-
726 
Type of control 
 Not Applicable 
Route of administration 
 Intravenous 
Trial Blinding 
 Open label 
Treatment Groups  
2 groups depending on when the progression disease is diagnosed
but the treatment after progression will be the same:
Pembrolizumab 
Number of trial subjects 
110 
Number of participant sites 
19 sites in Spain 
Estimated enrollment period 2 years 
Estimated duration of trial 
The sponsor estimates that the trial will require approximately 4
years (2 years of inclusion period  + 1 year to achieve (FPLV) + 1
year of follow up) 
Duration of Participation 
Each subject will participate in the trial from the time the subject
signs the Informed Consent Form (ICF) through the final protocol-
specified contact. Estimated period of time of two years per
patient. 
Estimated average length of
treatment per patient 
  According 
to 
previous 
data 
of 
patient 
treated 
with
Pembrolizumab, the estimated average length of the treatment is
approximately 7 to 10 months. 
Sponsor details 
Fundación GECP 
Avenida Meridiana 358, 6ª planta, 08027 Barcelona (Spain) 
 
 
 
 
 
 
 
 


 
 
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REPLAY_GECP17/02_v.3.0_14_Jan_2019 
2.0 TRIAL DESIGN 
2.1 Trial Identification 
Sponsor code: GECP 17/02 
Eudract: 2017-003947-39 
Protocol title: A Phase II open-label multicenter exploratory study to assess efficacy of 
Pembrolizumab re-challenge as second or further line in patients with advanced non - 
small cell lung cancer  REPLAY 
2.2 Patient selection diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Progression after chemotherapy treatment will not be mandatory 
REPLAY: Re-Treatment 
with Pembrolizumab 
Advanced/metastatic NSCLC 
>1st line who have failed prior 
PD1/PDL1 checkpoint inhibitor 
  
Non-responders
Response or Stable Disease  
for at least > 16 weeks  
Cohort 2
Stop treatment and 
PD > 12 weeks after stopping treatment  
Re-Treatment with 
Pembrolizumab 
Experience PD while on 
treatment  
OR 
PD < 12 weeks after 
stopping treatment 
Cohort 1
(free election for the PI)
PD* 
PD
PD


 
 
11 
REPLAY_GECP17/02_v.3.0_14_Jan_2019 
2.3 Trial diagram design 
 
This is a multi-center exploratory phase II trial of intravenous (IV) Pembrolizumab MK-3475 
as second or further line with advanced Non-small cell Lung Cancer (NSCLC) who have failed 
to a prior treatment with anti-PDL1 drug. 110 patients will be enrolled in this trial to 
examine the efficacy and outcomes of these patients. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart. - Section 5.0. Details of each 
procedure are provided in Section 6.0 
 Trial Procedures. In addition to the usual 
procedures in a phase II study (evaluation of response, toxicity, etc.) special attention will 
be paid in this trial to the molecular assessment in biological samples. 
Subjects will receive Pembrolizumab at a fixed dose of 200 mg every 3 weeks (Q3W) 
Subjects will be evaluated with radiographic imaging to assess response to treatment. 
Investigators will make all treatment-based decisions using the Immune-Related Response 
Criteria (irRC). However, for determination of overall response rate (ORR) and progression-
free survival (PFS), the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be 
used. Adverse events will be monitored throughout the trial and graded in severity 
according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. Treatment with Pembrolizumab will continue until documented 
disease progression, unacceptable adverse event(s), intercurrent illness that prevents 
further administration of treatment, 
 decision to withdraw the subject, subject 
withdraws consent, noncompliance with trial treatment or procedure requirements, or 
administrative reasons. After the end of treatment, each subject will be followed for a 
minimum of 30 days for adverse event monitoring (serious adverse events will be collected 
for up to 90 days after the end of treatment unless the subject starts a new anticancer 
therapy between days 31 and 90). Subjects will have post-treatment follow-up for disease 
status, including initiating a non-study cancer treatment and experiencing disease 
progression, until death, withdrawing consent, or becoming lost to follow-up. 
Participation in this trial will be dependent upon supplying tumor tissue from a newly 
obtained formalin-fixed specimen from locations not radiated prior to biopsy. The specimen 
will be evaluated at a central laboratory facility for expression status of PD-L1 in a 
prospective manner. Only subjects whose tumors express PD-L1 as determined by the 
central laboratory facility will be eligible for inclusion in this study. Also, it is highly 
recommended to send archival tumor tissue from the patient. 
 


 
 
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REPLAY_GECP17/02_v.3.0_14_Jan_2019 
3.1 3.0 OBJECTIVE(S) & HYPOTHESIS(ES)Primary Objective(s) & Hypothesis(es) 
 
- To evaluate the efficacy of Pembrolizumab re-challenge administered 200 mg iv every 
21 days in second or further line for advanced NSCLC after progression tocheck point 
PD1 / PDL1 inhibitors measured by Overall Response Rate (ORR) per RECIST v1.1 and per 
modified RECIST(irRC). 
Hypothesis:  Patients that have exhibit benefit to check point PD1 / PDL1 inhibitors may 
benefit from further Pembrolizumab therapy at the time of progression. The degree of 
benefit may depend on the initial response to previous check point PD1 /PDL1 inhibitors 
and its duration, and to the intercalation (or not) of any additional treatments such as 
chemotherapy among those patients without benefit to check point PD1/PDL1 
inhibitors. 
3.2 Secondary Objective(s) &Hypothesis(es) 
 
- To evaluate the efficacy of Pembrolizumab re-challenge administered 200 mg iv 
every 21 days in second or further line for advanced NSCLC after progression to 
check point PD1 / PDL1 inhibitors measured by Progression Free Survival (PFS)  per 
RECIST v1.1 and per modified RECIST. and Overall Survival (OS). 
 
