Clinical trial NCT02364609
Conditions: Recurrent Non-Small Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer
Sponsor: Jonathan Riess
Start date: 2015-09-30; Completion date: 2020-05-01
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/Ib trial studies the side effects and best dose of pembrolizumab when given together with afatinib dimaleate in treating patients with non-small cell lung cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, or has come back and does not respond to erlotinib hydrochloride. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and afatinib dimaleate together may be an effective treatment for non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of MK-3475 (pembrolizumab) when given in combination with afatinib (afatinib dimaleate) in patients with advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) activating mutations who have progressive disease on erlotinib (erlotinib hydrochloride).

SECONDARY OBJECTIVES:

I. To assess in a preliminary manner the efficacy of this combination (response rate, disease control rate and progression free survival).

OUTLINE: This is a dose de-escalation study of pembrolizumab. Patients assigned to 1 of 2 treatment arms.

ARM I (DOSE DE-ESCALATION COHORT): Patients receive afatinib dimaleate orally (PO) once daily (QD) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1.

6 patients were enrolled into Dose Level 0 at 40 mg QD of afatinib, no de-escalation was needed prior to expansion.

ARM II (EXPANSION COHORT): Patients receive pembrolizumab IV over 30 minutes on day 1 for 2 courses. Beginning course 3, patients receive afatinib dimaleate PO and pembrolizumab IV as in Arm I.

All 5 expansion patients were enrolled at the dose of 40 mg QD of afatinib.

In both Arms, courses repeat every 21 days (for up to 2 years for pembrolizumab) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks thereafter.

Arms: arm 1: DOSE DE-ESCALATION COHORT: Patients receive afatinib dimaleate PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days (for up to 2 years for pembrolizumab) in the absence of disease progression or unacceptable toxicity.

6 patients were enrolled into Dose Level 0 at 40 mg QD of afatinib, no de-escalation was needed prior to expansion. arm 2: EXPANSION COHORT: Patients receive pembrolizumab IV over 30 minutes on day 1 for 2 courses. Beginning course 3, patients receive afatinib dimaleate PO and pembrolizumab IV as in Arm I. Courses repeat every 21 days (up to 2 years for pembrolizumab) in the absence of disease progression or unacceptable toxicity.

All five expansion patients were enrolled at the dose of 40 mg QD of Afatinib.
Interventions: intervention 1: Afatinib Dimaleate intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A PHASE I/IB TRIAL OF MK-3475 (PEMBROLIZUMAB) AND AFATINIB IN EGFR-
MUTANT NON-SMALL CELL LUNG CANCER WITH RESISTANCE TO ERLOTINIB 
 
 
Funding Sources: 
Merck &Co., Inc. 
Boehringer Ingelheim Pharmaceuticals Inc. (BIPI) 
 
Protocol Number(s): 
UCDCC#250; 1200.237 (BIPI); 51657 (Merck) 
 
Phase: 
1 
 
Principal Investigator: 
Jonathan Riess, MD, MS 
University of California Davis Comprehensive Cancer   Center 
4501 X Street, Sacramento, CA 95817 
     Telephone: (916) 734-3771 
Fax: (916) 734-7946  
jwriess@ucdavis.edu 
 
Co-Investigators: 
David Gandara, MD 
UC Davis Comprehensive Cancer Center 
 
4501 X Street, Sacramento, CA 95817 
 
Telephone: (916) 734-3771 
Fax: (916) 734-7946  
drgandara@ucdavis.edu 
 
Karen Kelly, MD 
UC Davis Comprehensive Cancer Center 
4501 X Street, Sacramento, CA 95817 
Telephone: (916) 734-3771 
 
Fax: (916) 734-7946 
karkelly@ucdavis.edu 
 
STATISTICAN: 
Laurel Beckett, PhD 
 
Division of Biostatistics, MS1C 
 
University of California Davis 
 
One Shields Avenue 
Davis, CA 95616  
labeckett@ucdavis.edu 
 
IND # (Exemption):                         
 125235 
 
VERSION NO./VERSION DATE:   
Original/October 14, 2014 
 
Revision/November 4, 2014 
 
Version 1.0/August 4, 2015 
 
Version 2.0/July 26, 2016 
 
Version 3.0/September 10, 2018 


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INVESTIGATOR SIGNATURE PAGE 
 
 
Protocol Number: UCDCC#250 
 
Protocol Title: A PHASE I/IB TRIAL OF MK-3475 (PEMBROLIZUMAB) AND AFATINIB 
IN EGFR-MUTANT NON-SMALL CELL LUNG CANCER WITH RESISTANCE TO 
ERLOTINIB 
 
 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated, in accordance with all stipulations of the protocol and in accordance with Good 
Clinical Practices, local regulatory requirements, and the Declaration of Helsinki.  
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study agent(s) and the conduct of the study.  
 
