Clinical trial NCT02574598
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: PDL1 monoclonal antibody
Sponsor: Instituto Nacional de Cancerologia de Mexico
Start date: 2016-06-01; Completion date: 2020-11-19
Enrollment: 78 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase II open-label randomized clinical trial of MK-3475 (Pembrolizumab) on previously treated non-small cell lung cancer (NSCLC) patients . This drug has shown to allow partial response according to the immune-related response criteria and the response evaluation criteria in solid tumors (RECIST). The main endpoint is to compare the overall response rate (ORR) of MK-3475 with docetaxel or docetaxel alone in patients with advanced NSCLC.

Detailed description:
MK-3475 (MK-3475) is an IgG4 monoclonal antibody to PD1, which received a 'breakthrough therapy' designation for advanced melanoma from the FDA in January 2013. Preliminary results from the NSCLC cohort of a phase I dose expansion trial of MK-3475 were presented at the 2013 World Conference on Lung Cancer meeting. MK-3475 was administered intravenously every three weeks, and continued until disease progression based upon immune related response criteria (irRC) or unacceptable toxicity. IrRC take into account the potential for different patterns of response that can be seen with immunotherapy. Of the 38 patients with previously treated advanced NSCLC evaluable for efficacy, 9 (24 percent) achieved at least partial response by irRC. Standard oncology criteria for response (Response Evaluation Criteria In Solid Tumors, RECIST were available for 33 of these patients, with at least a partial response in seven patients (21 percent). Median overall survival was 51 weeks. Therapy was well tolerated, with one case of pneumonitis (grade 2) and one case of pulmonary edema (grade 3) reported. Tumor PDL1 expression (assessed with a different assay than that used for the trials evaluating Nivolumab and MPDL3280A; antibody used undisclosed) was available for 33 of the patients who had irRC assessments and 29 of those with standard oncology (RECIST) assessment. Of the 9 patients with PDL1 positivity and irRC response data, 6 achieved at least partial response (67 percent); of the 7 patients with PDL1 positivity and standard oncology response data, 4 achieved response (57 percent). Of note, 1 of 24 patients with PDL1 negativity achieved response by irRC; 2 of 22 patients with PDL1 negativity had response by standard oncology criteria (RECIST).

Based upon these results, a randomized phase II trial comparing MK-3475 to standard salvage docetaxel in patients with advanced NSCLC has been launched (NCT01905657), however there is no study in which the synergistic activity of Docetaxel + MK-3475 were evaluated, this could open the possibility of using this drug concurrently with Docetaxel as standard therapy in patients with progression of the disease despite a double platinum-based regimen.

Measure the expression levels of PD1/PD-L1/PD-L2 subpopulations tumor cells of patients with NSCLC who come to the clinic of the National Cancer Institute and relevant way, associating their role forecast and its potential as a biomarker, relating the PD-L1 levels with clinicopathologic characteristics of the patients studied.

Arms: arm 1: Docetaxel 75 mg/m2 every 3 weeks until progression of disease

MK-3475 (administered on day 8) 200mg every 3 until progression of disease arm 2: Docetaxel 75 mg/m2 every 3 weeks until progression of disease followed by MK-3475 200mg every 3 until progression of disease
Interventions: intervention 1: MK-3475 intervention 2: Docetaxel
Intervention descriptions: intervention 1: The dosing interval of pembrolizumab can be increased in case of toxicity. intervention 2: Use on both arms as standard of care.

Protocol documents:
Prot_SAP_000.pdf: 
Randomized phase II study of MK-3475 (Pembrolizumab) in 
combination with Docetaxel vs. Docetaxel alone in patients 
with Non-Small Cell Lung Cancer previously treated with 
platinum based chemotherapy 
 
NCT02574598 
 
Document date: July 21st, 2017  


1 
 
  Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
4 
 
 
 
 
 
 
 
I.   GENERAL DATA 
 
 1. PRINCIPAL INVESTIGATOR 
 
Name: 
Oscar Arrieta Rodríguez 
Mexican Tax number:: 
AIRO731030 
Nationality: 
Mexican 
Position: 
Medical Sciences Researcher Level “E”. 
 Office phone: 
56 28 04 00  ext.71113 
Email address 
ogarrieta@gmail.com 
Studies level: 
MD, MSc 
Discipline 
Medical Oncology 
Medical Specialty 
Oncology  
Research Category and Level: 
Medical Sciences researcher Level “E”. 
Adscription: 
Clinical Research Department 
  
 
 
 2.  PROJECT 
 
 
  
Name of the project 
 
 
  
 
Type of research  
  
    (Mark with an “X”) 
 
 
Basic 
Exploratory 
 X  Clínic 
 
Experimental                                                                                                      
 
Comparative 
  
 
              
 
                                                                          Dr. Luis Alonso. Herrera Montalvo. 
  __________________________                                 Head of the Department 
 
 
SINGLE FORMAT FOR THE REGISTRATION OF 
RESEARCH PROTOCOLS 
 
RESEARCH AND ETHICS COMMITTEE 
Í
Randomized phase II study of MK-3475 (Pembrolizumab) in 
combination with Docetaxel vs. Docetaxel alone in patients with 
Non-Small Cell Lung Cancer previously treated with platinum 
based chemotherapy. 
 Protocol version # 1 amendment  3. Date: July 21 of 2017.  
    Protocol origin ((Mark with a “X”) 
 
x 
Internal 
 
 
 
External 
 
 
 
Thesis 
 
Project timeline 
              Start:                                                 Ending:  
               Month       Year 
 
                Month   Year 
             10    15                                       10       17 


2 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
 3. COLLABORATORS 
 
 
NAME : 
Diana Flores Estrada 
RFC: 
FOED691215RV3 
JOB TITLE : 
Study Coordinator 
Maximum level of studies: 
Degree in social work 
Discipline: 
social Sciences 
Speciality: 
Specialization in Social Work Medical area. 
Category and level: 
Researcher C SCIENCE Medical "A" 
Assignment: 
Subdirectorate of Clinical Research 
  
  
  
Name: 
Feliciano Barrón Barrón 
RFC: 
BABF840301HSLRRL05 
Position: 
Resident 
Maximum level of studies: 
Internal Medicine specialist 
Discipline: 
Oncology 
Speciality: 
Medical Oncology 
Category and level: 
  
Assignment: 
Subdirectorate of Internal Medicine 
  
  
Name: 
Edgar Montes Servín 
RFC: 
MOSE910615CXA 
Position: 
Investigator 
Maximum level of studies: 
Bachelor of Biology 
Discipline: 
Biomedicine 
Speciality: 
Immuno-Oncology 
Category and level: 
None 
Assignment: 
Subdirectorate of Clinical Research 
 
 
 
 
4. PARTICIPATING INSTITUTIONS 
                 (A letter of support signed by the director of each participating institute must be attached) 
  
Name Institution I 
Does not apply 
Institution Name II 
Does not apply 
Name Institution III 
Does not apply 
Name Institution IV 
Does not apply 
Name Institution V 
Does not apply 
  
  
  
  
  
  


3 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
              Type of support 
              (Mark the type of help provided with an X) 
              
  
Type of help 
  
Infrastructure 
Personal 
Material 
Team 
International Agency for Research on 
Cancer 
X 
  
X 
X 
Institution Name II 
  
  
  
  
Name Institution III 
  
  
  
  
Name Institution IV 
  
  
  
  
Name Institution V 
  
  
  
  
  
  
  
II. SYNTHESIS OF THE PROJECT 
 
 
BACKGROUND: 
  
MK-3475 ( Pembrolizumab ) is an IgG4 monoclonal antibody directed against PD1 which was originally 
used as an advanced melanoma therapy approved by the FDA in January 2013. Preliminary results of a 
phase I cohort study in Non-Small Cell Lung Cancer (NSCLC) using MK-3475 ( Pembrolizumab ) were 
presented at the World Conference on the Lung Cancer Meeting of 2013, where compound MK-3475 
( Pembrolizumab ) was administered intravenously every three weeks and continued until the 
progression of the disease based on immunological response criteria (IRC) or unacceptable toxicity. 
  
Of the 38 patients evaluated, who were previously treated for advanced NSCLC, 9 (24 %) achieved an 
at least partial response by IRC. Through evaluation with standard oncological response criteria 
(Response evaluation criteria in solid tumours such as RECIST were available for 33 of these patients, 
presenting partial response in seven patients (21%). With a median overall survival of 51 weeks 
The therapy was well tolerated; a case of pneumonitis (grade 2) and a case of pulmonary oedema 
(grade 3) were reported. 
  
Based on these results, a randomized phase II trial comparing MK-3475 ( Pembrolizumab ) to docetaxel 
in patients with advanced NSCLC has been launched (NCT01905657), however, there is no study in 
which they were evaluated Docetaxel + MK-3475 ( Pembrolizumab ) to evaluate synergistic activity, this 
could open the possibility of using this medication simultaneously with docetaxel as a standard therapy 
in patients with disease progression to a double platinum-based regimen. 
 
Primary Objective 
Compare the overall response rate (ORR) of MK-3475 ( Pembrolizumab ) in combination with docetaxel 
versus docetaxel only in patients with NSCLC previously treated with platinum-based chemotherapy. 
  
 
Hypothesis 


4 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
In patients with metastatic NSCLC previously treated with double platinum-based chemotherapy, the 
co-administration of MK-3475 ( Pembrolizumab ) / Docetaxel will increase the overall response rate 
(ORR) compared with the administration of docetaxel alone in patients with previously treated NSCLC. 
  
 
METHODOLOGY 
 
Study design: This is a randomized, open-label phase 2 study in adult patients (≥18 years of age) in 
men and women with NSCLC after failure at the first line of platinum-based chemotherapy. Patients 
included will receive MK-3475 ( Pembrolizumab ) in combination with Docetaxel vs. Docetaxel only in a 
1: 1 ratio with the possibility of crossing to the combination arm in case of progression. Patients will 
undergo screening evaluations to determine eligibility within 28 days prior to randomization. Subjects 
will be assigned to one of two treatment groups.  The randomization will be carried out with a random 
numbers table. 
 
Obtaining the sample, plasma and immunophenotyping: A sample of peripheral venous blood (8 
ml) will be obtained from each subject included in the study. An aliquot of whole blood will be taken for 
staining with a combination of monoclonal antibodies for the development of the Immunophenotype 
panel. The samples will be acquired in an Attune NxT Acoustic Focusing Flow cytometer and analyzed 
with the FlowJo vX Software. The rest of the sample will be processed to obtain the plasma, stored at -
70 ° C until further analysis. Nuclear polymorph cells will be separated by a density gradient, Ficoll 
Polymorphprep and cryopreserved. 
 
Multiple quantification assay of soluble analytes: For quantification commercial kits of pearl-coupled 
immunoassays (CBA) will be used in plasma of the study subjects. 
 
Study evaluations and primary assessment criteria: Compare the overall response rate (ORR) of 
MK-3475 ( Pembrolizumab ) in combination with docetaxel versus docetaxel alone in patients with 
previously treated NSCLC. Evaluated by RECIST 1.1. 
  