 
 
- To evaluate the safety and tolerability profile of Pembrolizumab re-challange 
administered  200 mg iv every 21 days in second or further line for advanced NSCLC 
after  progression to check point PD1 / PDL1 inhibitors measured by Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 ( U.S. Department of 
Health and Human Services - National Cancer  
Institute - National Institutes of 
Health )  
 
3.3 Exploratory Objective 
 
 
- To evaluate predictive and prognostic exploratory biomarkers in archival or newly 
obtained formalin-fixed specimen and blood and their association with disease status 
and/or response to treatment.  
 


 
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REPLAY_GECP17/02_v.3.0_14_Jan_2019
3.4 Trial Study centers 
This trial will be carried out in 19 participant study sites in Spain. 
3.5 Trial duration 
 
Approximately 4 years (2 years of inclusion period  + 1 year to achieve (FPLV) + 1 year of follow 
up). 
3.6 Sponsor details and monitor identification 
 
Sponsor 
Fundación GECP 
Avenida Meridiana 358, 6ª  planta 
08027 Barcelona 
Monitors 
 
Fundación GECP 
Avenida Meridiana 358, 6ª  planta 
08027 Barcelona 
 
4.0 BACKGROUND & RATIONALE 
4.1 Background and rationale 
Lung cancer is the leading cause of cancer related deaths among men and women 
worldwide, with 1.2 million new cases diagnosed each year. Non-small cell lung cancer 
(NSCLC) is the most common type of lung cancer, accounting for 80% of all new cases. There 
are an estimated 1.1 million lives lost per year (approximately 500,000 in the United States 
and European Union alone) due to NSCLC. 


 
 
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REPLAY_GECP17/02_v.3.0_14_Jan_2019 
The majority of patients are not diagnosed until the tumor has progressed beyond the 
primary site. Despite step-wise advances in patient selection, targeted agents and 
optimizing chemotherapy regimens, patients with advanced NSCLC continue to have an 
unmet medical need (1). 
Platinum containing chemotherapy regimens remain the standard first line treatment in the 
majority of patients in the US and Japan. For first line therapy in patients with Stage IV 
NSCLC and good performance status, the American Society of Clinical Oncology (ASCO) 
clinical practice guideline recommends treatment with a platinum based two drug 
combination of cytotoxic drugs (2). For patients without disease progression, the option of 
maintenance monotherapy pemetrexed or erlotinib could also be considered (3). A trend 
that is becoming more prevalent is personalized NSCLC treatment based on tumor histology 
(squamous versus non squamous), on molecular characteristics of the tumor, and on the 
 clinical status using agents targeting specific receptors and kinases and pathways 
(ie, epidermal growth factor receptor [EGFR], echinoderm microtubule associated protein 
like 4 [EML4] and anaplastic lymphoma kinase [ALK] fusion protein). 
In second-line NSCLC, single agent chemotherapy (pemetrexed, EGFR-inhibitors and 
taxanes) are standards of care for treatment of patients with locally advanced or metastatic 
NSCLC after failure of prior platinum-based chemotherapy. Docetaxel has been widely 
evaluated in this setting and is currently approved by the US Food and Drug Administration 
(FDA) and the European Medicines Agency (EMA) as a single agent for the treatment of 
patients with locally advanced or metastatic non-small cell lung cancer after failure of prior 
platinum-based chemotherapy. For patients with a good performance status at the time of 
disease progression following first-line chemotherapy, docetaxel, despite a low response 
rate, is associated with a 10% to 20% prolongation of 1-year survival and an improved 
quality of life when compared with ifosfamide, vinorelbine, or BSC alone (4). Erlotinib is 
indicated for the treatment of patients with locally advanced or metastatic NSCLC after 
failure of at least one prior chemotherapy regimen. Pemetrexed is indicated as a single-
agent for the treatment of patients with locally advanced or metastatic nonsquamous 
NSCLC after prior chemotherapy.  
The programmed death receptor 1 (PD-1) is a key immune checkpoint receptor expressed 
by activated T cells that modulates a late stage of the immune response by negatively 
regulating the activation of T cells in peripheral tissues. The PD-1 receptor-ligand interaction 
is a major pathway hijacked by tumors to suppress immune control. PD-1 is an 
immunoglobulin (Ig) superfamily member related to CD28 and CTLA-4 which has been 
shown to negatively regulate antigen receptor signaling upon engagement of its ligands PD-
L1 and/or PD-L2 (5,6). 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 responsible for the binding of signaling molecules. Following T cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules which are 


 
 