 
 
__________________________________ 
Investigator Name (print) 
 
 
__________________________________ 
Investigator Signature  
 
 
_____________________ 
Date 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1.0  TRIAL SUMMARY .......................................................................................................... 6 
2.0  TRIAL DESIGN ................................................................................................................ 7 
2.1    Trial Design ...................................................................................................................... 7 
2.2 
Trial Diagram ................................................................................................................. 8 
3.0  OBJECTIVE(S) & HYPOTHESIS(ES) .......................................................................... 9 
3.1 
Primary Objective & Hypothesis.................................................................................. 9 
3.2 
Secondary Objective & Hypothesis .............................................................................. 9 
3.3 
Exploratory Objectives ................................................................................................ 10 
4.0  BACKGROUND & RATIONALE................................................................................. 10 
4.1 
Study Disease ................................................................................................................ 10 
4.2 
MK-3475 ....................................................................................................................... 10 
4.2.1 
Pharmaceutical and Therapeutic Background ..................................................... 10 
4.2.2 
Preclinical and Clinical Trial Data ...................................................................... 12 
4.3 
Afatinib ......................................................................................................................... 12 
4.3.1 
Pharmaceutical and Therapeutic ......................................................................... 12 
4.4 
Rationale ....................................................................................................................... 13 
4.4.1 
Rationale for the Trial and Selected Subject Population ..................................... 13 
4.4.2 
Rationale for Dose Selection/Regimen/Modification ......................................... 14 
4.4.3 
Rationale for Endpoints ...................................................................................... 16 
5.0  METHODOLOGY .......................................................................................................... 18 
5.1.1    Diagnosis/Condition for Entry into the Trial ........................................................ 18 
5.1.2    Subject Inclusion Criteria...................................................................................... 18 
5.1.3 
Subject Exclusion Criteria .................................................................................. 20 
5.1.4 
Trial Treatments .................................................................................................. 22 
5.1.5    Dose Selection/Modification ................................................................................ 24 
5.1.6    Timing of Dose Administration ............................................................................ 30 
5.1.7    Trial Blinding/Masking ......................................................................................... 30 
5.2    Treatment Allocation .................................................................................................... 30 
5.3    Definition of Dose Limiting Toxicities (DLT) ............................................................. 31 
5.4    Attribution of Adverse Events ..................................................................................... 32 
5.5.1    Acceptable Concomitant Medications .................................................................. 32 
5.5.2    Prohibited Concomitant Medications .................................................................... 33 
5.6    Rescue Medications & Supportive Care ...................................................................... 34 
5.6.1    Supportive Care Guidelines .................................................................................. 34 
5.6.2 Rescue medication for Afatinib ............................................................................... 38 
5.6.3    Management of Eye Complications of Afatinib ................................................... 38 
5.6.4    Management of expected adverse events .............................................................. 38 
5.6.5    Management of diarrhea and hydration status following treatment with afatinib 38 
5.6.6 
Management recommendations for dermatological AEs following treatment with 
afatinib 39 
5.6.7 
Management of mucositis/stomatitis .................................................................. 42 
5.7    Diet/Activity/Other Considerations ............................................................................. 43 
5.7.1    Diet ........................................................................................................................ 43 


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5.7.2    Contraception ........................................................................................................ 43 
5.7.3    Use in Pregnancy .................................................................................................. 45 
5.7.4    Use in Nursing Women ......................................................................................... 46 
5.8    Subject Withdrawal/Discontinuation Criteria ............................................................ 46 
5.8.1 
Discontinuation of Study Therapy after CR ....................................................... 47 
5.9    Subject Replacement Strategy ...................................................................................... 47 
5.10  Clinical Criteria for Early Trial Termination ............................................................ 47 
6.0  TRIAL FLOW CHART .................................................................................................. 48 
7.0  TRIAL PROCEDURES .................................................................................................. 51 
7.1    Trial Procedures ............................................................................................................ 51 
7.1.1    Administrative Procedures .................................................................................... 51 
7.1.2    Clinical Procedures/Assessments .......................................................................... 53 
7.1.3    Laboratory Procedures/Assessments..................................................................... 59 
7.2    Correlative Studies ........................................................................................................ 60 
Correlative Studies .................................................................................................................. 60 
7.2.1    EGFR-directed Correlative Studies ...................................................................... 60 
7.2.3    Immunology Correlates ........................................................................................ 63 
7.2.4    EGFR & Immunology Biopsy Processing .......................................................... 64 
7.2.5    Immunology Peripheral Blood Processing ........................................................... 67 
7.3   Withdrawal/Discontinuation ......................................................................................... 68 
7.4    Visit Requirements......................................................................................................... 68 
7.4.1   Screening ............................................................................................................... 68 
7.4.2   Treatment Period ................................................................................................... 69 
7.4. 3   Post-Treatment Visits ........................................................................................... 69 
7.5    Assessing and Recording Adverse Events ................................................................... 70 
7.5.1    Definition of an Overdose for This Protocol and Reporting of Overdose  ........... 71 
to Merck ............................................................................................................................ 71 
7.5.2    Reporting of Pregnancy and Lactation to Merck and BIPI ................................... 71 
7.5.3    Immediate Reporting of Adverse Events to Merck and BIPI ............................... 72 
7.5.4    Protocol-Specific Exceptions to Serious Adverse Event Reporting ..................... 74 
7.5.5 
Evaluating Adverse Events ................................................................................. 75 
7.5.6    Sponsor-Investigator Responsibility for Reporting Adverse Events .................... 75 
7.5.7    Safety Reporting Requirements for IND Exempt Studies .................................... 75 
8.0  STATISTICAL ANALYSIS PLAN ............................................................................... 75 
8.1    Statistical Analysis Plan Summary .............................................................................. 76 
8.2 
Correlative Statistical Analysis Plan .......................................................................... 77 
9.0  LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
................................................................................................................................................... 77 
9.1 
Investigational Product: MK-3475 ............................................................................. 77 
9.1.1 
Packaging and Labeling Information .................................................................. 78 
9.1.2    Clinical Supplies Disclosure ................................................................................. 78 
9.1.3    Storage and Handling Requirements ..................................................................... 78 
9.1.4    Returns and Reconciliation ................................................................................... 78 
9.2    Investigational Product: Afatinib ................................................................................ 79 
9.2.1    Packaging and Labeling Information .................................................................... 79 