 
III. PROJECT BACKGROUND 
Lung cancer is the leading cause of cancer-related death worldwide. (1) It is estimated that 221,130 
new cases of lung cancer were diagnosed in 2011. (2) Between 1999 and 2006, according to the SEER 
database, the overall 5-year survival rate was only 15.8%. The majority of subjects (approximately 78%) 
were diagnosed with advanced or metastatic disease. Progression occurred after first-line treatment in 
almost all of these subjects, and the 5-year survival rate is only 3.6%. There is a particular unmet need 
in subjects with non-squamous cell NSCLC (representing up to 75% of all NSCLC) since there are few 
treatment options after first-line treatment in most patients with cancer that It is not induced by 
mutations. According to the NCCN guidelines, the use of chemotherapy with a single agent is the 
standard care in subjects with recurrent and metastatic NSCLC after the platinum-based treatment  (2) 
has failed. The historical value of the median Progression-Free Survival (PFS) rates in second-line 
NSCLC average approximately 2.6 to 3.2 months, and the median OS is approximately 6.7 to 8.3 
months (3-6)  more in the most recent ZODIAC study (10+ months). (7)  Current second-line treatment 
includes docetaxel, erlotinib and pemetrexed. No agent has demonstrated superiority in OS when 
compared to docetaxel. Additional studies showed that gefitinib is non-inferior to docetaxel in previously 
treated NSCLC, except for study V-15-32. (8-20)  Regimens other than docetaxel (other than the 3-
week standard), double chemotherapies using docetaxel, and other comparative agents, have not 


5 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
shown improvement compared to docetaxel in this treatment line. (11-15) Among the different 
histologies of NSCLC, non-squamous cell carcinoma of the lung typically accounts for up to 75% of all 
cases of lung cancer. (16)  The majority of studies involving first-line and second-line treatment do not 
specifically separate subjects by histology, although this was recorded in all pivot studies. (4-6,17) The 
first study that demonstrated a difference in histology involved the comparison of gemcitabine and 
cisplatin with pemetrexed and cisplatin. In this study, subjects with non-squamous cell NSCLC 
presented a median composite survival time of 10.3 months with the combination of gemcitabine, and 
10.3 months with pemetrexed. This later changed when studying based on specific non-squamous 
histologies, which showed a median survival of 10.9 months with gemcitabine versus 12.6 months with 
pemetrexed in adenocarcinoma, and 6.7 months with gemcitabine versus 10.4 months with 
pemetrexed in large cell lung cáncer. (18)  A sub-analysis of the non-inferiority study with pemetrexed in 
second-line treatment 19 showed a statistically significant improvement in the combined non-squamous 
histologies when docetaxel (9.3 months vs. 8.0 months (HR 0.778)) was compared, but not in the 
squamous ones ( 6.2 months vs. 7.4 months (HR 1,563)). (19) Additional data have shown that the risk 
of recurrence of the disease after initial treatment is equal between adenocarcinoma and squamous cell 
lung cancer, despite a worse prognosis in the squamous cell subgroup. (20) 
 
The treatment of NSCLC has also been defined by developing an understanding of the somatic 
mutations that drive tumour growth and development. Higher responses were observed in female, non-
smoking and adenocarcinoma subjects, compared to male smoking subjects with squamous cell lung 
carcinoma treated with erlotinib. (21) For example, a significant clinical benefit was observed in subjects 
with EGFR mutations treated with EGFR TKI (representing 5 to 26% of all subjects with non-squamous 
NSCLC). (22-24) This was subsequently evaluated in the EURTAC study, which analyzed virgin 
chemotherapy subjects who presented EGFR mutations by exon 19 deletion, or L858R mutation in 
exon 21. The median PFS was 9.7 months in the erlotinib group and 5.2 months in the chemotherapy 
group (cisplatin/docetaxel or cisplatin/gemcitabine), with an HR of 0.37. (1) The use of the docetaxel-
based combination, although not frequently used in first-line treatment, showed equivalent efficacy 
when compared to combinations based on pemetrexed and paclitaxel. (25) An additional mutation that 
is aberrantly activated in the non-squamous NSCLC is the EML4-ALK translocation found in 
approximately 4% of the subjects. Better tumour responses were observed with the use of ALK TKI 
crizotinib, while the median overall survival has been reached so far. (26)  
 
The current unmet need in non-squamous NSCLC continues to be that, the majority of subjects who do 
not have known mutations or who have mutations, do not have a targeted treatment. In addition, once 
the subjects have developed resistance to several TKIs, there are few treatment options and the 
disease progresses rapidly. Docetaxel continues to be the preferred treatment (27),  in this line of 
treatment, as there are few additional options. 
  
 
Rationale for MK-3475 
  
MK-3475 ( Pembrolizumab ) is a highly selective humanized monoclonal antibody of the IgG4 kappa 
isotype against PD-1 that is designed to block the negative immune regulatory signalling of the PD-1 
receptor expressed by T cells. Very high variable region sequences affinity to the PD-1 anti-human 
mouse PD-1 (dissociation constant, 28 pM) mouse were grafted onto a human IgG4 immunoglobulin 
with an Fc stabilization alteration S228P. The IgG4 immunoglobulin subtype does not bind to Fc 
receptors, nor does it activate complement, thus avoiding the cytotoxic effects of the antibody when it 
binds to the T cells it is intended to activate. In the T cell activation assays using blood cells from 
human donors, the 50% effective concentration was in the range of 0.1 to 0.3 nM (unpublished 


6 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
data). The first phase of dose escalation in a phase I study with patients with solid tumours showed that 
MK-3475 ( Pembrolizumab ) was safe at the dose levels tested (1 mg per kilogram of body weight, 3 mg 
per kilogram, and 10 mg per kilogram, administered every 3 weeks) without reaching a maximum 
tolerated dose. In addition, clinical responses were observed at all dose levels. (27-28) 
 
Of the 135 patients who received at least one dose of MK-3475 ( Pembrolizumab), 79% reported the 
presence of adverse events related to the drug of any grade and 13% reported grade 3 or 4 events 
related to the drug. However, general symptoms, such as fatigue and fatigue, fever and chills, myalgia 
and headache, were reported frequently but were low grade in more than 95% of cases. Eruptions and 
pruritus were reported in 21% of patients; Grade 3 or 4 pruritus was reported in 1% of patients, and 
rash grade 3 or 4 in 2%. Vitiligo was attributed to MK-3475 ( Pembrolizumab ) in 9% of patients. The 
highest incidence of overall adverse events related to treatment was observed among patients who 
received 10 mg of MK-3475 per kilogram every 3 weeks, compared to patients who received 3 mg per 
kilogram every 3 weeks and those who received 1 mg per kilogram every 3 weeks (23%, versus 4% 
and 9%, respectively) Treatment-related pneumonitis was reported in 4% of patients; none of the cases 
was grade 3 or 4. One patient, a 96-year-old man, died during the study. Initial asymptomatic 
pneumonitis was identified in CT, and MK-3475 ( Pembrolizumab ) was discontinued. Subsequently, I 
present dyspnea and the patient received glucocorticoids. Grade 3 or 4 elevations in aminotransferase 
levels were reported in 1% of patients. Two cases of grade 3 renal insufficiency were recorded, both 
cases were potentially mediated by autoimmunity presented improvement of renal function with 
glucocorticoid treatment at the same time as the interruption of MK-3475. (29,30)  
 
Based on these and other preclinical and clinical data, the blockade of PD-1 induced by MK-3475 has 
been studied as a promising therapeutic strategy to reverse immune tolerance and enhance the effector 
function of T cells in various types of tumours, including CPCNP. 
 
 
Justification for the use of docetaxel as a comparator 
 
Docetaxel is one of the many agents that are approved for use after progression with the first-line 
treatment for NSCLC based on PFS and OS, compared to the best supportive care (BSC) 17 or active 
chemotherapies (4) It has been used as a reference comparator vs. pemetrexed in a non-inferiority 
study in which the PFS and OS in the docetaxel group were 2.9 months and approximately 8 months, 
respectively. (5)  Erlotinib is another agent that was studied in the second line. In the BR.21 study, 
erlotinib demonstrated a PFS of 2.2 months and an OS of 6.7 months. placebo with BSC. (6) Docetaxel 
was chosen in this study because its activity continues to be the frame of reference for the evaluation of 
other agents. In addition, double treatments based on pemetrexed have been used more frequently in 
the first-line scenario, reducing the number of options for this subgroup of patients. Docetaxel can also 
be used in subjects presenting with conductive mutations and who had previously been treated with 
EGFR TKI or ALK TKI (including crizotinib) and double platinum-based chemotherapy. 
This study will stratify and balance the groups in terms of previous use of maintenance treatment vs. no 
use of maintenance treatment, and second-line treatment vs. third-line treatment. The reason for 
maintenance treatment as a stratification factor, involves improvement in progression-free survival 
(PFS) and in OS observed in patients who received a change in maintenance treatment with 
pemetrexed after a double platinum-based régimen. (29) This is still being evaluated in the continuation 
of maintenance treatment with pemetrexed. (30)  The maintenance change using erlotinib showed a 
statistically significant improvement in OS, but not as large as in the pemetrexed study. (31) The 
stratification and balance of second-line studies vs. the Third line, it was also chosen due to the 


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 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
differences observed in the OS between these two groups, as demonstrated in the studies using 
afatinib. (32)  
 
 
Rationale for the dose and schedule of MK-3475 ( Pembrolizumab) 
 
A phase II study by Hamid et al. showed that among 135 patients who received at least one dose of the 
MK-3475, 79% reported the presence of any grade adverse events related to drug and 13% reported 
grade 3 or 4 drug-related events. However, general symptoms, such as fatigue and fatigue, fever and 
chills, myalgia and headache, were reported frequently but were low grade in more than 95% of 
cases. Eruptions and pruritus were reported in 21% of patients; Grade 3 or 4 pruritus was reported in 
1% of patients, and rash grade 3 or 4 in 2%. The vitiligo was attributed to the MK-3475 in 9% of 
patients. The highest incidence of overall adverse events related to treatment was observed among 
patients who received 10 mg of MK-3475 per kilogram every 3 weeks, compared to patients who 
received 3 mg per kilogram every 3 weeks and those who received 1 mg per kilogram every 3 weeks 
(23%, versus 4% and 9%, respectively) Treatment-related pneumonitis was reported in 4% of 
patients; none of the cases was grade 3 or 4. One patient, a 96-year-old man, died during the 
study. Initial 
asymptomatic 
pneumonitis 
was 
identified 
in 
CT, 
and 
MK-3475 
was 
discontinued. Subsequently, I present dyspnea and the patient received glucocorticoids. Grade 3 or 4 
elevations in aminotransferase levels were reported in 1% of patients. Two cases of grade 3 renal 
insufficiency 
were 
recorded, both 
cases 
were 
potentially 
mediated 
by 
autoimmunity 
presented improvement of renal function with glucocorticoid treatment at the same time as the 
interruption of MK-3475. (27-28) 
 The adverse events of special interest were autoimmune or 
inflammatory nature. Hypothyroidism was reported in 8% of patients and was treated effectively by 
administering 
thyroid 
hormone 
replacement 
therapy. Grade 
3 
hyperthyroidism 
and grade 
2 adrenal insufficiency developed in a patient; these were handled with standard measures, and the 
patient continued in the study with a lasting response. (33-34)  
 
Justification for the Crossing-over 
 
Preliminary data suggest that nivolumab has clinical activity both in patients with previously treated 
NSCLC and in the first line (45-46). Similar preliminary results have also been reported in clinical 
studies of other immuno-oncological agents whose therapeutic target is the PD-1 pathway in patients 
with NSCLC. According to these data, the clinical activity of MK-3475 in patients with NSCLC who have 
progressed after the second line of chemotherapy may be similar or potentially greater than another 
third-line chemotherapy. Therefore, this study will give patients randomized in Arm B the option of 
receiving MK-3475 as monotherapy when documented progression exists and such crossover 
treatment is discussed with and approved by the MSD Medical Monitor. It is recognized that this cross-
treatment with MK-3475 may decrease any potential benefit in OS (General Survival), but it will not 
affect the PFS criteria. 
 