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REPLAY_GECP17/02_v.3.0_14_Jan_2019 
involved in the CD3 T cell signaling cascade (6, 7, 8). The mechanism by which PD-1 down 
modulates T cell responses is similar to, but distinct from, that of CTLA-4, as both molecules 
regulate an overlapping set of signaling proteins (9). 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 (10). Expression has also been shown during thymic development on CD4-
CD8- (double negative) T cells, as well as subsets of macrophages and dendritic cells (11). 
The ligands for PD-1 (PD-L1 (B7-H1) and PD-L2 (B7-DC)) are constitutively expressed or can 
be induced in a variety of cell types including non-hematopoietic tissues and in various 
tumors (9,12, 13,14). Binding of either PD-L1 or PD-L2 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 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 PDL1 serves to dampen T cell function in peripheral tissues (9). 
Although healthy organs express little PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T cell inhibitor. High expression of PD-L1 on tumor cells has 
been found to correlate with poor prognosis and survival in various cancer types ( 15, 16). 
PD-L1 expression was described in many cancer types and in particular in lung cancer where 
up to 50% of NSCLCs are reported to express PD-L1 (17, 18, 19). High expressers of PD-L1 on 
IHC of tumor samples appear to get the best benefit from PD-1 or PD-L1 inhibitors although 
the benefit is not exclusive to this group (20, 21, 22, 23) 
Antibody directed therapies against check point PD1/PDL1 have demonstrated efficacy in 
some malignancies, and now are true options in management of metastatic lung cancer. 
Two monoclonal antibodies directed to PD-1 (Nivolumab, Pembrolizumab) have reach the 
clinical practice as second line options for NSCLC. Also, monoclonal antibodies directed to 
PDL1 /PD1 (Atezolizumab, Durvalumab, Avelumab, Pidilizumab) are under investigational 
exploration. Three anti-PD-1 (Nivolumab, Pidilizumab, Pembrolizumab) and four anti-PD-L1 
(BMS-936559, Durvalumab, Atezolizumab, Avelumab) antibodies have been investigated in 
phase I studies and are under further development in NSCLC (24). In all phase I trials, the 
maximum-tolerated dose was not reached, and all doses were found to be safe. The 
frequency of immune-related toxicities from anti PD-1/anti PD-L1 treatments appears less 
than that from anti-CTLA4 treatment. The common drug-related AEs were decreased 
appetite, anemia, diarrhea, nausea, pruritus, fatigue, pneumonitis, and elevated 
transaminase (25, 26, 27, 28, 29, 30).  
The clinical efficacy of check point PD1/PDL1 inhibitors has been tested and confirmed in 
four randomized clinical trials. Two phase III trial to compare Nivolumab versus docetaxel in 
patients that have progression to doublet platinum-based chemotherapy, both squamous 
or non-squamous NSCLC (20, 21). In the squamous trial Nivolumab resulted in improved 
overall survival (HR, 0.59, p< 0.001; median 9.2 vs 6 months), PFS (HR: 0.62, p<0.001; 
median 3.5 vs 2.8 months) and RR (20% vs 9%; p<0.008). The preplanned analysis for 


 
 
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efficacy and survival for PDL1 positive or negative resulted in global benefit for both groups 
(20). In the non-squamous trial Nivolumab resulted in improved OS (HR, 0.73. p<0.002; 
median 12.2 vs 9.4 months) and RR (19% vs 12%, p<0.02) but not PFS benefit was shown in 
global population. The preplanned analysis for efficacy and survival for PDL1 status emerged 
as a significant biomarker to determine Nivolumab benefit; patients with PDL1 positive 
doubled median OS when treated in the experimental arm versus docetaxel. On the other 
group of PDL negative there was a trend in PFS benefit and RR but there was no difference 
in OS between Nivolumab or Docetaxel (21). Another PD1 check point inhibitor also 
confirmed in a phase III randomized trial  Keynote 010 - comparing Pembrolizumab (two 
doses levels) versus docetaxel in patients that have progression to doublet platinum-based 
chemotherapy but limited to patients that expressed PDL1 (at least >1% of cells). OS was 
longer for Pembrolizumab versus Docetaxel (for 2 mg/kg dose HR, 0.71 p<0.0008; median 
10.4 vs 8.5 months and for 10 mg/kg dose HR, 0.61 p<0.0001; median 12.7 vs 8.5 months). 
Similar to Nivolumab there was no significant PFS benefit. Among patients with at least 50% 
of tumor cells expressing PD-L1, OS was significantly longer with Pembrolizumab (HR, 0.54 
p=0.0002; median 14.9 vs 8.2 months and HR, 0.50 p<0.0001; median 17.3 vs 8.2 months) 
(22). Based on previous data Nivolumab and Pembrolizumab have been approved for the 
treatment of patients with advanced disease that have progressed to first line 
chemotherapy. Atezolizumab, an anti PDL1 check point inhibitor showed consistent benefit 
over docetaxel in a phase II randomized trial in patients that have progressed to first or 
second-line chemotherapy (31) 
Refer to the 
 Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 
4.2 Pharmaceutical and Therapeutic Background 
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. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PDL2).  
The structure of murine PD-1 has been resolved.  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 


 
 
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immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD1 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 
 
 and ZAP70 which are involved 
in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins. 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.  Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors .  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.  Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of 
this T-cell inhibitor.  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. 
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.  KeytrudaTM (pembrolizumab) has been approved in the United 
Stated and by 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. Also, it was approved for first and second-line lung cancer, head and neck cancer, 
and relapsed/refractory 
 disease..  
4.3 Preclinical and Clinical Trial Data 
Refer to the 
 Brochure for Preclinical and Clinical data. 
4.4 Rationale for the Trial and Selected Subject Population 
Lung cancer remains the most common cause of cancer related death in US and second one 
of the majors causes of cancer related death in EU. Despite latest progress with check point 
PD1/PDL1 inhibitors many patients still experience progression, recurrence disease  or 
primary resistance being a challenge the treatment options of these patients. As previously 
explained PDL1 has been correlated with prognosis fueling the hypothesis that PDL1 


 
 
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expression is a mechanism for tumor immune evasion. Additionally PD1 is highly expressed 
on infiltrating human and circulating tumor specific T cells, a phenotype correlated with 
impaired T cell function (32, 33) These findings suggest that interrupting PD1-PDL1 
interaction after progression could be an effective anticancer therapy in the context of 
immuno-editing: a)PD1 blockade, similar to CTL4 inhibition has the potential to establish a 
favorable equilibrium between adequate T cell response against the tumor and immune 
evasion by the tumor; b) tumor recurrence after successful treatment with PD1 blockade 
indicates disruption of this equilibrium; c) re-treatment with PD-1 inhibition after 
recurrence can reset this balance (34). Based on this rational Lipson reported a melanoma 
stage IV patient with good partial response to Nivolumab and after discontinuation of the 
drug the patient experienced progression; re induction with the same anti PD1 could swing 
immunological pendulum back in favor of the patient redirecting the immune system, after 
re treatment with Nivolumab again partial response was observed.  
 