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9.2.2    Storage Conditions ................................................................................................ 79 
9.2.3    Drug Accountability.............................................................................................. 79 
10.0  ADMINISTRATIVE AND REGULATORY DETAILS ............................................ 80 
10.1  Confidentiality ......................................................................................................... 80 
10.2  Good Clinical Practice ............................................................................................. 80 
10.3  Patient Information and Informed Consent ............................................................. 80 
10.4  Records and Retention............................................................................................. 81 
10.5  Data and Safety Monitoring .................................................................................... 81 
10.6  Compliance with Trial Registration and Results Posting Requirements ................. 82 
10.7  Quality Assurance and Control ............................................................................... 82 
10.8  Registration Guidelines ........................................................................................... 83 
10.9  Data Management ................................................................................................... 84 
11.0  LIST OF REFERENCES .............................................................................................. 85 
12.0  APPENDICES ................................................................................................................ 89 
12.1  ECOG Performance Status ...................................................................................... 89 
12.2  Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ...................... 90 
12.3  Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria forEvaluating 
Response in Solid Tumors ................................................................................................ 91 
12.4  New York Heart Association Classification of Heart Failure ................................. 92 
12.5  List of Potent Inhibitors and Inducers of P-glycoprotein (MDR1).......................... 93 
12.6. Liquid Genomics Sample Requisition Form............................................................ 94 
12.7  Laboratory Tests ...................................................................................................... 96 
12.8  Evaluating Adverse Events ...................................................................................... 97 
12.9  Event of Clinical Interest Guidance Document ....................................................... 99 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0  TRIAL SUMMARY 
 
Abbreviated Title 
MK-3475 and Afatinib in EGFR-Mutant Non-Small Cell 
Lung Cancer 
Trial Phase 
Phase I 
Clinical Indication 
The treatment of subjects with incurable, advanced, metastatic or 
recurrent non-small cell lung cancer with EGFR activating 
mutations who have progressive disease either clinically or 
radiographically on erlotinib. 
Trial Type 
Interventional 
Type of control 
N/A 
Test product(s)/Route of 
administration 
Afatinib (Oral Tablets)  
MK-3475 (Intravenous) 
Trial Blinding 
Unblinded Open-label 
Treatment Groups 
• Dose De-Escalation of Concurrent afatinib + MK-3475 Dose 
Expansion:  
(Cohort A) 
• Concurrent afatinib + MK-3475  
(Cohort B) 
• Lead in MK-3475 for 2 cycles followed by Concurrent afatinib 
+ MK-3475  
Number of trial subjects 
A minimum of 9 patients, if trial is terminated early due to 
unacceptable toxicity and a maximum of 38 patients (18 patients in 
dose de-escalation cohort plus 20 in the expansion cohorts). 
Estimated duration of trial 
Approximately 36 months from the time the first subject 
signs the informed consent until the last subject’s last visit. 
Duration of Participation 
• Patients will be followed through 30 days (+/- 5 days) after 
the last dose of study drugs. 
• All new drug related events will be reported for 30 days after 
the last study drug administration. 
• AEs will be followed until resolution, return to baseline, or it 
is deemed that further recovery is unlikely. 
• Patients should be contacted by telephone every 12 weeks to 
assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first. 
• Each subject may receive treatment with MK-3475 for up to 
2 years from the time of first dose of MK-3475. 


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2.0  TRIAL DESIGN 
2.1    Trial Design 
 
This is a prospective, non-randomized, open label Phase I clinical trial of intravenous (IV) MK-
3475 (pembrolizumab, Keytruda®) and afatinib (oral tablets) in subjects with advanced or 
metastatic NSCLC with EGFR activating mutations (exon 19 deletion, exon 21 L858R, G719X, 
L861Q) who have experienced disease progression on erlotinib, gefitinib or osimertinib.  It is a 
phase I dose de-escalation study followed by a phase Ib expansion with two cohorts for further 
safety evaluation and correlative studies of immune modulation with repeat biopsy and peripheral 
blood collection. 
 