Justification for the initial evaluation of the tumour  
 
The accumulation of clinical evidence indicates that some patients treated with agents that stimulate the 
immune system may develop disease progression (using conventional response criteria) before 
demonstrating clinical objective responses and/or stable disease. This phenomenon was observed in 
the CA209003 phase 1 study of Nivolumab (another anti-PD-1). Two hypotheses have been proposed 
to explain this phenomenon. First, elevated inflammation within tumours can lead to an increase in 


8 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
tumour size appearing as enlarged index lesions and as newly visible small non-index lesions. Over 
time, both the malignant and inflammatory portions may decrease leading to obvious signs of clinical 
improvement. Another hypothesis is that the tumour growth kinetics may initially overcome the 
antitumor immune activity in some individuals. With enough time, it will dominate the antitumor activity 
and will become clinically evident. For these reasons, the initial evaluation of the tumour in CA209003 
was carried out at 8 weeks and it is unknown if an earlier assessment would demonstrate similar activity 
due to the premature termination of the treatment under study. (34-35)  
 
To mitigate the risk of detecting false progression at an early stage within the period of treatment with 
MK-3475, the initial evaluation of the tumour for both arms in this study will take place at Week 9 ( 5 
days). Thereafter, all subsequent tumour assessments every 6 weeks (will regularly place 5 days) until 
documented disease progression or discontinuation of treatment, whichever comes later. 
 
Justification for the collection of tumour tissue and evaluation of the PD-L1 expression of the 
tumour as a potential predictive biomarker 
 
Aberrant expression of PD-L1 protein has been reported by tumour cells (retrospectively detected by 
IHC) in several human malignancies, especially in relation to poor prognosis in various types of 
tumours, including squamous and non-squamous NSCLC. (33-41) These findings can be explained by 
the fact that the high expression of PD-L1 causes immune evasion. This hypothesis is supported by 
several studies that demonstrate that PD-L1 expressed by tumour cells increases apoptosis of tumour-
specific activated cells in vitro, (40)  and that PD-L1 expression protects tumour cells from induction of 
Apoptosis by effector T cells. (42) In NSCLC, blocking PD-L1 to increase allows the number of CD8 + T 
cells infiltrating the tumour, and cause increased production of IFN- , but no differences were observed 
in CD8 + peripheral blood cells when subjects with NSCLC were compared with healthy controls. 
(43)  These high levels of PD - L1 protein expression in NSCLC have also been significantly associated 
with poor prognosis and with the presence of tumour infiltration by immature dendritic cells. (44)  
 
Interestingly, preliminary data indicate that PD-L1 protein expression in tumours can be correlated with 
the clinical activity of MK-3475. Archived tumour samples from a limited subgroup (N=30) of subjects in 
CA209003 were evaluated for the expression of PD-L1 protein measured by immunohistochemistry 
(IHC). In this subgroup, 100% of the subjects whose tumors lacked detectable expression of the PD-L1 
protein (N=13), did not present evidence of clinical benefit (response, stable disease, or mixed 
response) with Nivolumab, while the subjects whose tumours were positive for PD-L1 (based on the 
expression of PD-L1 protein in a pre-defined threshold of tumour cells), were more likely to demonstrate 
clinical benefit. Despite the limited number of subjects evaluated in this initial study, our findings 
indicate that the expression status of the PD-L1 protein may have a profound impact on the likelihood of 
the patient responding to treatment with Anti PD-1. Because the clinical benefit seemed to correlate 
with the PD-L1 status measured in baseline pretreatment samples, these data also suggest that PD-L1 
expression could serve as a predictive biomarker to select patients. As such, the analysis of a larger 
number of samples merits, and the evaluation of additional patients (and their tumours) recruited in the 
CA209003 study is ongoing. (33-41)  
 
In this Phase II study, basal tumour tissue will be collected prospectively from randomized patients, and 
a retrospective efficacy analysis will be performed based on PD-L1 protein expression. The sponsor is 
in the process of developing a simple IHC assay, adjusted for what is proposed, which can be used to 
reproduce the expression of PD-L1 in tumour tissues reproducibly, and that could one day serve as a 
diagnostic aid for Select patients for treatment. Compulsory collection of tumour tissue in this phase II 


9 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
scenario ensures that the number of subjects and samples needed to optimize the IHC assay is 
achieved, and by generating data on PD-L1 in a larger group of subjects, it will help to achieve analysis 
with statistical power. Contingently with the development of an optimized trial and the continuous 
indication that the expression status of the PD-L1 protein is predictive of clinical benefit (patients with a 
partial response as well as patients with complete response). 
Justification for the evaluation of blood cells and soluble protein parameters of patients 
The composition and characteristics of the cellular populations of the immune system as well as the 
soluble factors that mediate the different responses (cytokines, chemokines and growth factors) vary 
widely according to the location of the tumour and are important in determining the anti-immune 
response. -tumoral. For example, certain immune system cells, including natural killer cells (NK), 
dendritic cells (DC) and CD8 + T cells, are capable of conducting potent antitumor responses. However, 
tumour cells often induce an immunosuppressive microenvironment, which favours the development of 
immunosuppressive populations of immune cells, such as myeloid suppressor cells and regulatory T 
cells. Being able to understand the complex network of interactions of the various cell and protein types 
in peripheral blood, which are involved in the regulation of the immune processes involved in lung 
cancer. The development of a model that allows generating groups of patients or clusters characterized 
by the patterns generated that integrate the values of markers of evasion of the immune response 
simultaneously in the cells of the immune system, together with plasma protein levels. Associated with 
the clinical-pathological characteristics of the patients and the feasibility that may be potential 
biomarkers associated with prognosis and/or survival of clinical utility.  
Justification for the evaluation of the results reported by the patient 
Due to the proposed increase in ORR, OS and PFS of treatment with MK-3475 / Docetaxel in relation to 
docetaxel, it is hypothesized that the time for significant symptoms related to the disease according to 
the measurements of the EORTC QLQ C30 Questionnaire and LC-13 will also increase in relation to 
the combination MK-3475 / Docetaxel on docetaxel. EORTC QLQ-C30 questionnaire will be used to 
assess the general state of health and the data will be used to calculate the utilities of its use in 
economic models. 
 
IV.   REFERENCES 
 
 
1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011; 61: 9-90. 
2. NCCN Guidelines version 3.2012 CPCNP 
3. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best 
supportive care in subjects with non-small-cel lung cancer previously treated with platinum-
based chemotherapy. J Clin Oncol. 2000; 18: 2095-2103. 
4. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase II trial of docetaxel versus 
vinorelbine or ifsofamide in subjects with advanced non-small-cel lung cancer previously treated 
with platinum-containing chemotherapy. J Clin Oncol. 2000; 18: 2354-62 


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 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
5. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus 
docetaxel in subjects with non-small-cel lung cancer previously treated with chemotherapy. J 
Clin Oncol. 2004; 22: 1589-97. 
6. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non-small-cel lung 
cancer previously treated with chemotherapy. N Engl J Med. 2005; 353: 123-32. 
7. Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as 
second-line treatment for patients with advanced non-small-cel lung cancer (ZODIAC): a 
double-blind, randomised, phase 3 trial. Lancet Oncol. 2010; 11: 619-26. 
8. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cel 
lung cancer (INTEREST): a randomised phase III trial. The Lancet. 2008; 372: 1809-18. 
9. Lee DH, Park K, Kim JH, et al. Randomized phase III trial of gefitinib versus docetaxel in non-
small cel lung cancer subjects who have previously received platinum-based chemotherapy. 
Clin Cancer Res. 2010; 16: 1307-14. 
10. Maryama R, Nishiwaki Y, Tamura T, et al. Phase III study, V-15-32, of gefitinib versus 
docetaxel in previously treated Japanese subjects with non-small-cel lung cancer. J Clin Oncol. 
2008; 26: 4244-52. 
11. Gebba V, Gridelli C, Verusio C, et al. Semanaly docetaxel vs docetaxel-based combination 
chemotherapy as second-line treatment of advanced non-small-cel lung cancer subjects: the 
DISTAL-2 randomized trial. Lung Cancer. 2009; 63: 251-8. 
12. Pallis AG, Agelaki S, Agelidou A, et al. A randomized phase III study of docetaxel/carboplatin 
combination versus docetaxel single-agent as second line treatment for subjects with 
advanced/metastatic non-small cel lung cancer. BMC Cancer. 2010; 10: 633-40. 
13. Krzakowski M, Ramlau R, Jassem J, et al. Phase III trial comparing vinflunine with docetaxel in 
second-line 
non-small-cel 
lung 
cancer 
previously 
treated 
with 
platinum-containing 
chemotherapy. J Clin Oncol. 2010; 28: 2167-73. 
14. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with 
erlotinib in subjects with previously treated advanced non-small-cel lung cancer. J Clin Oncol. 
2011; 29: 1059-66. 
15. De Boer RH, Arrieta O, Chang C-H, et al. Vandetanib plus pemetrexed for the second-line 
treatment of advanced non-small-cel lung cancer: a randomized, double-blind phase III trial. J 
Clin Oncol. 2011; 29: 1067-74. 
16. Wahbah M, Boroumand N, Castro C, et al. Changing trends in the distribution of the histologic 
types of lung cancer: a review of 4439 cases. Ann Diagn Pathol. 2007; 11: 89-96. 
17. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best 
supportive care in subjects with non-small-cel lung cancer previously treated with platinum-
based chemotherapy. J Clin Oncol. 2000; 18: 2095-2103 
18. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine 
with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-
cel lung cancer. J Clin Oncol. 2008; 26: 3543-51. 


11 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
19. Peterson P, Park K, Fossella F, et al. Is pemetrexed more effective in adenocarcinoma and 
large cel lung cancer than in squamous cel carcinoma? A retrospective analysis of a phase III 
trial of pemetrexed vs. docetaxel in previously treated patients with advanced non-small cel 
lung cancer (CPCNP). J Thorac Oncol. 2007; 2: S851 (abstr. P2-328). 
20. Kawase A, Yoshida J, Ishii G, et al. Differences between squamous cel carcinoma and 
adenocarcinoma of the lung: are adenocarcinoma and squamous cel carcinoma prognostically 
equal? Jpn J Clin Oncol. 2012; 42: 189-95 
21. Clark GM, Zborowski DM, Santabarbara P, et al. Smoking history and epidermal growth factor 
receptor expression as predictors of survival benefit from erlotinib for patients with non-small-
cel lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21. 
Clin Lung Cancer 2006; 8: 214-6 
22. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor 
receptor underlying responsiveness of non-small-cel lung cancer to gefitinib. N Engl J Med. 
2004; 350: 2129-39 
23. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med. 2009; 361: 947-57 
24. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line 
treatment for European patients with advanced EGFR mutation-positive non-small-cel lung 
cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13: 
239-46. 
25. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for 
advanced non-small-cel lung cancer. N Engl J Med. 2002; 346: 92-8 
26. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with 
advanced non-small-cel lung cancer harbouring ALK gene rearrangement: a retrospective 
analysis. Lancet Oncol. 2011; 12: 1004-12 
27. Garon E, Balmanoukian A, Hamid O et al. Preliminary clinical safety and activity of MK-3475 
monotherapy for the treatment of previously treated patients with non-small cell lung cancer. 
Presented at: IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia. 
MO18.02.  
28. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) 
in melanoma. N Engl J Med 2013; 369:134.  
29. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care 
versus placebo plus best supportive care for non-small-cel lung cancer: a randomized, double-
blind, phase 3 study. Lancet. 2009; 374: 1432-40. 
30. Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best 
supportive care versus placebo plus best supportive care after induction therapy with 
pemetrexed 
plus 
cisplatin 
for 
advanced 
non-squamous 
non-small-cel 
lung 
cancer 
(PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012; 13: 
247-57. 