Moreover, the mechanism of governing homeostasis of the memory T cells remain 
undefined.   Charlton published the crucial role of the negative co-stimulator PD1 in 
regulating developmental fates of memory phenotype cells. Thus, in lymphoid organs and 
tissues of PD1 knockout mice a marked accumulation of functional effector memory 
phenotype CD8 T cells was observed. CD8 T effector memory cells from PD1 knockout mice 
exhibit decreased proliferation but increased survival potential. In a elegant way is shown 
that the ablation of the PD1 pathway drives CD8 memory phenotype to CD8 T effector 
memory cells. That implies that increased duration of signal, in the absence of PD1, favors 
CD8 T effector memory cells differentiation through a T cell central memory (35) 
 
For those tumors that experience primary resistant to check point PD1/PDL1 inhibitors as 
pancreatic cancer Winograd and colleagues reported their experience using a genetically 
engineered mouse model of pancreatic ductal adenocarcinoma, showing that PDL1 is 
prominent in the tumor microenvironment, a phenotype confirmed in patients. But 
treatment with check point PD1 monoclonal antibodies failed in well-established tumors, 
recapitulating clinical results. The combination of anti CD40 antibody and chemotherapy 
(especially gemcitabine) plus check point PD monoclonal antibody induced regression of 
subcutaneous tumors and improved OS. This finding suggests that in those patients with 
primary resistant to check point PD1/PDL1 inhibitors can be rescued by the priming of a T 
cell response with chemotherapy (36). 
 
 
4.5 Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of MK-3475 showed evidence of target 


 
 
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engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 
mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, was the dose and schedule utilized in Cohorts A, B, C and D of 
this protocol to test for initial tumor activity.  Recent data from other clinical studies within 
the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the 
range observed for other antibodies and would support both body weight normalized 
dosing or a fixed dose across all body weights.  MK-3475 has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg 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 MK-3475 
in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 
mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed 
that there was no significant impact of tumor burden on exposure. In addition, exposure 
was similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of 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. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab showing 
that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain 


 
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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. 
 
4.6 Rationale for Endpoints 
Current experience with immunomodulatory treatments shows that the objective response 
rate ant the progression-free survival may not correlate with the final clinical benefit for the 
patients, in terms of overall survival.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
4.7 Efficacy Endpoints 
ORR is the portion of patients with a tumor size reduction of a predefined amount for a 
minimum time period. Response duration is measured from the time of initial response 
until documented tumor progression. The FDA has generally defined RR as the sum of 
partial responses (PRs) and CRs. When defined in this manner, ORR is a direct measure of 
the 
 antitumor activity. Stable disease is not included in the ORR. Stable disease is 
optimally evaluated in randomized trials examining TTP or PFS. The selected response 
criteria to be used in registration trials should be prospectively discussed with the FDA. 
When comparing ORRs in different arms, the number of PRs and CRs, response durations, 
locations of responses, and associations between responses and symptom improvement 
should be examined. The clinical significance of the ORR should be assessed by the 
magnitude and duration in a risk-benefit analysis. 
The progression-free survival (PFS) duration is defined as the time from randomization to 
objective tumor progression or death. Compared with TTP, PFS may be a preferred 
regulatory endpoint because it includes death and may correlate better with OS. In TTP 
analysis, deaths are censored either at the time of death or at an earlier visit. Assessment of 
either PFS or TTP needs to be conducted in randomized trials. Because of the subjectivity 
that may be introduced in endpoint assessment, blinding of trials or the use of an external 
blinded review committee is recommended. In assessing TTP or PFS, patients must be 
evaluated on a regular basis in all treatment arms, and an assessment of all disease sites 
should be performed. To reduce bias, the same assessment technique should be used at 
each follow-up, and the same evaluation schedule should be consistently used. 
OS is the gold standard for demonstrating clinical benefit. Defined as the time from 
randomization to death, this endpoint is unambiguous and is not subject to investigator 


 
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interpretation. Survival is a direct clinical benefit to patients, and assessment can be 
calculated to the day. Patient benefit can be described as superior survival or noninferior 
survival after consideration of toxicity and the magnitude of benefit. Survival analysis 
requires a large sample size and may require long follow-up. 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
-
 
 
 
  
 
  
 
  
 
 
 
 
 


 
 
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5.0 METHODOLOGY 
 
5.1 Eligibility Criteria 
 
 
5.1.1 Subject Inclusion Criteria 
 
1. Patients with hystologically or cythologically confirmed NSCLC advanced or locally 
advanced disease (according to 8th version of the International Association for the 
Study of Lung Cancer Staging Manual in Thoracic Oncology) not amenable to radical 
treatment (IIIA, IIIB, IIIC, IV), squamous or non-squamous, recurrent after at least 
one prior line.   
2. The subject must be willing and able to provide written informed consent/assent for 
the trial. 
3. Patient must be aged  18 years of age on day of signing informed consent. 
4. Measurable disease (at least 1 lesion) based on RECIST 1.1. Patients will not be 
eligible if this lesion was irradiated before inclusion. 
5. Documented prior benefit (Stable Disease, Partial Response, Complete Response) to 
check point PD1/PDL1 inhibitor (Nivolumab, Pembrolizumab, Durvalumab, 
Atezolizumab, Avelumab or others) for at least 16 weeks (Stable Disease, Partial 
Response, Complete Response) and progression while on treatment (or <12 weeks 
after stopping) with the same PD-1/PD-L1 inhibitors. These patients should have 
received subsequent treatment with Chemotherapy for at least 4 courses (Cohort 1) 
OR 
Documented prior benefit (Stable Disease, Partial Response, Complete Response) to 
check point PD1/PDL1 inhibitor (Nivolumab, Pembrolizumab, Durvalumab, 
Atezolizumab, Avelumab or others) for at least 16 weeks (Stable Disease, Partial 
Response, Complete Response) and progression >12 weeks after stopping treatment 
(Cohort 2).  No subsequent treatment before re-challenge is allowed in this cohort 
6. Patient must be willing to provide tissue from a newly obtained core or excisional 
biopsy of a tumor lesion. PDL1 must be evaluable and at least 1% positive in tumor 
tissue.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) 
prior to initiation of treatment on Day 1.  Subjects for whom newly-obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may submit 
an archived specimen only upon agreement from the Sponsor.* 