For the dose de-escalated phase, patients will receive MK-3475 and afatinib as outlined in Table 
1 and Section 5.1.5 with escalation of MK-3475 to the maximum tolerated dose (MTD). A 
fixed dose of MK-3475 (200 mg q3 weeks) will be tested in combination with afatinib starting 
at the FDA approved dose for EGFR-mutated NSCLC (40 mg PO daily). The dose  d e -
escalation phase will establish the MTD of MK-3475 in combination with afatinib. 
 
Once the MTD is reached, patients will initially be allocated to one of two different arms at this 
dose: concurrent afatinib + MK-3475 (Arm A) or lead in MK-3475 followed by afatinib 
+ MK-3475 (Arm B). For Arm A, there is no lead-in phase. For Arm B, MK-3475 will be 
given for 2 cycles (6 weeks) as a lead in followed by combination afatinib and MK-3475. 
Ten patients will be enrolled for each cohort (20 patients total). These two expansion cohorts 
will further define toxicities at the MTD in order to determine the recommended phase II dose 
(RP2D) and to assess initial estimates of efficacy and examine correlative studies-particularly 
regarding immune modulation of afatinib and MK-3475 between the differing cohorts.   
 
Subjects will be evaluated every 6 weeks with radiographic imaging to assess response to 
treatment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Adverse events will 
be monitored throughout the trial and graded in severity according to the guidelines outlined in 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0. Treatment with MK-3475 and afatinib will continue until documented disease progression, 
2 years from first cycle of MK-3475 (afatinib may continue past 2 years), unacceptable adverse 
event(s), intercurrent illness that prevents further administration of treatment, investigator’s 
decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, 
noncompliance with trial treatment or procedure requirements, or administrative reasons. 
 
After the end of treatment, each subject will be followed for a minimum of 30 days for safety 
monitoring. Subjects will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment (such as chemotherapy, other targeted 
therapy, other treatment for lung cancer), withdrawing consent, or becoming lost to follow-up 
(progression free survival). 
 
 


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2.2 
Trial Diagram 
 
 
 
 
 
 
 
 
Advanced  
EGFR-mutant NSCLC; 
Prior erlotinib therapy 
with progressive disease 
Lead in MK-3475  
for 2 cycles  
(Each cycle is 21 days) 
Concurrent Afatinib 
+ 
MK-3475 
(Each cycle is 21 days) 
Disease assessment  
every 6 weeks 
Biopsy at Baseline and at 
6 weeks (after 2 cycles) 
Progressive disease 
RECIST 1.1 
Progressive disease 
RECIST 1.1 
Safety Follow up 
Expansion Cohort B 
Dose De-escalation  
and 
Expansion Cohort A 
Concurrent Afatinib 
+ 
MK-3475 
(Each cycle is 21 days) 
Safety Follow up 
Disease assessment  
every 6 weeks 
Biopsy at Baseline and at 
6 weeks (after 2 cycles) 


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Table 1: Dose De-Escalation Schema 
 
Dose Level 
Number of Patients 
Afatinib  
(Daily) 
MK-3475  
(q3 weeks) 
0 
3+ 
40 mg D1 
200 mg D1 
-1 
3+ 
30 mg D1 
200 mg D1 
-2 
3+ 
20 mg D1 
200 mg D1 
 
 
Dose Level 0 is the starting combination dose level (in bold). If ≥ 2 patients experience a 
DLT at dose level 0, the next dose level will be dose level -1. If ≥ 2 patients experience a 
DLT at dose level -1, the next dose level will be dose level -2. 
 
The phase I dose de-escalation portion of the trial will be closed when the MTD or dose level 0 is 
reached and six patients have been treated at that dose level. 
 
Please see section 5.1.5 for further details of the dose de-escalation schema. 
 
 
3.0  OBJECTIVE(S) & HYPOTHESIS(ES) 
 
3.1 
Primary Objective & Hypothesis 
 
Objective: To evaluate the safety and tolerability of MK-3475 when given in combination with 
afatinib in patients with advanced or metastatic non-small cell lung cancer with EGFR activating 
mutations who have progressive disease on erlotinib. 
 
 
Hypothesis: We hypothesize that MK-3475 and afatinib will be tolerable and that we can 
reach an effective maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). 
 
3.2 
Secondary Objective & Hypothesis 
 
Objective: To assess in a preliminary manner the efficacy of this combination (response rate, 
disease control rate and progression free survival) 
 
Hypothesis: We hypothesize that MK-3475 and afatinib in combination will be efficacious. 
 


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3.3 
Exploratory Objectives 
 
Objective 1: To determine in an exploratory manner changes in PD-L1 expression in the tumor 
microenvironment and other immune correlates in blood and in the tumor microenvironment 
induced by afatinib with concurrent MK-3475 versus MK-3475 preceding combination 
afatinib/MK-3475. 
 
Objective 2: To determine in an exploratory manner changes in EGFR-mutant plasma DNA 
in response to treatment with MK-3475 and afatinib. 
 