12 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
31. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced 
non-small-cel lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet 
Oncol. 2010; 11: 521-9. 
32. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, 
metastatic non-small-cel lung cancer after failure of erlotinib, gefitinib, or both, and one or two 
lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012; 13: 
528-38. 
33. Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med. 
2003; 81: 281-7. 
34. Konishi J, Yamazaki K, Azuma M, et al. B7-H1 expression on non-small cel lung cancer cels 
and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer 
Res. 2004; 10: 5094-10. 
35. Ma C-Y, Huang J-A, Chen Y, et al. High expression of PD-L1 in lung cancer may contribute to 
poor prognosis and tumor cels immune escape through suppressing tumor infiltrating dendritic 
cels maturation. Med Oncol. 2011; 28: 682-8. 
36. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cel carcinoma 
subjects: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci 
USA. 2004; 101: 17174-9. 
37. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cel death 1 ligand 1 and tumor-
infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad 
Sci. 2007; 104: 3360-5. 
38. Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death -1 ligand-1 and 
programmed death -1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 
2005; 11: 2947-53. 
39. Tsushima F, Tanaka K, Otsuki N, et al. Predominant expression of B7-H1 and its 
immunoregulatory roles in oral squamous cel carcinoma. Oral Oncol. 2006; 42: 268-74. 
40. Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. 
Trends Immunol. 2001; 22: 265-8. 
41. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and 
metastatic clear cel renal cel carcinoma. Cancer. 2005; 104: 2084-91. 
42. Azuma T, Yao S, Zhu G, et al. B7-H1is a ubiquitous antiapoptotic receptor on cancer cels. 
Blood. 2008; 111: 3635-43 
43. Zhang Y, Huang S, Gong D, et al. Programmed death -1 upregulation is correlated with 
dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell 
and Mol Immunol. 2010; 7: 389-95 
44. Ma C-Y, Huang J-A, Chen Y, et al. High expression of PD-L1 in lung cancer may contribute to 
poor prognosis and tumour cells immune escape through suppressing tumour-infiltrating 
dendritic cels maturation. Med Oncol. 2011; 28: 682-8. 


13 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
45. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-
Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. 
46. Rizvi, NA, Mazieres J, Pkanchard D, et al. Activity and safety of nivolumab, an anti-PD-1 
immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell 
lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar;16(3):257-
65 
 
LIST OF ABBREVIATIONS 
 
ADA 
Anti Drug Antibody 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
ALK 
Anaplastic lymphoma kinase (CD246) 
ALT 
Alanine Aminotransferase 
APC 
Antigen-presenting cells 
AST 
Aminotransferase Aspartate 
Bcl- xL 
Extra-large B cell lymphoma 
BID 
Twice daily 
B7-DC 
B7 human dendritic cells 
B7-H1 
Homologue 1 of human B7 
BSC 
Better supportive care 
BTLA 
B and T cell attenuator 
CD28 
A cluster of differentiation 28 
CD273 
A cluster of differentiation 273 
CD274 
A cluster of differentiation 274 
C57BL/6 
C57 black inbred mice 6 
CI 
Confidence interval 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
COX2 
Cyclooxygenase 2 
CR 
Complete answer 
NSCLC 
Non-Small Cell Lung Cancer 
CRF 
Case Report Form 
CT 
CT scan 
CTA 
Clinical Study Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T lymphocyte 
CTLA-4 
Antigen 4 associated with Cytotoxic T lymphocyte 
CYP 
Cytochrome P450 


14 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
D 
Day 
DCF 
Data clarification form 
LANGUAGE 
Drug-induced liver injury 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DOOR 
Duration of objective response 
ECL 
Electrochemiluminescence 
ECOG 
Eastern Cooperative Cancer Group 
eCRF 
Electronic form of case report 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
NO 
Equivalence interval 
ELISA 
Immunoabsorbent Assay Linked to Enzymes 
EOI 
End of the infusion 
ESOI 
Special Interest Events 
I 
European Union 
FLIP 
Caspase 8-like inhibitory protein (FLICE) 
FSH 
Follicle Stimulating Hormone 
FU 
Tracing 
GCP 
Good clinical practices 
GMP 
Good manufacturing practices 
HCG 
Human Chorionic Gonadotropin 
HIPAA 
Portability and Social Security Responsibility Act 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HR 
Risk ratio 
HTA 
Sanitary Authority 
ICF 
Informed consent form 
I 
International Conference on Harmonization 
ICOS 
With the inducible T cell stimulator (CD278) 
GONE 
With the inducible stimulator 
IFN 
Interferon 
IFNGR1 
Interferon Gamma 1 receiver 
IFN-γ 
Interferon Gamma 
IgG4 
G4 immunoglobulin 
IHC 
Immunohistochemistry 
THE 
Interleukin 
ITIM 
Reason for immuno receptor tyrosine inhibitor 
ITSM 
Reason changed based on tyrosine of the immuno receptor 
IRB/IEC 
Institutional review board / independent ethics committee 


15 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
IV 
Intravenous 
IVRS 
Interactive voice response system 
KM 
Curve the Kaplan Meier 
LMP 
Low molecular mass protein 
mAb 
Monoclonal antibody 
mCRPC 
Castration resistant metastatic prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEL 
Metastatic melanoma 
mg 
Milligram 
mL 
Milliliter 
MLR 
Mixed Lymphocyte Reaction 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
M² 
Square meter 
NCI 
National Cancer Institute 
NK 
Natural killer 
NSAID 
Nonsteroidal anti-inflammatory drugs 
CPCNP 
Non-small cell lung cancer 
WE 
Not specified 
NOS2 
Nitric Oxide Syntase 2 
ORR 
Objective Response Rate 
THE 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Scheduled Death-1 
PD-L1 
Ligand 1 of programmed death 
PD-L2 
Ligand 2 of programmed death 
PFS 
Progression free survival 
PGE2 
Prostaglandin E2 
PK 
Pharmacokinetics 
PO 
Orally 
P19 
Serine protease inhibitor 
PR 
Partial response 
PRO 
Results reported by the subject 
PSA 
Prostate Specific Antigen 
PVG 
Pharmacovigilance 
q 
Every 
PRO 
Results reported by the patient 
RAG 
Recombination activator gene 
RCC 
Renal cell carcinoma 


16 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ácido ribonucleico 
RT 
Radiation treatment 
SAE 
Serious adverse event 
SD 
Stable disease 
SLD 
Sum of the larger diameters 
SNP 
Single nucleotide polymorphism 
SOC 
Organic System Class 
SOP 
Standard Operating Procedures 
Src 
Sarcoma 
STAT 
Signal Transducers and Transcription Activators 
TAP1 
Conveyor associated with antigen processing 1 
TCR 
T cell receptor 
teaer 
Emerging adverse event with treatment 
TGF 
Transforming growth factor 
TO 
Tumor infiltrating lymphocytes 
TKI 
Tyrosine kinase inhibitor 
TNF 
Tumor necrosis factor 
TRAIL 
Inductor Ligand Treatment Related to Tumor Necrosis Factor 
Apoptosis 
Tregs 
Regulatory T cells 
TTOR 
Time to objective response 
ULN 
Upper limit than normal 
WBC 
Leukocytes 
WOCBP 
Women of reproductive age 
  
  
V. CONTRIBUTION OF THE PROJECT IN THE ADVANCE OF THE KNOWLEDGE 
IN  YOUR OWN THEME AND IN YOUR KNOWLEDGE AREA 
 
The current unmet need in NSCLC continues to be the majority of subjects who do not have known 
mutations, or who present mutations for which there is no targeted treatment. In addition, once the 
subjects have developed resistance to TKI, there are few treatment options and the disease progresses 
rapidly. Docetaxel continues to be the reference treatment in this line of treatment since there are few 
additional options 
Based 
on 
the 
background, 
a 
randomized 
phase 
II 
clinical 
trial 
comparing 
MK-
3475 ( Pembrolizumab ) against docetaxel as a standard second-line therapy in patients with advanced 
NSCLC has been launched (NCT01905657), However, there is no study in which the synergistic activity 
of Docetaxel + MK-3475 ( Pembrolizumab ) was evaluated , this could open the possibility of using this 
medication simultaneously with docetaxel as a standard therapy in patients with disease progression 
despite a double regimen based on platinum . 


17 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
  
 
OBJECTIVES 
  
Primary objective  
 
To compare the objective response rate (ORR) of MK-3475 / Docetaxel compared to Docetaxel 
alone in patients with previously treated NSCLC. 
Secondary objectives: Secondary objectives include the following: 
 
To compare the OS of MK-3475 ( Pembrolizumab ) / Docetaxel compared to docetaxel alone in 
patients with previously treated NSCLC. 
 
To compare progression-free survival (PFS) of MK-34 75 / Docetaxel compared to Docetaxel 
alone. 
 
To evaluate the clinical benefit of MK-3475 / Docetaxel versus docetaxel, in the PD-L1 + protein 
expression subgroups versus PD-L1 negative.  
 
To assess the proportion of subjects showing a progression of disease-related symptoms, 
measured by LCSS, with MK-3475 / Docetaxel and docetaxel. 
 
To evaluate the overall safety and tolerability of MK-3475 / Docetaxel versus docetaxel. 
 
To evaluate the general health status of the subject using the EORTC QLQ C30 and LC-
13 questionnaire. 
 
To evaluate the percentage of expression and the average intensity of fluorescence CD279 (PD-1), 
CD274 (PD-L1), CD47 and CD172a / b (SIRP α / β ) in the populations of immune cells by 
multiparametric blood flow cytometry peripheral of patients before the start of treatment and at the 
end of the 4 cycle. 
  
- Virgin CD4 T lymphocytes, central memory, effectors and effector memory          
- Virgin CD8 lymphocytes, central memory, effectors and effector memory          
- Double negative lymphocytes          
- Memory and Virgin Regulatory T lymphocytes          
- Th1, Th2 and Th17 lymphocytes          
- B lymphocytes in transition, plasma, Memory and Virgins          
-Classic and non-classic monocytes          
- Myeloid and Plasmacytoid dendritic cells          
- Mature and immature neutrophils          
- Natural Killer immunoregulatory and cytotoxic cells          
- NKT cells          
 
* To quantify plasma levels of soluble mediators of the immune response in peripheral blood 
in the patients before the initiation of treatment and at the end of the four-cycle. 
- Cytokines: IL-1 , IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A.          
- Growth Factors: TNF- , TGF- , VEGF, IFN- .          
- Chemokines: CXCL8 / IL-8, CXCL9 / MIG, CXCL10 / IP-10, CCL2 / MCP-1, CCL5 / RANTES.          
  
 
 VII. HYPOTHESIS 


18 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
  
In patients with metastatic NSCLC previously treated with double platinum-based chemotherapy, 
administration MK-3475 / Docetaxel increases the overall response rate (ORR) compared with the 
administration of docetaxel alone. 
  
  
VIII. GOALS PER YEAR 
  
Approximately 70 patients will be randomized in the two treatment arms in a 1: 1 ratio. The study 
requires at least 45 deaths. It will take approximately 24 months to obtain the required number of 
deaths for the final OS analysis (12 months for accumulation and 12 months for survival monitoring). It 
is projected that an observed risk ratio of 0.74 or less, corresponding to 2.5 months or more of 
improvement in the median OS (7 vs. 9.5 months) would result in a statistically significant improvement 
in the final OS analysis. 
The team of researchers will conduct eligibility assessments for the study during the patient selection 
phase for approximately 6 months, subsequently safety assessments at each visit, which will include 
physical examination, vital signs and laboratory tests, as well as Continuous monitoring of the survival 
and clinical and radiological response of the subjects who are taking the study drug, and every 3 
months through personal or telephone contact after the subjects suspend the study drug, these 
activities are outlined in the tables contained in the Procedures section per visit. 
 