 
 
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 NOTE: If a new sample core or excisional biopsy cannot be obtained but the patient has the PDL1 
analyzed and positive in a archival tissue sample the patient can be included in the study and start the 
treatment and the archival tumor tissue could be sent afterwards for central laboratory confirmation 
If no previous PDL1 result is available from the archival tissue, the patient cannot  be included in the 
trial until central laboratory PDL1 result is available. 
Other cases could be consulted with the trial chair. 
7. Have a performance status of 0-1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in Table 1, all screening labs 
should be performed within 7 days of treatment initiation.   
Table 1Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
 /mcL 
Platelets 
 / mcL 
Hemoglobin 
 g/dL or 
 mmol/L without transfusion or EPO
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
 X upper limit of normal (ULN) OR 
 
 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
 1.5 X ULN OR 
 
Direct bilirubin  ULN for subjects with total bilirubin 
levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
 2.5 X ULN  OR 
 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time
(aPTT) 
 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 


 
 
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9. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.   
10. Female subjects of childbearing potential (Section 5.9.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.9.2  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. 
11. Male subjects of childbearing potential (Section 5.9.2) must agree to use an 
adequate method of contraception as outlined in Section 5.9.2- Contraception, 
starting with the first dose of study therapy through 120 days after the last dose of 
study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
12. All patients will be required to submit a tumor sample for PD-L1 IHC expression. 
If the sample is inadequate for analysis, another sample could be provided. If a new 
sample cannot be obtained due to technical or clinical reasons, archival tissue can be 
sent. Other cases could be consulted with the trial chair. 
 
5.1.2 Subject Exclusion Criteria 
 
The subject must be excluded from participating in the trial if: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment. 
2. 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 
trial treatment. 
 
3. Has a known history of active TB  (Bacillus Tuberculosis) 


 
 
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4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. 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. 
6. 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. 
- 
Note:  Subjects with  Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects 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 any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, 
and are not using steroids at a dose over 10 mg of prednisone or equivalent, 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 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 (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
10. Has a history of (non-infectious) pneumonitis that required steroids or  current 
pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Documented EGFR sensitizing mutation. 
13. Documented ALK translocation. 


 
 
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14. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.   
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
16. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
19. Has received a live vaccine within 30 days of planned start of study therapy. 
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. 
20. Received radiation therapy to the lung of >30Gy within 6 months of the first dose of 
trial treatment.  
21. Evidence of interstitial lung disease. 
22. Has had previously serious adverse reactions (grade 3-4) related to previous PD1 / 
PDL1 inhibitors that preclude their treatment according to the principal 
 criteria 
 
 
 
 
 
 


 
 
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5.2 Trial Treatments 
 
The treatment to be used in this trial is outlined below in Table 2 
Table 2 Trial Treatment 
Drug 
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment
Period 
Use 
Pembrolizumab 200 mg  
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Chemotherapy will be at investigators choice.  
 
The treatment will continue until progression, unacceptable toxicity, consent withdraw, or 
until the treatment is administered during 24 months, whichever occurs first. 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Drug Supply Manual. 
5.3 Dose Selection/Modification 
5.3.1 Dose Selection 
 
The rationale for selection of doses to be used in this trial is provided in Section 4.0  
Background and Rationale.   
5.3.2 Dose Modification (Escalation/Titration/Other) 
 
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 3 below. See 
Section 5.8.3.1 for supportive care guidelines, including use of corticosteroids. 
Table 3  
Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab 
 
 


 
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5.4 Timing of Dose Administration and trial compliance 
 
 
 
 
 
 
 
  
 
 
The Drug Supply Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
 
 
 
 
 
 
 
5.5 Trial Blinding/Masking
 


 
 
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This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.6 Randomization or Treatment Allocation 
 
Step 1. Registration 
Upon signing the informed consent, patients will be registered, and a sample of the tumor 
will be shipped and evaluated for PD-L1 expression at the central laboratory.  
All patients will be required to submit a tumor sample for PD-L1 IHC expression. If the 
sample is inadequate for analysis, another sample could be provided. If a new sample 
cannot be obtained, archival tissue can be sent. Other cases could be consulted with the 
trial chair. 
 
If PDL1 status cannot be assessed by the central laboratory in the archival or newly 
obtained sample (not enough tissue available, not concluding result, etc.) patients with 
previous PDL1 positive analyzed before stating the trial, can be evaluated by  Trial Chair to 
grant the inclusion of the patient in the study.  
 
Detailed instructions for tissue collection, processing and shipment are provided in the 
samples manual. 
Step 2. Central Tumor Confirmation 
Confirmation of PD-L1 status will be provided by the central laboratory in 7 working days 
(DAKO IHC 22C3) if possible. 
Step 3. Treatment Allocation 
The confirmation of PD-L1 ( 
 expression must be available before proceeding with the 
Pembrolizumab treatment. The patient's written informed consent to undergo screening for 
the clinical trial must be given prior to the performance of any protocol laboratory/imaging 
tests that are not part of local routine guidelines. 
Once patients are confirmed to be eligible they will be automatically enrolled. 
A maximum of 110 eligible patients will be enrolled. 