4.0  BACKGROUND & RATIONALE 
4.1 
Study Disease 
 
Lung cancer is the leading cause of cancer deaths worldwide due to the majority of patients 
presenting with metastatic disease for which there is no cure. In recent years, advances in the 
systemic treatment of non-small cell lung cancer (NSCLC) have increased survival by several 
months and subsets of patients enjoy prolonged survival beyond two years (Subramanian J, et al. 
J Thorac Oncol 7:260-5, 2012).  More efficacious therapies have been a direct result of our 
increased understanding and exploitation of the molecular basis of lung cancer. The development 
of inhibitors to the epidermal growth factor receptor (EGFR) and the resultant blockade of its 
signaling pathway were the first molecularly targeted agents to improve outcome in this disease 
(Shepherd FA et al. N Engl J Med 353:123-32, 2005).  Patients whose tumors harbor a 
sensitizing mutation in EGFR derive the most benefit from EGFR tyrosine kinase inhibitor (TKI) 
therapy (Mok TS et al. N Engl J Med 361:947-57, 2009, Maemondo M. et al. N Engl J Med 
362:2380-8, 2010).  However, despite impressive responses and significantly prolonged survival 
in this specialized patient population, all patients develop resistance to EGFR TKIs resulting in 
tumor progression and death. Concentrated efforts to understand the mechanisms of resistance to 
EGFR-TKIs are underway. The development of treatment combinations to overcome or delay 
resistance to erlotinib represents a major unmet need. 
4.2 
MK-3475 
4.2.1 Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis 
and long-term survival in many solid tumors. 


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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T- cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 8]. The structure of murine PD-1 has 
been resolved [9].  PD-1 and family members are type I transmembrane glycoproteins containing 
an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which 
is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine- based switch motif (ITSM). Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade [7; 10; 11; 12].  The mechanism by 
which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as 
both molecules regulate an overlapping set of signaling proteins [13; 14].  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs 
and Natural Killer cells [15; 16].  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells [17].  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors [18; 19; 20; 
13].  Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains 
in the extracellular region and contain short cytoplasmic regions with no known signaling motifs. 
Binding of either PD-1 ligand to PD-1 inhibits T- cell activation triggered through the T-cell 
receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to 
control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen 
unwarranted T-cell function in peripheral tissues [13].  Although healthy organs express little (if 
any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell 
inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with 
melanoma (MEL) [21].  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor 
immune evasion and should be considered as an attractive target for therapeutic intervention. 
 
MK-3475 (Keytruda®, pembrolizumab, and previously known as SCH 900475) is a potent and 
highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 has 
recently been approved in the United Stated for the treatment of patients with unresectable or 
metastatic melanoma and disease progression following ipilumumab and, if BRAF V600 
mutation positive, a BRAF inhibitor.  It has also been approved for NSCLC positive for PD-L1 
by the DAK 22C3 antibody after progression on platinum-based chemotherapy, as well as for 
first-line treatment of patients with metastatic (NSCLC whose tumors have high PD-L1 
expression [Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved test, 
with no EGFR or ALK genomic tumor aberrations. 


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4.2.2 Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for MK-3475 Preclinical and Clinical data. 
4.3 
Afatinib 
4.3.1 Pharmaceutical and Therapeutic 
 
Afatinib (BIBW2992) is a small molecule, selective and irreversible erbB family blocker. In 
preclinical models it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting in 
tumour growth inhibition and regression of established subcutaneous tumors derived from four 
human cell-lines known to co-express ErbB receptors. 
 
For the latest information on the drug profile of afatinib, please refer to the current Investigator’s 
Brochure (IB) (U03-3218).  All references in this protocol concerning afatinib refer to the free 
base compound afatinib BI which is used as the oral formulation. 
 
Afatinib is moderately fast absorbed after oral administration. Maximum plasma concentrations 
of afatinib were achieved mainly at 2 to 5 hours after oral drug administration. Afatinib 
maximum plasma concentrations and area under the curve increased slightly over- proportional 
with increasing doses in the therapeutic range of 20-50mg. Moderate to high inter- and intra-
individual differences in plasma concentration were seen. Afatinib is highly distributed out of the 
blood and has a moderate to high clearance. The overall gMean terminal half-life at steady state 
was 37.2 hours in cancer patients. Steady state was reached no later than 8 days after the first 
administration. The major route of elimination of afatinib was via feces. After food intake, a 
decreased systemic exposure was observed compared to administration under fasted conditions. 
Therefore, afatinib should be taken without food (i.e. food should not be consumed for at least 1 
hour before and at least 2 hours after meal). The PK characteristics in Caucasian cancer patients 
were comparable to those observed in Japanese cancer patients. 
 
Afatinib is bound covalently to proteins to a variable extent and covalent protein adducts were the 
major circulating metabolites in the plasma. Afatinib did not show relevant inhibition or 
induction of cytochrome P450 isoenzymes, and it appears unlikely that drug- drug interactions 
based on this mechanism will occur. 
 