IX.   RESEARCH STRATEGIES OR METHODOLOGIES 
  
UNIVERSE OF STUDY AND DESIGN 
This is an open, randomized Phase 2 study in adult subjects ( 18 years of age) men and women with 
NSCLC who progressed to the first line of platinum-based chemotherapy. Subjects will be randomized 
to MK-3475 ( Pembrolizumab ) / Docetaxel vs. Docetaxel only in a 1: 1 ratio. 
Initial Cohort 
To ensure that the concomitant administration of docetaxel and MK-3475 is safe, a cohort of ten 
patients who will receive a fixed dose of 200mg will be followed. 
  
Dose Increase 
Since we will only use a fixed dose of 200 mg, a dose increase study is not required. 
  
Safety Assessment 
The safety assessment will be determined by concomitant review of laboratory tests (blood and urine 
samples to assess clinical parameters), pregnancy test (if warranted), ECOG, physical examination 
including measurement of vital signs, electrocardiogram (ECG ), and adverse events. Safety will also 
include immunological safety assessments (serum autoimmunity tests, inflammation events regardless 
of causation and immunogenicity). 
  
DESIGN AND SAMPLE SIZE: 
Study design 


19 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
 
 
 
 
 
 
 
 
Sample size: 
 
The sample size was calculated to estimate a two-sample proportion with a difference of 25%. The null 
hypothesis stated that the proportion between groups would be equal (Ho:P2=P1), whereas the 
alternative hypothesis stated that the proportion between groups would not be equal (Ha:p2 
(7%)!=p1(32%)). The alpha value was set at 0.05, and power was set at 0.80. Therefore, the sample 
size estimate resulted in 78 patients (39 patients per group). 
Inclusion criteria 
1) Signed written informed consent       
a) Patients must have signed and dated a written informed consent form approved by the IRB / IEC 
in accordance with regulatory and institutional guidelines. This must be obtained before 
performing any procedure related to the protocol that is not part of the patient's normal care.       
b) Patients must be willing and able to comply with scheduled visits, the treatment program, 
laboratory tests including filling in the questionnaires of the results reported by the patient and 
other study requirements.       
 
 
2) Target population      
                                                    
a) Subjects with locally advanced non-squamous cell NSCLC, histologically or cytologically 
documented, who present with Stage IIIB / Stage IV or recurrent disease after receiving 
radiation treatment or surgical resection.       
b) Men and women 18 years of age.       
c) Performance status of the Eastern Cooperative Cancer Group (ECOG) 1.       
d) Subjects must have measurable disease by CT or MRI according to RECIST 1.1 
criteria; Radiographic Evaluation of Tumor performed within 28 days before randomization.       
e) Target lesions may be located in a previously irradiated field if there is a progression of 
documented (radiographic) disease at that site.       
Disease 
progression 
after 
platinum 
based 
chemothera
py in first 
and second 
line 
 
Docetaxel   
75mg/m2  MK-3475(Day 8) every 3 weeks for 6 
cycles  + 200mg every 3 weeks until progression 
5mg/m2  MK-
3475(Day 8) every 3 
weeks for 6 cycles 
Arm  A 
Arm B 
Randomizationn   
Primary criteria 
 ORR 
Secondary criteria 
OS, PFS , QoL. 
Pembrolizumab, 
200 mg fixed dose 
every 3 weeks until 
progression. 
If progression” 
cross over” 


20 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
Subjects must have experienced progression or recurrence of the disease during or after a 
previous chemotherapy regimen containing platinum for metastatic disease. This includes 
subjects who meet the following criteria: 
(1) Subjects who received pemetrexed, bevacizumab, or erlotinib as maintenance 
treatment (non-progressors with double platinum-based chemotherapy) and progressed 
are eligible. However, patients with wild-type EGFR who received a tyrosine kinase 
inhibitor after the failure of previous platinum-based treatment are excluded.     
(2) Patients who received double chemotherapy based on adjuvant or neo-adjuvant 
platinum (after surgery and/or radiation) and developed recurrent or metastatic disease 
within 6 months after finishing treatment are eligible     
(3) Subjects with recurrent disease> 6 months after receiving platinum-based adjuvant or 
neoadjuvant chemotherapy are eligible, who also subsequently progressed during or 
after a double platinum-based regimen to treat recurrences     
(4) Subjects with a known EGFR mutation and who received a TKI EGFR (erlotinib, gefitinib 
or experimental) and double platinum-based chemotherapy (regardless of the order of 
administration).     
(5) Subjects with a known translocation of ALK who received double platinum-based 
chemotherapy and an ALK inhibitor (crizotinib or experimental)     
(6) Patients who have received> 30Gy to the chest should have waited a minimum of 6 
months from the end of the radiation scheme at the beginning of pembrolizumab.     
f) A blood sample must be available for the evaluation of biomarkers.        
g) All baseline laboratory requirements will be evaluated and must be obtained -14 days from 
randomization. The scrutiny laboratory values must meet the following criteria:       
i) WBC 2000 / µL        
ii) Neutrophils 1500 / µL      
iii) Platelets 100 x 10³ / µL     
iv) Hemoglobin 9.0 g / dL     
v) Serum creatinine 1.5 X ULN or creatinine clearance> 40 mL / minute (using the 
Cockcroft / Gault formula)       
Women: CrCl = (140 - age in years) x weight in kg x 0.85 
                                          72 x serum creatinine in mg / dL 
  
Men: CrCl = (140 - age in years) x weight in kg x 1.00 
                                          72 x serum creatinine in mg / dL 
vi) AST 1.5 X ULN     
vii) ALT 1.5 X ULN   
viii) Total bilirubin 1.5x ULN (except in subjects with Gilbert's syndrome, who must have 
total bilirubin <3.0 mg / dL) 
 
h) The previous treatment with radiotherapy or radiosurgery must have been completed at least 2 
weeks before randomization.      


21 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
i) Patients with a history of previously treated brain metastases may participate if they are stable 
(without evidence of progression verified by image for at least four weeks with neurological 
symptoms that have recovered at baseline), without evidence of new metastases or growth of 
the same , without the use of steroids for at least 7 days prior to the start of the study 
treatment or under a stable dose 10mg daily . The fulfilment of all the previously mentioned 
requirements makes them eligible to participate in the understanding that they are 
asymptomatic. This exception does not include carcinomatous meningitis that is excluded 
despite presenting clinical stability.        
 
3) Age and Reproductive Status       
 
a) Women with reproductive potential (WOCBP) should use contraception methods based on the 
tables found in Appendix 2. When a teratogenic study drug is used, and/or a drug for which 
there is insufficient information available to assess its teratogenicity (no pre-clinical studies 
have been conducted), it is required to use a highly effective method of contraception (failure 
rate less than 1% per year). Individual methods of contraception should be determined by 
consulting the investigator.       
b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity of 25 IU / L or 
equivalent units of HCG) 24 hours before starting the product under investigation.       
c) Women should not be breastfeeding.       
d) Sexually active men with WOCBP should use any contraceptive method with a failure rate of less 
than 1% per year. The researcher should review the contraceptive methods and the period of 
time during which contraception should be used. Men who are sexually active with WOCBP 
must follow the birth control instructions for a period of 90 days, plus the time required for the 
investigational drug to undergo five half-lives.      
 
Exclusion criteria 
1. 
Exceptions for Target Disease 
 
a) Subjects with carcinomatous meningitis.       
b) Subjects with active CNS metastases are excluded. Subjects are eligible if CNS metastases are 
treated appropriately and if the subjects return neurologically to the baseline (except for 
symptoms or residual signs related to CNS treatment), at least for 2 weeks before 
recruitment. In addition, subjects should not be taking corticosteroids, or they should be taking a 
stable dose or that is decreasing ≤ 10 mg daily of prednisone (or equivalent).      
  
2. 
Clinical History and Concurrent Diseases 
 
a) Any serious or uncontrolled medical disorder or active infection with hepatitis or HIV that could be 
reactivated.       
b) Other malignancies that require concurrent intervention.       
c) Subjects with previous malignancies (except skin cancers other than melanoma, and the 
following cancers in situ: bladder, gastric, colon, cervical / dysplasia, endometrial, melanoma, or 


22 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
breast) are excluded unless remission has been achieved Complete at least 2 years before 
entering the study and do not require additional treatment or anticipate that additional treatment 
will be required during the study period.       
d) Subjects with a condition that requires systemic treatment with corticosteroids (> 10 mg daily of 
prednisone or equivalent), or other immunosuppressive medications within 14 days before 
randomization. Inhaled or topical corticosteroids and doses of adrenal replacement steroids> 10 
mg daily or equivalent is allowed in the absence of active autoimmune disease.       
e) Subjects with known or suspected active autoimmune disease. Subjects with vitiligo, type I 
diabetes mellitus, residual hypothyroidism requiring hormonal replacement, or conditions that 
are not expected to recur in the absence of an external trigger may be recruited.       
f) All toxicities attributed to a previous treatment against cancer other than alopecia and fatigue 
must have been resolved to grade 1 (NCI CTCAE version 4) or to baseline, before 
administration of the study drug.        
g) Previous treatment with vaccines against the tumour or other immuno-stimulating anti-tumour 
agents.       
h) Previous treatment with anti-PD-1, anti-PD-L1, anti-PD-L-2, anti-CD-137, or anti-CTLA-4 
antibodies (including ipilimumab or any other antibody or drug specifically directed to co-
stimulate T cells or the checkpoint pathways).      
i) Prior treatment with docetaxel.        
j) Subjects with a history of interstitial lung disease.        
k) Subjects must be recovered from the effects of major surgery, or significant traumatic injury at 
least 14 days before the first dose of study treatment.       
 
3. 
Physical Findings and Laboratory Tests 
a) Positive tests for the Hepatitis B virus surface antigen (HBV sAg) or Hepatitis C ribonucleic acid 
(HCV RNA) indicating acute or chronic infection   
b) Known history of positive test for Human Immunodeficiency Virus (HIV) or Acquired 
Immunodeficiency Syndrome (AIDS).   
4. 
Allergies and Adverse Drug Reactions 
a) History of severe hypersensitivity to other monoclonal antibodies.       
b) Previous history of severe hypersensitivity reaction to paclitaxel.       
c) History of allergy or intolerance (unacceptable adverse event) to the components of the study 
drug, or to infusions containing Polysorbate 80.       
5. 
Sexual and Reproductive State 
a) WOCBP pregnant or nursing.       
b) Women with a positive pregnancy test at recruitment or before administration of the study 
medication.       
6. 
Prohibited Treatments and / or Restricted Treatments 
a) Ongoing or planned administration of cancer treatments other than those specified in this 
study.   
b) Use of corticosteroids or other immunosuppressive medications according to the exclusion 
criteria contained in 2d.   
c) Strong CYP3A4 inhibitors (See Section 3.4.1).   


23 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
d) Treatment with any investigational drug 28 days before the first administration of the study 
treatment.  
7. 
Other Exclusion Criteria 
a) Any other serious or uncontrolled medical disorder, active infection, physical examination finding, 
laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the 
investigator, would limit a subject's ability to meet the requirements of the study, which 
significantly increases the risk to the subject, or affects the interpretability of the study results.       
The eligibility criteria of this study have been carefully considered to ensure the safety of the study 
subjects, and to ensure that the study results can be used. 
Elimination criteria: 
Patients withdrawing informed consent, patients with disease progression according to RECIST 1.1, or 
patients presenting unacceptable toxicity. 
Dose of the Groups 
Medicine 
Dose / Potency 
Dose 
frequency 
Route of 
Administration 
Treatment 
Scheme / Period 
Use 
Pembrolizumab 
200 mg 
Every 3 
weeks 
IV infusion 
2 years or until 
progression 
Experimental 
Docetaxel 
75 mg / m 2 
Every 3 
weeks 
IV infusion 
6 cycles 
Experimental 
/ Control 
The dosage range of pembrolizumab can be modified if toxicity occurs, it is mentioned in the section on 
Modification and Selection of the Dose. 
  