 
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5.7 Stratification 
 
Patients will be stratified by PDL1 expression levels (TPS 1-49% vs TPS 
 50%) and 
Performance Status (PS 0 vs1). 
5.8 Concomitant Medications/Vaccinations (allowed & prohibited) 
 
 
   
 
 
   
  
 
  
5.8.1 Acceptable Concomitant Medications 
 
 
 
   
 
 
 
 
 
  
 
 
 
5.8.2
Prohibited Concomitant Medications
 
 
 
  


 
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5.8.3 Rescue Medications & Supportive Care 
5.8.3.1 Supportive Care Guidelines 
 
 
 
  
 
 
   
 
 
 
 
 
  


 
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-
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
-
 
 
 


 
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5.9 Diet/Activity/Other Considerations 
5.9.1 Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.9.2 Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known 
that pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 


 
 
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women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after 
the last dose of study drug by complying with one of the following:   
(1) Practice abstinence  from heterosexual activity;  
OR  
(2) Use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception that can achieve a failure rate of less than 1% are : 
Single method (one of the following is acceptable): 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
 
Vasectomy of a female 
 male partner  
 
   
Sexual abstinence combined (estrogen and progesterone containing) 
hormonal contraception associated with inhibition of ovulation:  
- 
Oral  
- 
Intravaginal 
- 
Transdermal 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
- Oral 
- Injectable 


 
 
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- Implantable 
 (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the 
 preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
 a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
Acceptable methods of contraception which may not be considered as highly effective are: 
 
 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
  
Male or female condom with or without spermicide 
  
Cap, Diaphragm or sponge with spermicide 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  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. 
5.9.3 Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the 
 status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor, and the 
sponsor will inform MSD Global Safety (GS) by fax (034 91 571 64 66) afterwards. 


 
 
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The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to the marketing authorization 
holder of the drug used in this trial and followed as described above. 
5.9.4 Use in Nursing Women 
 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.10 Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.   
Specific details regarding discontinuation or withdrawal are provided in section 7.6.1. 
A subject must be discontinued from the trial for any of the following reasons: 
- 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
- 
Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved. All 
these cases must be approved by Trial Chair before starting the treatment 
beyond progression. 
- 
Unacceptable adverse experiences  
- 
Intercurrent illness that prevents further administration of treatment 
- 
In
 decision to withdraw the subject 
- 
The subject has a confirmed positive serum pregnancy test 
- 
Noncompliance with trial treatment or procedure requirements 


 
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-
The subject is lost to follow-up 
-
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose.  
-
Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart).  After the end of treatment, each subject will be followed for 30 days for adverse 
event monitoring (serious adverse events will be collected for 90 days after the end of 
treatment as described in section 7.9.).  Subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost 
to follow-up.  After documented disease progression each subject will be followed by 
telephone for overall survival until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
5.11 Discontinuation of Study Therapy after CR 
 
 
 
   
5.12 Clinical Criteria for Early Trial Termination 
 
 
 
 
 
 
 
 
 
 


 
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6.0 TRIAL FLOW CHART 


 
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7.0 TRIAL PROCEDURES 
7.1 Trial Procedures 
 
The Trial Flow Chart- Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
 
 
 
 
 
7.2 Administrative Procedures 
7.2.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the 
 dated signature or by the 
 legally 
acceptable 
 dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the 
 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the 
 willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the 
 dated signature 
or by the 
 legally acceptable 
 dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   


 
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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
7.2.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.2.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
The investigator or qualified designee will obtain prior and current details regarding 
disease status. 
In the case of patients who have progressed to a metastatic stage after having been treated 
for early NSCLS stage, the investigator or qualified designee will review all prior cancer 
treatments including systemic treatments, radiation and surgeries.
7.2.4 Prior Medications 
 
 
 
.  
7.2.5 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.4 Assignment of Screening Number 
All screened subjects will be given a unique screening number that will be used to identify 
the subject throughout the screening phase. Each subject will be assigned only one 
screening number. Screening numbers must not be re-used for different subjects. Any 
subject who is screened multiple times will retain the original screening number assigned at 
the initial screening visit. 


 
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After the PDL1 analysis, if positive result in the archival or newly obtained sample or 
previous PDL1 positive result , the subject will be included in the data base (Case report 
form, CRF) of the study that will assign the final inclusion number of the subject. Also, the 
screening number will be recorded in the CRF.
 
7.5 Clinical Procedures/Assessments 
7.5.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 4.0.  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
 
 
 
     
 
 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening. 
 
 
 
7.5.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified 
in the Trial Flow Chart (section 6.0).  Vital signs should include temperature, pulse, 
respiratory rate, weight and blood pressure.  Height, weight and body surface will be 
measured at screening only. 
7.5.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart(section 6.0).   


 
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7.5.6 Tumor Imaging and Assessment of Disease 
 
 
 
 
 
  
 
. 
 
Imaging assessment will be performed more frequently if clinically indicated. 
 