Afatinib is a substrate of the P-gp transporter. Concomitant administration of the potent P-gp 
inhibitor ritonavir did not relevantly change the exposure to 40 mg afatinib when taken 
simultaneously with or 6 h after afatinib but increased the bioavailability of afatinib (single dose 
of 20 mg) by 48% and 39% for AUC0-∞ and Cmax when given 1 h before afatinib, respectively. 
Pretreatment with the potent P-gp inducer rifampicin decreased the plasma exposure of 40 mg 
afatinib by 34 % afatinib (AUC0-∞) and 22 % (Cmax), respectively. Caution should be exercised 
when combining afatinib with potent P-gp modulators. In pre-clinical studies, afatinib is not an 
irritant to intact skin but an ocular irritant. Afatinib is mutagenic in a single bacteria strain, but 
did not show genotoxic potential in vivo when tested up to overt toxic/lethal doses. Studies on 
embryo-fetal development in rats and rabbits up to life- threatening doses have revealed no 
indication of teratogenicity. 


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Two phase I open label dose-escalation studies determined the MTD with continuous dosing of 
afatinib in patients with advanced solid tumors at 40mg and 50mg daily, respectively ( Ould-
Kaci  M.  Investigator’s  brochure.  Afatinib  (BIBW  2992).  Version  14,  1200.P1 1200. 
P10. 2013, Temple G, et al. A Phase I open-label dose escalation study of continuous once-
daily oral treatment with BIBW 2992 in patients with advanced solid tumours.  Trial 
1200.3.  2010.).  Adverse events (AE) observed with afatinib are consistent with those 
reported for other EGFR and dual EGFR/HER2 inhibitors. The most frequent investigator 
defined drug-related  AEs   were   associated  with   gastrointestinal  disorders  (including 
diarrhoea, and stomatitis), skin and subcutaneous tissue disorders (rash, dry skin, pruritus, 
acneiform rash,  acne),  nail  effects,  epistaxis, fatigue  and  decreased appetite. Early  and 
proactive  management  of  diarrhea,  mucositis/stomatitis  and  skin  rash  together  with 
treatment interruptions and dose reductions is recommended in line with recent guidelines in the 
management of common toxicities of EGFR and EGFR/HER2 TKIs and monoclonal 
antibodies  (Lynch  TJ,  Jr.  et  al.  Oncologist.  2007  May;12(5):610-21.  PubMed  PMID: 
17522250. Lacouture ME et al. Expert Rev Anticancer Ther. 2013 Jun;13(6):721-8. PubMed 
PMID: 23506519. Yang JC et al. Expert Rev Anticancer Ther. 2013 Jun;13(6):729-36. PubMed 
PMID: 23506556. Moy B, Goss P. Oncologist 1007;12(7):756-65. Giaccone G et al. A 
consensus position from the EGFRI dermatologic toxicity forum.   ECCO; Barcelona 
2007). 
 
Refer to the Investigator’s Brochure for Afatinib Preclinical and Clinical data. 
 
4.4 
Rationale 
4.4.1 Rationale for the Trial and Selected Subject Population 
 
The discovery of EGFR activating mutations in NSCLC and the targeting of these mutations with 
EGFR-TKIs represents a substantial advance in the treatment of metastatic NSCLC. EGFR is a 
member of the ERBB family of receptor tyrosine kinases. Mutations that render EGFR 
constitutively active in NSCLC are sensitive to inhibition with EGFR tyrosine kinase inhibitors. 
Invariably, acquired resistance to erlotinib develops; more than 60% of patients experience 
progression within a year (Rosell R et al Lancet Oncol 2012; 13:239-46). New strategies to 
overcome or circumvent acquired resistance to EGFR-TKIs represent a major unmet need. 
 
Afatinib, an irreversible inhibitor of EGFR and other complexes formed by the ErbB family of 
hetero- and homo-dimers, represents a good first step in addressing acquired resistance to first 
generation EGFR-TKIs. Of note, afatinib is FDA approved as frontline therapy for use in patients 
with EGFR-activating mutations based on a significant PFS benefit compared to platinum based 
chemotherapy in patients whose tumors harbor EGFR activating mutations (Sequist, LV et al. 
JCO 2013 31:27 3327-34). Additionally, in patients with EGFR-mutated cancers and established 
acquired resistance to erlotinib, afatinib prolongs progression-free survival, with a disease control 
rate of 57% and a 7% response rate (Miller VA et al. Lancet Oncol 2012; 13:528-38). 
Combination approaches with afatinib appear more promising. For example, the combination of 


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afatinib and cetuximab has substantially higher response rates (29% RR) and activity (100% 
DCR) (Y. Y. Janjigian et al. Cancer Discovery 2014 4:9; 1036-45). This combination activity of 
afatinib/cetuximab in patients with acquired resistance is in contrast to erlotinib/cetuximab in this 
setting, where very little activity is seen. Thus afatinib (as an irreversible EGFR inhibitor with 
activity against mechanisms such as T790M) is a more promising EGFR-TKI to pair with other 
therapeutics such as MK-3475. MK-3475 is a potent and highly selective humanized mAb of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2. 
 