Criteria 
For subjects previously assigned to the Docetaxel arm and who experienced disease 
progression by RECIST 1.1 criteria. 
 They must continue to meet all the inclusion criteria specified above and all exclusion criteria 
with the exception of criterion 2 (i). 
  
 Any toxicity from previous therapy must be resolved to the baseline or Grade 1 (except for 
alopecia, fatigue, and neuropathy, which may be grade 2) before beginning the crossing to 
Pembrolizumab. 
  
The clinical activity of Pembrolizumab in patients with advanced NSCLC who have progressed after 
second-line chemotherapy may be similar to or potentially greater than that of third-line 
chemotherapy. Therefore, this study will provide subjects who were randomly assigned to arm B the 
option of receiving monotherapy with Pembrolizumab in those with documented progression, 
conditioned on the progression being confirmed after review and said treatment being evaluated by the 
principal investigator. It is recognized that this crossing of treatment to Pembrolizumab could reduce 
any possible benefit in the OS, but it will not affect the PFS. 


24 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
Drug allocation process (randomization) 
After the subject's eligibility is established and informed consent has been obtained, the subject will be 
recruited and assigned a number to be randomized. Each subject that signs the informed consent must 
have an assigned subject number. Once recruited, recruited subjects who have signed in informed 
consent and who meet all eligibility criteria will be ready to be randomized. Subjects who meet all 
eligibility criteria and who are randomized will be assigned to one of two treatment groups. 
Patient Safety Procedures 
The safety assessment will be determined by examinations of clinical laboratory tests (blood and urine 
sampling for clinical laboratory parameters), pregnancy tests, ECOG functional status, physical 
examination that includes measurements of vital signs and Adverse events. 
Patients will be treated with docetaxel at 75 mg / m 2 every 3 weeks on day 1 of the cycle, on day 8 of 
the cycle (1 week later) MK-3475 ( Pembrolizumab ) will be applied intravenously at a fixed dose of 200 
mg every 3 weeks until disease progression compared with docetaxel only intravenously administered 
at two is 75 mg / m 2 on day 1 of the first cycle, with subsequent toxicity assessment on day 8 (1 week 
after) of the first cycle Then, the D1 of each cycle will only be evaluated for treatment (every 3 
weeks) until 6 cycles are completed , because of unacceptable toxicity and / or investigator criteria, 
docetaxel can be suspended and continue only with MK-3475 or close monitoring. 
For patients experiencing limiting toxicities, the dose modification criteria of MK-3475 and Docetaxel will 
be any grade 4 toxicity such as hypothyroidism, diarrhoea, increased level of aminotransferase, renal 
failure, dyspnea, pneumonitis that lasted more than 1 week. 
Patients will be treated with MK-3475 until disease progression, unacceptable toxicity or revocation of 
consent, and Docetaxel until completing 6 cycles will be treated at the discretion of the principal 
investigator. 
Modification and Selection of the Dose. 
Adverse events (both severe and non-severe) associated with exposure to Pembrolizumab may present 
an immunological aetiology. These adverse events may occur just after the start of the first dose or 
different 
months 
after 
the 
last 
dose 
of 
treatment. Adverse 
events 
probably 
caused 
by Pembrolizumab should be classified as drug-related or serious or life-threatening toxicities, 
according to Table 1, presented below. 
  
Table 1. Dose Change Guidelines for Adverse Drug-Related Events 
Toxicity 
Stop 
treatment 
for 
Grade 
Treatment re-start time 
Suspend in the Patient 
Diarrhea / Colitis 
2-3 
  
Toxicity resolves or becomes 
Grade 0-1. 
The toxicity is not resolved within 12 weeks of the 
last dose or inability to reduce the steroid to 10 mg or 
less of prednisone or its equivalent per day 
within 12 weeks. 
4 
Suspend permanently. 
Suspend permanently. 
Increase in AST, ALT, 
or Bilirubin to 
2 
Toxicity resolves or becomes 
Grade 0-1. 
Toxicity does not resolve within 12 weeks of the last 
dose 


25 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
Toxicity 
Stop 
treatment 
for 
Grade 
Treatment re-start time 
Suspend in the Patient 
3-4 
Suspend permanently. 
(see exception 1 ) 
Suspend permanently. 
Type 1 diabetes (recently 
diagnosed ) or 
Hyperglycemia 
DM T1 or 
3-4 
Suspend Pembrolizumab in case 
of newly diagnosed type 1 DM or 
Grade 3-
4 hyperglycemia associated with 
evidence of beta-cell failure. 
Restart Pembrolizumab when patients are clinically 
and metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves or becomes 
Grade 0-1. 
The toxicity is not resolved within 12 weeks of the 
last dose or inability to reduce the steroid to 10 mg or 
less of prednisone or its equivalent per day 
within 12 weeks. 
4 
Suspend permanently. 
Suspend permanently. 
Hyperthyroidism 
3 
Toxicity resolves or becomes 
Grade 0-1. 
The toxicity is not resolved within 12 weeks of the 
last dose or inability to reduce the steroid to 10 mg or 
less of prednisone or its equivalent per day 
within 12 weeks. 
4 
Suspend permanently. 
Suspend permanently. 
Hypothyroidism 
2-4 
Treatment with Pembrolizumab can 
be continued while on treatment for 
dysfunction thyroid On. 
Pembrolizumab treatment can be continued 
while in treatment for dysfunction thyroid On. 
Infusion Reaction 
3-4 
Suspend permanently. 
Suspend permanently. 
Pneumonitis 
2 
Toxicity resolves or becomes 
Grade 0-1. 
The toxicity is not resolved within 12 weeks of the 
last dose or inability to reduce the steroid to 10 mg or 
less of prednisone or its equivalent per day 
within 12 weeks. 
3-4 
Suspend permanently. 
Suspend permanently. 
Kidney Failure or Nephritis 
2 
Toxicity resolves or becomes 
Grade 0-1. 
The toxicity is not resolved within 12 weeks of the 
last dose or inability to reduce the steroid to 10 mg or 
less of prednisone or its equivalent per day 
within 12 weeks. 
3-4 
Suspend permanently. 
Suspend permanently. 
Any other toxicity related 
to Medication 2 
3 or Grave 
Toxicity resolves or becomes 
Grade 0-1. 
The toxicity is not resolved within 12 weeks of the 
last dose or inability to reduce the steroid to 10 mg or 
less of prednisone or its equivalent per day 
within 12 weeks. 
4 
Suspend permanently. 
Suspend permanently. 
Note: Suspend permanently in case of any serious EA or Grad or 3 related to the medication that is recurring or a life-threatening 
event. 
1 In the event that patients present with metastases and begin treatment with AST or Grade 2 ALT, if AST or ALT increases greater than or equal to 
50% relative to baseline and for at least one week then it should be suspended in patients. 
2 Patients with persistent grade 2 AD may be temporarily suspended according to the doctor's opinion. It should be discontinued permanently if 
Grade 2 adverse AE persists for which treatment with the study medication has been temporarily suspended, and those who do not recover 
from Grade 0-1 within 12 weeks of the last dose. 
 
Dose Modification 
The application of MK-3475 will be stopped in case of haematological or grade 3 toxicities for drug-
related non-haematological, including laboratory, serious or life-threatening abnormalities as in Table 
2 below. 
Dose modification rules for adverse events related to the drug. 
Table 2 : Dose modification rules for adverse events related to the drug and experimental. 


26 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
Toxicity 
Grade 
Maintain 
Treatment 
(Y / N) 
Time to 
restart 
treatment 
Dose and 
scheme to 
restart 
treatment 
Treatment 
Suspension 
Haematological Toxicity 
  
1, 2 
Do not 
N / A 
N / A 
N / A 
3* 
* Excluding 
neutropenia, 
anaemia, and 
grade 3 
thrombocytopenia 
Yes 
Toxicity 
Resolved or 
grade 1 
The 
application 
interval can be 
increased by 1 
week 
Toxicity does 
not resolve 
after 12 weeks 
of infusion 
The permanent 
interruption 
must be 
considered for 
any serious or 
life-threatening 
event 
4 
Yes 
Toxicity 
Resolved or 
grade 1 
The 
application 
interval can be 
increased by 1 
week 
Non-
 Hematological Toxicity 
  
Note: Exception to be 
treated similar to grade 1 
toxicity 
• 2 grade alopecia 
• 2 degree fatigue 
one 
Do not 
N / A 
N / A 
N / A 
2 
Consider 
retention 
for 
persistent 
symptoms 
Toxicity 
Resolved or 
grade 1 
EA Clinically 
resolves in 4 
weeks: The 
same dose 
and schedule 
Clinically EA 
does not 
resolve in 4 
weeks: You 
can increase 
the dosage 
interval by 1 
week for each 
case 
Toxicity does 
not resolve 
after 12 weeks 
of infusion 
  
3. 4 
  
Yes 
  
Toxicity 
Resolved or 
grade 1 
The 
application 
interval can be 
increased by 1 
week 
Toxicity does 
not 
resolve after 12 
weeks of 
infusion 
Permanent 
interruption 
must be 
considered for 
any serious or 
life-threatening 
event 
 
  
In case the toxicity is not resolved to grade 0-1 within 12 weeks after the last infusion, the treatment 
should be discontinued. Subjects with an adverse laboratory event still in grade 2 after 12 weeks may 
continue treatment if, in the opinion of the investigator, it is an asymptomatic and controlled reaction. 
  
Subjects who experience a recurrence of the same serious or life-threatening event in the same or 
greater degree, with MK-3475 ( Pembrolizumab ) should be discontinued trial treatment. 
The dose of Docetaxel can be modified in patients presenting with febrile neutropenia, neutropenia 
<500 cells / mm 3 for more than a week despite support with granulocyte stimulating factor, severe skin 


27 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
reactions or other non-hematological grade 3/4 toxicity according to CTCAE criteria during treatment 
with Docetaxel, if required it will be carried out according to the following table : 
 
Table 3: Dose modification standards for adverse events related to Docetaxel. 
Docetaxel dose reduction 
Dose level 
Docetaxel 
Initial dose 
75 mg / m 2 
First reduction 
55 mg / m 2 
Second reduction 
37.5 mg / m 2 
Third reduction 
Discontinue Docetaxel 
  
  
Rescue Medications and Supportive Care 
 
 
Supportive Care Guidelines 
  
Subjects should receive therapeutic support measures when deemed necessary by the investigator that 
includes but is not limited to the elements described below: 
  
o Diarrhoea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhoea, abdominal pain, blood or mucus in the stool, with or 
without fever) and intestinal perforation (such as peritoneal signs and ileus). In 
symptomatic subjects, infectious etiologies should be ruled out, and if the symptoms are 
persistent and/or severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (grade 3), MK-3475 should be permanently 
discontinued and treatment with systemic corticosteroids should be initiated with a dose 
of 1 to 2 mg/kg/ day of prednisone or equivalent. When symptoms improve to grade 1 or 
less, the decrease in corticosteroids should be initiated and continued for at least 1 
month. 
o In subjects with moderate enterocolitis (grade 2), MK-3475 should be suspended and 
anti-diarrheal treatment should be initiated. If the symptoms are persistent for more than 
a week, systemic corticosteroids should be initiated (for example, 0.5 mg /kg/day of 
prednisone or equivalent). When symptoms improve to grade 1 or less, the decrease in 
corticosteroids should be initiated and continued for at least 1 month. 
o All subjects experiencing diarrhoea should advise drinking plenty of clear liquids. If 
there is sufficient fluid intake by mouth, it is not necessary to replace fluids and 
electrolytes by IV infusion. 
o Nausea / Vomiting: Nausea and vomiting should be treated aggressively, and should 
be considered in the cycles following the administration of prophylactic antiemetic 