 
  
 
 
  
 
 
 
 
7.5.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
 
 
 
  
 
 
 
   
 


 
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.  
7.5.9 Blood Collection for Serum Pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Blood Samples Manual. 
7.6 Other Procedures 
7.6.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.   
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements, outlined in section 7.7 Assessing and 
Recording Adverse Events.   
Subjects who a) attain a CR or b) complete 24 months of treatment with pembrolizumab 
may discontinue treatment with the option of restarting treatment if they meet the criteria 
specified.  After discontinuing treatment following assessment of CR, these subjects should 
return to the site for a Safety Follow-up Visit and then proceed to the Follow-Up Period of 
the study. 
7.6.2 Visit Requirements 
Visit requirements are outlined in Trial Flow Chart (section 6.0).   Specific procedure-related 
details are provided above in Trial Procedures. 
7.6.3 Screening 
7.6.4 Screening Period 
Screening period will be 28 days from ICF signature. 
7.6.5 Treatment Period 
Extension of treatment with Pembrolizumab will be up to 24 months.  
7.6.6 Post-Treatment Visits 
Follow up visits are outlined in Trial Flow Chart (section 6.0) 
7.6.7 Safety Follow-Up Visit 
 
, 


 
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7.6.8 Follow-up Visits 
 
 
 
 
 
 
    
7.6.9 Survival Follow-up 
 
 
 
  
7.6.10 Subsequent Anti-Cancer Therapy Status 
 
 
 
 
 
7.7 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to 
the medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the use of the 
s product, is also an adverse event. 


 
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Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
 
 
 
 
 
 
 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before beginning the 
treatment must be reported by the investigator if they cause the subject to be excluded 
from the trial or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation 
of treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms.  The investigator 
will make every attempt to follow all subjects with non-serious adverse events for 
outcome. The reporting timeframe for adverse events meeting any serious criteria will be 
described in next sections. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs.) 
The severity and causality will be classified according to the NCI CTCAE v.5 The CTCAE is 
available for downloading on the internet, see Appendix 11.2. 
 
The adverse event severity grade provides a qualitative assessment of the extent or 
intensity of an adverse event, as determined by the investigator or as reported by the 
patients.  The severity grade does not reflect the clinical seriousness of the event, only the 
degree or extent of the affliction or occurrence (e.g. severe nausea, mild seizure), and does 
not reflect the relationship to study drug. 
 
 
 
 


 
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Severity grade for other adverse events not covered in the toxicity grading scale: 
 
1 = Grade 1 
Mild 
2 = Grade 2 
Moderate 
3 = Grade 3 
Severe 
4 = Grade 4 
Life-threatening 
5 = Grade 5 
Fatal 
 
7.7.1   Main adverse events related to Pembrolizumab 
 
 
 
. 
7.7.2Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to MSD. Reporting of pregnancy 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  


 
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7.7.2.2Reporting of Pregnancy and Lactation to the Sponsor 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if they cause the 
subject to be excluded from the trial or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of 
 product, or 30 days following cessation 
of treatment, 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. 
 
7.8Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.8.1
Definition of Serious Adverse Event (SAE) 
A Serious Adverse Event is defined as any untoward medical occurrence that at any dose:  
results in death (fatal due to any cause) 
is life-threatening or places the subject, in the view of the investigator, at 
immediate risk of death from the event as it occurred (Note: This does not 
include an adverse event that, had it occurred in a more severe form, might have 
caused death.)Results in or prolongs an existing inpatient hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay, 
even if the hospitalization is a precautionary measure for continued observation. 
(Note: Hospitalization for an elective procedure to treat a pre-existing condition 
that has not worsened is not a serious adverse event.  A pre-existing condition is 
a clinical condition that is diagnosed prior to the use of IMP and is documented 
 
results in persistent or significant disability/incapacity 


 
 
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 is a congenital anomaly/birth defect  
 is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but 
are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)  
 Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE.  
 Although pregnancy, overdose (defined as accidental or intentional dose of a 
product that is considered both excessive and medically important), and cancer 
are not always serious by regulatory definition, these events must be handled as 
SAEs. 
Second malignancies are always considered SAEs, no matter when they are diagnosed. 
These events should be reported on the Serious Adverse Event Forms.(although not serious 
per ICH definition, is reportable to the Sponsor within 24 hours and to MSD Global Safety 
(GS) by fax (+ 34 91 571 64 66) within 2 working days to meet certain local requirements) 
The following hospitalizations are not considered SAEs:  
 a visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life-
threatening event) 
 elective surgery, planned prior to signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy) 
 Medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases 
 Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason). 
Progression of cancer under study is not considered an adverse event. All subjects with 
serious adverse events must be followed up for outcome. 


 
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Other definitions 
Non-serious adverse event: All adverse events not classifiable as severe.  
Unexpected adverse event: An event not described in nature in terms of 
gravity or incidence and not included in the basic product information 
 
Expected adverse event: An event described in the basic product 
 
Adverse event associated with the use of the drug: Adverse event with a 
reasonable possibility of being related to the drug (adverse reaction).  
The investigator will use the following definitions to evaluate the possible relationship 
between the adverse event and the medications of the study: 
- 
Not related: Any event, illness or effect of other medications not related with the 
medication of the study (e.g. if transitory, or not having temporal relationship with 
the study drug, or presence of a definitive alternative etiology). 
- 
Related: A temporal relationship with the administration of the study drug of the 
study, which reappears on re-instatement and in which there does not appear to be 
an alternative etiology 
7.8.2 Events of Clinical Interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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7.8.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.9 Communication of Adverse Events 
An AE classified as SEVERE must conform to the legal requirements. 
When a severe AE occurs, based on the classification described above, the investigator must 
not only record it in the appropriate page in the CRF but must notify it IMMEDIATELY to the 
health authorities and to the Ethical Committee; as must notify all Suspected Unexpected 
Serious Adverse Reaction (SUSAR).


 
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Similarly, severe AE possibly related to the treatments in the study must be communicated 
by the study sponsor to the respective owners of the authorization of commercialization of 
the drugs used in the trial (MSD Global Safety (GS) by fax + 34 91 571 64 66). 
Reporting SAE and targeted adverse events to the Sponsor 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 


 
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Table 6 Evaluating Adverse Events 
An investigator, who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE
Grading 
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not
indicated. 
 