In preclinical cell lines and genetically engineered (GEMM) mouse models EGFR driven 
tumors expressed higher levels of PD-L1 with a more immunosuppressive tumor 
microenvironment (increased FoxP3+ T-cells, decreased CD8+/CD4+ ratio) (Akbay EA et al. 
Cancer discovery 2013; 3:1355-63). Increased PD-L1 expression was shown across a range of 
EGFR activating mutations and the EGFR T790M resistance mutation. Addition of an EGFR-
TKI that decreased EGFR pathway activity also decreased PD-L1 expression. The irreversible 
EGFR-TKI WZ004 was more effective in this regard than the reversible EGFR- TKI gefitinib in 
preclinical models with EGFR T790M (the most common (~60%) EGFR- TKI resistance 
mutation). Thus, EGFR mutated NSCLC may be particularly sensitive to PD1 antibodies such as 
MK-3475. An irreversible EGFR inhibitor such as afatinib may be more effective than the 
reversible EGFR-TKI erlotinib in this setting. 
 
 
4.4.2 Rationale for Dose Selection/Regimen/Modification 
 
The dose regimen of 200 mg Q3W of MK-3475 (pembrolizumab) is planned for all urothelial 
cancer trials. Available PK results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in PK exposures obtained at a given dose among 
tumor types. An open-label Phase I trial (PN001) in melanoma subjects is being conducted to 
evaluate the safety and clinical activity of single agent MK-3475.  The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated 
and no dose- limiting toxicities were observed. This first in human study of MK-3475 showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels (1 
mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The clinical 
efficacy and safety data demonstrate a lack of clinically important differences in efficacy 
response or safety profile at these doses.  For example, in Cohort B2, advanced melanoma 
subjects who had received prior ipilimumab therapy were randomized to receive pembrolizumab 
at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate (ORR) was 26% (21/81) in the 
2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)).  The proportion 
of subjects with drug-related adverse events (AEs), grade 3-5 drug-related AEs, serious drug-
related AEs, death or discontinuation due to an AE was comparable between groups or lower in 
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Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given 
dose among tumor types.  Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to pembrolizumab to a clinically 
meaningful extent.  Taken together, these data support the use of lower doses (with similar 
exposure to 2 mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being evaluated in 
NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and 
neck cancer in PN012, which are expected to provide additional data supporting the dose 
selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within 
the exposure range established in melanoma as associated with maximal clinical response.  A 
population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 subjects from 
PN001.   The distribution of exposures from the 200 mg fixed dose are predicted to considerably 
overlap those obtained with the 2 mg/kg dose, with some tendency for individual values to range 
slightly higher with the 200 mg fixed dose.   The slight increase in PK variability predicted for 
the fixed dose relative to weight-based dosing is not expected to be clinically important given 
that the range of individual exposures is well contained within the range of exposures shown in 
the melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety.  The population 
PK evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there 
are no anticipated changes in exposure between different tumor types and indication settings.  
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe. 
  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
 


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Afatinib will be combined with MK-3475 at the FDA approved single-agent starting dose for 
afatinib. Dose de-escalation is permitted per protocol.  
 
4.4.3 Rationale for Endpoints 
 
This is a phase I dose 3+3 dose de-escalation study followed by expansion cohorts for safety and 
correlative studies. Therefore, the endpoints include determination of MTD, and recommended  
phase  II  dose  (RP2D)  correlative  and  pharmacokinetic  endpoints  and secondary efficacy 
endpoints. MTD and RP2D are standard endpoints for phase I dose de-escalation studies. 
 
• The MTD is defined in section 5.1.5. 
 
• The recommended dose expansion and recommended phase II dose (RP2D) will be 
determined by the overall assessment of the MTD and toxicities observed in the dose de-
escalation portion of this study. 
 
4.4.3.1 
Efficacy Endpoints 
 
• Overall response rate (ORR). ORR is an acceptable measure of clinical benefit in 
early phase clinical trials to provide a preliminary signal of activity to consider later 
phase trials. 
 
• Progression-free survival (PFS). PFS is an acceptable measure of assessing benefit in 
NSCLC clinical trials. 
 
As this is a phase I study, our goal is a preliminary assessment of a signal of efficacy as defined 
in the statistical plan. 
 
4.4.3.2   Biomarker Research 
 
The investigator will conduct biomarker research on biopsy and blood collected on trial patients. 
These studies will focus on mechanisms EGFR-TKI resistance and immune correlates. 
 
1. Immunology Correlates 
 
Immunology correlates will be performed by collaborators at the Translational Immuno-
Oncology Laboratory Yale University and/or by the Human Immune Monitoring Core at UC 
Davis as defined in the protocol. The Human Immune Monitoring Core at UC Davis is under the 
supervision of Emanual Maverakis, MD. Dr.  Maverakis’  laboratory  is  a  world  renowned  
immunology  laboratory  and  has  the equipment and expertise to conduct the proposed studies. 
The Translational Immuno-Oncology Laboratory at Yale University is under the direction of 
David Rimm MD, Ph.D and Kurt Schalper, MD, Ph.D and has been a leader in the translational 
immuno-oncology of immune checkpoint inhibitors. 
 
a. Biopsy (Biopsy at Baseline and prior to Cycle #3): 


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• PD-L1 expression by immunohistochemistry at  baseline  and  in  repeat  biopsy 
specimens to assess for changes in PD-L1 expression in response to treatment will be 
conducted by Yale Immuno-Oncology under the direction of Kurt Schalper using the 
approved DAKO 22C3 antibody and in addition quantitative IHC assays for PD-L1 if 
tissue permits. UC Davis may also perform IHC for PD-L1 using the standard DAKO 
22C3 antibody. 
 