28 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
treatment according to medical practice. Subjects should be strongly encouraged to keep 
the intake free of oral fluids. 
o Anti-infectives: Subjects with a documented infectious complication should receive oral 
or intravenous antibiotics or other anti-infectious agents as deemed appropriate by the 
investigator. 
o Management of infusion reactions: acute infusion reactions (which may include 
cytokine release syndrome, angioedema or anaphylaxis) are different from allergic 
reactions/hypersensitivity, although some of the manifestations are common to both 
entities. Signs and symptoms usually develop during or shortly after the infusion of the 
drug and usually resolve completely within 24 hours of the end of the infusion. Signs / 
symptoms may include: Allergic reaction / hypersensitivity (such as drug fever); Arthralgia 
(joint 
pain); Bronchospasm; Cough; Dizziness; Shortness 
of 
breath 
(trouble 
breathing); Fatigue 
(asthenia, 
lethargy, 
malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle 
pain); Sickness; Itching 
/ 
itching; Rash 
/ 
peeling; Rigors 
/ 
chills; Sweating 
(diaphoresis); tachycardia; Tumor pain (onset or exacerbation of pain due to tumor 
treatment); Hives (rash, hives, hives); Vomiting 
o Table 4 shows the treatment guidelines for subjects experiencing an infusion reaction 
associated with the administration of MK-3475. 
o The use of palliative radiotherapy to bone lesions that remain symptomatic will be 
allowed, treatment will be suspended one week before, during and after treatment for 
patient safety 
 
Table 4 Infusion Reaction Treatment Guidelines 
  
NCI CTCAE grade 
Treatment 
subsequent dose medication 
Grade 1 
Mild reaction; infusion 
interruption is not 
indicated; intervention not 
indicated 
  
Increased control of vital signs as 
medically indicated until the subject is 
considered medically stable in the 
opinion of the investigator. 
  
Any 
Grade 2 
It requires infusion interruption 
but responds quickly to 
symptomatic treatment (for 
example, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for <= 24 
hrs 
  
Stop infusion and monitor symptoms. 
Appropriate additional medical therapy 
may include but is not limited to: 
IV liquids 
antihistamines 
NSAID 
Paracetamol 
narcotics 
Increased control of vital signs as 
medically indicated until the subject is 
considered medically stable in the 
opinion of the investigator. 
If the symptoms resolve within an hour 
of stopping the infusion of the drug, the 
infusion can be restarted at 50% of the 
  
The subject can be 
premedicated 1.5 hours (± 
30 minutes) before infusion 
of MK-3475 with: 
  
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
  
Paracetamol 500-1000 mg 
po (or equivalent dose of 
antipyretic). 


29 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
NCI CTCAE grade 
Treatment 
subsequent dose medication 
initial infusion rate (for example, from 
100 ml / hr to 50 ml / h). Otherwise, the 
dosage will be carried out until the 
symptoms resolve and the issue should 
be premedication for the next dose. 
Subjects who develop grade 2 toxicity 
despite adequate premedication should 
be permanently interrupted from the 
subsequent administration of the trial 
treatment. 
Grades 3 or 4 
3rd grade: 
Prolonged (ie, does not 
respond quickly to 
symptomatic medication and / 
or brief interruption of the 
infusion); recurrence of 
symptoms after initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg renal failure, 
pulmonary infiltrates) 
  
Grade 4: 
Life threatening; vasopressor 
or ventilatory support indicated 
  
Stop Infusion 
Appropriate additional medical therapy 
may include but is not limited to: 
IV liquids 
antihistamines 
NSAID 
Paracetamol 
narcotics 
oxygen 
pressors 
Corticosteroids 
Epinephrine 
  
Increased control of vital signs as 
medically indicated until the subject is 
considered medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
The subject is permanently interrupted 
from the subsequent administration 
treatment trial. 
  
No subsequent dose 
  
Supportive Care Guide for Pneumonitis 
  
Subjects with symptomatic pneumonitis should stop receiving MK-3475 and have an evaluation. The 
evaluation may include imaging studies (Chest Tomography, X-rays) and lung function tests to rule out 
other causes, such as an infection. If the subject is determined pneumonitis associated drug study, the 
suggested treatment plan is detailed in Table 5. 
  
  
Table 5 Recommended approach for Pneumonitis Management  
Drug-associated 
pneumonitis 
Maintain / Discontinue MK-
3475? 
Support Treatment 
Grade 1 (asymptomatic) 
No action 
No intervention 
Grade 2 
Maintain the MK-3475, you 
can return to your treatment 
if it improves to grade 1 or 
resolves in 12 weeks 
Systemic corticosteroids are indicated. 
Grade 3 and Grade 4 
Suspend MK-3475 
Systemic corticosteroids are indicated. The use 
of infliximab may be indicated, as appropriate. 
  


30 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 in the 12 weeks, the following rules will apply: 
• In the first episode of pneumonitis, the dosage interval can be increased by one week in subsequent 
cycles 
• The second episode of pneumonitis - permanently discontinue MK-3475 if subject to reexposure 
develops pneumonitis ≥ Grade 2 
MK-3475 
Prior medications are not recommended for the start of dosing. 
Docetaxel 
Dexamethasone should be administered with a dose of 8mg. 
Treatment arms : 
Arm A: Will include treatment with Docetaxel at 75 mg / m2 every 3 weeks with MK-3475, 200 mg every 
3 weeks until progression. 
Arm B: Will include treatment with Docetaxel at 75 mg / m2 every 3 weeks, where there will be the 
possibility of crossing to start treatment with MK-3475, 200 mg every 3 weeks until progression. 
Methods and techniques that will be used for the analysis and interpretation of the data 
Primary Efficacy Assessment 
All subjects will be monitored by a radiological evaluation on a calendar, first evaluation at 9 weeks later 
every 6 weeks, to determine changes in tumour size. The RECIST 1.1 criteria will be used for the 
evaluation ( see Appendix 1 ). To determine the overall response rate (ORR), patients with partial 
response and complete response evaluated according to RECIST 1.1 criteria will be taken into account. 
Secondary and exploratory efficacy evaluations 
Every effort will be made to collect the survival data of all subjects, including subjects withdrawn from 
treatment for any reason, who are eligible to participate in the study and who have not withdrawn their 
consent for the collection of data from survival. If the death of the subject is not reported, all dates in 
this study that represent a date of contact with the subject will be used to determine the last date on 
which it was known that the subject was alive. 
Additional data will be collected to determine the change in the proportion of disease-related symptoms 
in subjects with NSCLC, using the EORTC QLQ-LC13 questionnaire. 
Evaluation of the modification of symptoms. 
The results reported by the patients (PRO) will be measured using the following two self-applied 
questionnaires and validated: EORTC QLQ-C30 and EORTC QLQ-LC13. 
Subjects will be asked to fill out the questionnaires before performing any clinical activity during the 
study clinic visits in the scrutiny, on the days of the start of the cycle every 9 weeks, at the end of the 
treatment or when withdrawing from the study. 


31 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
Questionnaires will be provided in the language preferred by the subject. 
Procedures per visit (Annex protocol diagram) 
 
                     Flowchart / Calendar of Times and Events 
Table 6 .1A: Screening Assessments and Procedures for GROUPS A and B              
Process 
Scrutiny 
Visit 
Notes 
Eligibility Assessments 
  
  
Informed consent 
X 
  
Inclusion / Exclusion Criteria 
X 
Assessed before randomization 
Clinic history 
X 
  
Security Assessments 
  
  
Vital Signs and Oxygen Saturation 
X 
Vital signs include: Temperature, BP, HR, RR 
O 2 saturation by pulse oximetry (obtained at rest, also 
monitor the amount of supplemental oxygen, if 
applicable) 
Obtain vital signs at the screening visit and within 72 
hours after the first dose 
Physical Measurements (including 
Performance Status) 
X 
Height and Weight and ECOG status 
Lab tests 
X 
Done locally 14 days before randomization 
CBC with differential, Blood chemistry in serum 
(BUN or serum urea level, serum creatinine, albumin, 
sodium, potassium, calcium, magnesium, phosphate, 
chlorine and bicarbonate), AST, ALT, total bilirubin, 
alkaline phosphatase, glucose, LDH, and endocrine 
panel (including free TSH, T3 and T4), Hep B and C- 
(HBV sAg, HCV RNA), 
Pregnancy test 
X 
Performed 24 hours before randomization (in serum 
or urine only for women of reproductive age) 
Evaluation of Adverse Events (AE) and 
Serious Adverse Events (SAE) (of signs 
and symptoms) 
X 
After obtaining the Informed Consent, all the signs 
and symptoms will be evaluated 14 days before 
randomization and beginning the study treatment. 
Concomitant Drug Collection 
X 
14 days before randomization 
Efficacy Assessments 
  
  
Radiographic Evaluation of Tumor 
(Thorax and abdomen) 
X 
It must be done 28 days before randomization. 
  
Electrocardiogram 
X 
Only on this visit will it take place 
  Protocol version # 1 amendment 3. Date: July 21 of 2017. 


32 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
 
 
one 
  
Table 6 .1B: Evaluations During the Study for GROUP A (Docetaxel / MK 3475 Pembrolizumab)              
Process 
C1D1 
C1D8 
Every 3 cycles 
(6 weeks 5 
days) 
Notes 
(add notes on the cycles) 
Security Assessments 
  
  
  
  
Vital Signs and Oxygen 
Saturation 
  
X 
  
X 
  
  
Vital signs include: Temperature, BP, HR, RR 
O 2 saturation by pulse oximetry should be at rest 
without supplemental oxygen (also monitor the 
amount of supplemental oxygen, if 
applicable); Oximetry should be performed before 
dosing and at any time when the subject has new or 
worsening respiratory symptoms. 
Evaluation of Adverse Events 
(AE) and Serious Adverse Events 
(SAE) 
Related to the treatment. Evaluated using the NCA CTCAE v. 4.0 
Physical measurements (including 
Performance Status) 
X 
X 
  
Including Weight and ECOG status 
Complete blood counts (CBC) 
(Results obtained before dosing 
on infusion days) 
X 
X 
  
Includes differential WBC count, ANC, 
lymphocyte count, haemoglobin, hematocrit, and 
platelet count 
Blood Chemistry Tests 
X 
X 
  
Blood chemistry (BUN or serum urea level, serum 
creatinine, sodium, potassium, calcium, 
magnesium, phosphate, chlorine), LDH, glucose 
Liver Function Tests 
(Results obtained 72 hours before 
dosing on infusion days) 
X 
X 
  
It includes aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), total bilirubin, 
alkaline phosphatase, albumin. 
Endocrine Tests 
X 
  
X 
TSH (see free T3 and T4 if the result is abnormal) 
every 6 weeks (+/- 5 days) throughout the study 
from C1D1 
Concomitant Meds Review 
X 
X 
  
It must be checked at each visit 
Pregnancy test 
  
  
X 
The serum or urine test should be performed every 
6 weeks. 
Efficacy Assessments 
  
  
  
  


33 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
Table 6 .1B: Evaluations During the Study for GROUP A (Docetaxel / MK 3475 Pembrolizumab)              
Process 
C1D1 
C1D8 
Every 3 cycles 
(6 weeks 5 
days) 
Notes 
(add notes on the cycles) 
Radiographic Tumor Evaluation 
  
  
X 
Evaluations should include thorax and abdomen 
(with contrast). It must be done 5 days from the 
date of the visit. According to RECIST criteria 
1.1. The tumour assessments should continue 
every 6 weeks ( 5 days), starting at week 9 ( 5 
days) from randomization until it is documented 
disease progression or suspension of treatment, 
whichever comes later. 
Evaluation of Patient-Reported 
Results (PRO) 
X 
  
  
For C1D1 - performed after randomization, but 
BEFORE the first dose (day -3 to +1).  
  