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental
ADL. 
 
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4
Life threatening consequences; urgent intervention indicated.
 
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
 
Results in death; or
 
Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused
death.); or 
 
Results in a persistent or significant disability/incapacity (substantial disruption of
ability to conduct normal life
functions); or 
 
Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission,
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note:
Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a serious adverse
event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is
documented in the 
 medical history.); or 
 
Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the
Sponsor within 24 hours and to Merck within 2 working days to meet certain local requirements); or 


 
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Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a
serious adverse event for collection purposes. An overdose that is not associated with an adverse event is considered a
non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to Merck within 2
working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may
be considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the
subject and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated
above by a 
 
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken Did the adverse event cause Merck product to be discontinued?
 
  
  
 
 
 
 
 
 
 
 
 
 


 
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The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician
according to his/her best clinical judgment, including consideration of the above elements. 
 
 
 
 
 
 
 
 
  
 
 


 
 
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7.10Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 Statistical Analysis Plan Summary 
 
This is a non randomized phase II study designed to evaluate the ORR of Pembrolizumab 
rechallange after prior check point PD1/PDL1 treatment. All safety analysis will include all 
patients who recieved at least one dose os study drug. Primary ans secondary efficacy 
analysis will include all subjets   
The goal of the primary analysis is to obtain an estimation of ORR. All eligible and treated 
patients will be included into this analysis. We hypothesize that the trial treatment with 
Pembrolizumab will results in an increase of the ORR. May be possible that a clinically 
meaningful effect may not be significant because of the low expected number of events and 
low power, specially for OS.  
We have use a two stage design (Minimax) to estimate the trial sample size. Then we have 
taken into account the following statistical premises for each cohort of the study 
P0: 0.05 
P1: 0.15 
 0.05 
 0.2 
First stage: needs to document at least 1 response in 24 patients to go on to second stage. 
Second Stage: needs at least 5 responses out of a total of 55 patients (including those on 
the first stage) to consider further study of Pembrolizumab in this context. Therefore, for 
each stratum a maximum of 55 patients (110 in total) will be recruited. 
 
 


 
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
 
 
 
 
 
 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the 
label text; random code/disclosure envelopes or lists are not provided. 
9.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 Returns and Reconciliation 
 
 
  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator  responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 


 
 
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local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
10.0 ETHICAL ASPECTS AND REGULATORY DETAILS 
10.1 General Considerations 
The study will be conducted according to the requirements of the Helsinki Declaration as 
amended in Tokyo, Venice, Hong Kong and South Africa and will follow the Rules of Good 
Clinical Practice of the European Community as well as complying with current Spanish 
legislation. 
10.2 Protocol approval by Ethic committee and Health Authority 
Before starting the study, this protocol together with the informed consents (oral and 
written before witnesses) and the patient information documentation will be submitted for 
approval by the ECCI responsible. This notification of approval by the ECCI will be submitted 
to the clinical monitor together with the names and responsibilities of the Committee 
members. 
If the protocol needs to be amended, this amendment will be submitted for approval to the 
Ethic Committees and Health Authorities (if applicable) 
10.3 Confidentiality and data protection 
The data obtained from this study will be assessed and used exclusively to obtain scientific 
conclusions. The identity of the patient is confidential and will be known only to the 
investigator and his/her collaborators, the auditors, monitors and inspectors of the relevant 
authorities. 
The samples and data collected will be coded to protect patient confidentiality. Each patient 
will have a unique identifier assigned by the EDC (electronic Data Capture) system. Sites are 
responsible to keep a patient log locally in order to be able to link the unique identifier to 
the record of the patient.  
 
Biological material will be assigned the same unique identifier. No identifiable / personal 
data will be stored in the trial database or the tissue repositories in the central labs. 
Biological material will be transferred outside the treating institution for central screening 
and review. Results of the assays will be coded only by the patient identifier. 
 
Regulatory authorities and pertinent Ethics Committees (IRB/ERB) may have access to 
patient data on-site.  


 
 
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In Spain, to ensure the patient confidentiality of the data applies the Reglamento (UE) 
2016/679 del Parlamento europeo y del Consejo de 27 de abril de 2016 de Protección de 
Datos (RGPD). 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease 
conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.     
10.5 Insurance policy 
Spanish legislation demands cover with a civil responsibility policy for subjects participating 
in a clinical trial. The sponsor of the study provides this in accordance with the current legal 
requirements. 
10.6 Study monitoring 
The clinical monitor is obliged to rigorously follow the study. For this, the clinical monitor 
will regularly visit the study centers and the investigators as well as maintain necessary 
written and telephone communications. 
The clinical monitor will assess the data collected in the acquisition forms and compare 
them with the original data of the clinical history and other original documents in 
conjunction with the study investigator.  
The monitoring tasks will be carried out by the Fundación GECP staff. 
10.7 Publication policy 
Authorship on the final manuscript or publications or provisional extracts will be decided in 
accordance with the Fundación GECP publication and authorship guidelines. (PNT GECP: 
Política de publicaciones y autorías). 
None of the participants will present data to his center in isolation from the rest of the 
results of the study and will need to seek approval from the sponsor. 
 
 
 


 
 
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11.0 APPENDICES 
11.1 ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease
performance without restriction. 
1 
Symptoms, but ambulatory. 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 
In bed <50% of the time. 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 
In bed >50% of the time. Capable of only limited self-care, confined to
bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care.
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E.,
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D.,
Group Chair. 
 
 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
11.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
 


 
 
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RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in 
this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
11.4 SAE form and Pregnancy form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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