For visits during the study: Evaluations (EORTC 
QLQ-C30 and EORTC QLQ-LC13) will be carried 
out BEFORE any procedure and treatment of the 
study. They will be carried out every 9 weeks. 
Clinical Drug Supplies 
  
MK -3475 Pembrolizumab 
(10mg / Kg) on day 8 of the 
cycle 
Docetaxel 75 mg / m2 on day 1 
of the cycle 
  
  
X 
X 
  
  
Every 21 days 
Record the start and 
end times of the 
Study Drug Infusion. 
Premedication with 
Dexamethasone 8mg. 
 
 
 
        Table 6 .1C: Evaluations During the Study for GROUP B (Docetaxel)              
Process 
C1D1 
C1D8 
5 days 
Every Cycle 
every 3 weeks 
on Day 1  
( 5 days) 
Every 2 cycles 
(6 weeks 5 
days)  
Notes 
  
Security 
Assessments 
  
  
  
  
  
Vital Signs and 
Oxygen 
Saturation 
  
X 
  
X 
  
X 
  
Temperature, BP, HR, RR, O2 
saturation by pulse oximetry 
(obtained at rest without 
supplemental O2, before dosing 
and at any time when a subject 
has new or worsening respiratory 
symptoms) 
Physical 
X 
X 
X 
  
Includes Weight (calculated BSA) 


34 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
        Table 6 .1C: Evaluations During the Study for GROUP B (Docetaxel)              
Process 
C1D1 
C1D8 
5 days 
Every Cycle 
every 3 weeks 
on Day 1  
( 5 days) 
Every 2 cycles 
(6 weeks 5 
days)  
Notes 
  
measurements 
(including 
Performance 
Status) 
and ECOG status 
Evaluation of 
Adverse Events 
(AE) and Serious 
Adverse Events 
(SAE) 
  
-------------------continually-------------
----------------- 
Evaluated using the NCA CTCAE v. 4.0 
Complete blood 
counts (CBC) 
(Results obtained 
before dosing on 
infusion days) 
X 
X 
X 
  
Includes differential WBC count, 
ANC, lymphocyte count 
d, hemoglobin, hematocrit, and 
platelet count 
Blood Chemistry 
Tests 
X 
X 
X 
  
It includes serum creatinine, 
blood urea nitrogen, or blood urea 
level, sodium, calcium, 
magnesium, phosphate, 
potassium, chlorine, glucose, 
LDH, 
Liver Function 
Tests 
(Results obtained 
72 hours before 
dosing on infusion 
days) 
X 
X 
X 
  
It includes aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), total 
bilirubin, alkaline phosphatase, 
albumin. 
Thyroid Function 
Tests 
X 
  
  
X 
TSH (see free T3 and T4 if the 
result is abnormal) 
Concomitant 
Meds Review 
X 
X 
X 
  
Revised at each visit 
Pregnancy test 
  
  
  
X 
The serum or urine test should be 
performed every 6 weeks. 
Efficacy 
Assessments 
  
  
  
  
  


35 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
        Table 6 .1C: Evaluations During the Study for GROUP B (Docetaxel)              
Process 
C1D1 
C1D8 
5 days 
Every Cycle 
every 3 weeks 
on Day 1  
( 5 days) 
Every 2 cycles 
(6 weeks 5 
days)  
Notes 
  
Radiographic 
Tumor Evaluation 
  
  
  
  
  
X 
Evaluations should include thorax 
and abdomen (with contrast. It 
should be done 5 days from the 
date of the visit. According to 
RECIST 1.1 criteria. 
The First Tumor Evaluation 
should be carried out in Week 9, 
and then every 6 weeks ( 5 
days) from week 9 ( 5 days) 
from randomization, until disease 
progression or treatment 
discontinuation is documented, 
whichever occurs most late.  
Evaluation of 
Patient Reported 
Results (PRO) 
X 
  
  
  
For C1D1 - performed after 
randomization, but BEFORE the 
first dose (day -3 to +1).  
  
For visits during the study : 
Evaluations (EORTC QLQ-C30 
and EORTC QLQ-LC13) will be 
performed BEFORE any 
procedure and treatment of the 
study. They will be held every 9 
weeks. 
Clinical Drug 
Supplies 
  
  
  
  
  
Docetaxel (75 mg 
/ M 2 ) 
X 
  
X 
  
Every 21 days . 
Record the start and end times of 
the Study Drug Infusion. 
Premedication with 
Dexamethasone 8mg. 


36 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
STATISTIC ANALYSIS 
Data collection will be done through the electronic file and by a direct interview in the lung cancer 
clinic's office. The information that will be collected will be variables such as age, gender, symptoms, 
date of diagnosis, factors associated with lung cancer such as; smoking, smoking rate, exposure to 
asbestos, wood smoke, hours-years exposed to wood smoke, type and histological subtype, 
response to chemotherapy, among others. 
For descriptive purposes, continuous variables will be measured as arithmetic means, medians and 
standard deviations, categorical variables will be understood in proportions with 95% confidence 
intervals. Differential comparisons will be made using the Student t-test or the Mann-Whitney U test, 
according to the data (Normal and abnormal) determined from the Kolmogorov-Smirnov test. The 
Chi-square test will be used to determine significant differences between categorical variables. The 
probability value less than or equal to 0.05 (p <0.05) is determined statistically significant, with a two-
tailed design. Statistically significant and marginally significant variables (p <0.1) will be included in 
the multivariate logistic regression analysis. Progression-free and overall survival will be calculated 
using the Kaplan-Meier survival tables, while comparisons between subgroups will be analyzed with 
the Log Rank tests or the Breslow tests. 
All statistical analyses will be carried out with the SPSS version 21 software program (SPSS, Inc. 
Chicago, IL, USA). 
ETHICAL CONSIDERATIONS 
Good Clinical Practices 
This study will be conducted in accordance with Good Clinical Practices (GCP), defined by the 
International Conference on Harmonization (ICH) and complying with the ethical principles of the 
European Union Directive 2001/20 / EC and the Code of Federal Regulations of United States, Title 
21, Part 50 (21CFR50).The study will be conducted in compliance with the protocol. The protocol 
and any of its amendments, as well as the subject's informed consent, will receive approval 
/favourable opinion from the Institutional Review Board / Independent Ethics Committee (IRB / IEC) 
before beginning the study. All potential violations must be reported to MSD immediately. A serious 
violation is a violation of the conditions and principles of the CPGs related to the study or the 
protocol, which probably affect, to a significant degree, the safety or physical or mental integrity of 
the subjects of the study or the scientific value of the study. The personnel involved in conducting 
this study will be qualified by their level of education, training and experience to perform their 
respective task (s). This study will not use the services of the study staff when sanctions have been 
appealed. or when there has been scientific misconduct or fraud (eg, cancellation of medical 
license, suspension). 
 
 
Institutional Review Board / Independent Ethics Committee 
Before the start of the study, the researcher must have written and dated the approval / favorable 
opinion of the IRB / IEC for the protocol, consent form, patient recruitment, materials/processes (for 
example, commercials) and any other written information that It will be provided to patients. The 


37 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
researcher or sponsor must also provide the IRC / IEC with a copy of the Researcher's Manual or 
product data sheet, the information provided to the patients and any updates. 
The researcher or sponsor must provide the IRB / IEC with reports, updates and other information 
(for example, urgent safety reports, amendments and administrative letters) in accordance with 
regulatory requirements or institutional procedures. 
Informed consent 
Researchers must ensure that patients are clearly and fully informed about the purpose, potential 
risks and other critical issues related to clinical studies in which patients voluntarily participate. In 
situations where consent cannot be granted by patients, their legally acceptable representatives 
must be clearly and fully informed about the purpose, potential risks and other critical issues related 
to clinical studies in which patients voluntarily participate. 
Researchers must: 
1) Provide a copy of the consent form and written information about the study in the language in which 
the patient is most skilled before participating in the clinical study. The language must be non-
technical and easily understandable.              
2) Give the necessary time for the patient or the legally acceptable representative of the patient to ask 
about the details of the study              
3) Obtain an informed consent signed and dated personally by the patient or the legally acceptable 
representative of the patient and by the person who carried out the discussion of the informed 
consent.              
4) Obtain the approval /favourable opinion of the written informed consent form of the IRB / IEC and any 
other information that will be provided to the patients, before the start of the study, and after all the 
reviews are completed in relation to the new information.              
5) If the informed consent is initially granted by the legally acceptable representative or legal guardian of 
a patient, and the patient subsequently becomes able to perform and communicate their informed 
consent during the study, then the consent must be additionally obtained from the patient.              
6) Review the informed consent whenever new important information that is relevant to the patient's 
consent is available. The investigator, or a person designated by the investigator, must fully inform 
the patient or the legally acceptable representative or legal guardian, of all relevant aspects of the 
study and of any new relevant information for the patient to voluntarily continue with his participation 
in the study. This communication must be documented.              
  
Researchers should ensure that the subjects, or, in those situations where the subjects cannot 
provide consent, their legally acceptable representatives are clearly and fully informed about the 
purpose, potential risks and other critical aspects related to clinical studies in They participate 
voluntarily. 
Researchers must: 
2) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most competent before the clinical study participates. The language should 
not be technical and should be easily understood.       


38 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
Allow the time necessary for the subject or the legally acceptable representative of the subject to ask 
questions about the details of the study. 
Obtain a signed and dated consent form personally by the subject or the legally acceptable 
representative of the subject and by the person who addressed the informed consent talk. 
Obtain the favourable approval/opinion of the IRB / IEC in the form of informed written consent and any 
other information that will be provided to the subjects before the start of the study and after any 
review has been completed for new information. 
If the informed consent is initially granted by the legally acceptable representative or legal guardian and 
subsequently the subject becomes able to make and communicate their informed consent during 
the study, then the consent must also be obtained from the subject. 
Review informed consent whenever important new information that is relevant to the subject's consent 
is available. The investigator, or a person designated by the investigator, must fully inform the 
subject or the legally acceptable representative of the subject or legal guardian of all relevant 
aspects of the study and any relevant new information so that the subject wishes to continue their 
participation in the study. This communication must be documented. 
The consent form must also include a statement that MSD and regulatory authorities have direct 
access to the subject's records. 
The rights, security and welfare of the subjects of the study are the most important considerations 
and should be imposed on the interests of science and society. According to the General Law of 
Health in Research Matters, the format will be signed by 2 witnesses. 
  
3. AGREEMENTS FOR INDEMNIFICATION TO PARTICIPATING PATIENTS BY 
          POTENTIAL DAMAGES DERIVED FROM THE STUDY 
 
4. INCOME FOR RESEARCHERS:  
      a) The income will be distributed according to the regulations                   
         in force in the Institute.  
       b) There is no income, it is a protocol of researchers initiative. 
 
RESEARCH PROTOCOL 
  
  
5. THE STUDY WILL BE CONDUCTED IN ACCORDANCE WITH WHAT IS SIGNED IN: 
 
 
 
 
 
 
 
 
- 
Declaration of Helsinki 
 
- 
Good Clinical Practice 
 
- 
Norms established in the General Health Law in Mexico 
 
 
  
x 
YES              NO                     N/A 
x 
x 
x 


39 
 
        
 Protocol version #1 amendment  3. Date: July 21 of 2017. 
 
 
 
6. APPENDIX THE LETTER OF INFORMED CONSENT 
SEE DOCUMENT SEPARATELY