• Enumeration and changes in immune cell subsets by immunohistochemistry in repeat 
biopsy specimens in response to treatment will be conducted by Yale Translational 
Immuno-Oncology. 
 
• Whole exome DNA/RNA next generation sequencing and assessment of mutational load 
will be performed by the Broad Institute in Boston. The Broad Institute is a world leader 
in genomic sequencing and analysis. 
 
• RPPA (Reverse Phase Protein Assays) for on-target EGFR pathway inhibition will be 
performed by Theranostics in collaboration with the Mack lab at UC Davis. 
 
b. Peripheral blood will be collected at relevant time points for enumeration of immune cell 
subsets and changes in cytokine expression in response to treatment with methods including 
Flow Cytometry and Luminex Cytokine Assays by the Human Immune Monitoring Core at UC 
Davis.  
 
Plasma PD-L1 DNA/RNA levels will be assayed by Liquid Genomics in a CLIA certified 
laboratory. 
 
2. EGFR Correlates  
a. Biopsy 
The type of EGFR activating mutation and the presence of EGFR T790M resistance mutation 
will be performed per standard of care in a CLIA certified laboratory at the investigators 
discretion (if previous EGFR T790M mutation negative or not performed).  
 
Whole exome DNA/RNA next generation sequencing and assessment of mutational load will be 
performed by the Broad Institute in Boston. The Broad Institute is a world leader in genomic 
sequencing and analysis. 
 
b. Plasma EGFR-mutant DNA/RNA Levels 
Changes in plasma EGFR-mutant DNA/RNA in patients with EGFR-mutant NSCLC may be 
prognostic for recurrence, the development of resistance to existing therapies and may track 
response or lack of benefit to existing treatment (T. Mok, WCLC 2013). Determination of 
plasma EGFR-mutant DNA levels will be conducted at Liquid Genomics in a CLIA certified 
laboratory. 
 


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c. If tissue permits, analysis for pharmacodynamic markers of on-target EGFR- inhibition with 
RPPA will be performed by Theranostics and the Mack lab at UC Davis. 
 
5.0  METHODOLOGY 
 
5.1    Entry Criteria 
5.1.1    Diagnosis/Condition for Entry into the Trial 
 
Incurable, Advanced and/or Metastatic/Recurrent Non-Small Cell Lung Cancer with EGFR 
Activating Mutations (Exon 19 del, Exon 21 L858R, L861Q, G719X). Who Have Radiologic 
and/or Clinically Progressive Disease on Erlotinib or Gefitinib or Osimertinib at any point during 
the patient’s cancer treatment as determined by the Investigator. 
 
5.1.2    Subject Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 
 
1.   Be willing and able to provide written informed consent for the trial. 
 
2.   Be ≥ 18 years of age on day of signing informed consent. 
 
3.   Have a life expectancy of at least 3 months. 
 
4.   Have measurable disease based on RECIST 1.1. 
 
5.   Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a 
leftover cell block (or equivalent) for additional immune correlates from a tumor lesion 
biopsied in the last 60 days (prior to signed consent) that has not been previously irradiated 
occurring: 1) after progression on erlotinib and no intervening systemic treatment between 
biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy.  
 
      If inadequate archival tissue as above, patients must be willing to consent for biopsy at 
baseline and an on treatment biopsy. Patients must also have a tumor in a location that in the 
opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and 
other biomarker analysis from a newly obtained formalin fixed tumor tissue from a recent 
biopsy of a tumor lesion not previously irradiated. No systemic antineoplastic therapy may 
be administered between the PD- L1 biopsy and initiating study medication. Fine needle 
aspirates are not acceptable. Core needle or excisional biopsies, or resected tissue is 
required.  
 
6.   Have a performance status of 0 or 1 on the ECOG (Zubrod) Performance Scale. 
 
7.   There is no limit to the number of prior treatments for this phase I trial. 
8.   Demonstrate adequate organ function as defined in Table 2, all screening labs should be 


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performed within 10 days of treatment initiation. 
 
 
 
Table 2  Adequate Organ Function Laboratory Values 
 
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L
Renal
Serum creatinine  OR 
Measured or calculateda  creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN)  OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic
Serum total bilirubin
≤1.5 X ULN
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN
 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN   OR 
< 5 X ULN for subjects with liver metastases 
Coagulation
 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin  Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
 
9. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for the 
course of the study through 120 days after the last dose of study medication (Section 5.7.2). 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject. 
 
11. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1 – Contraction, starting with the first 
dose of study therapy through 120 days after the last dose of study therapy. 


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Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject. 
 
5.1.3 Subject Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
1.   Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment. 
 
2.   Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
 
3.  Has a known history of active TB (Bacillus Tuberculosis).  
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to study Day 1 
or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. Denosumab is allowed as long as not < 1 week 
prior to study day 1 and not administered on day of MK-3475 infusion. 
 
6.   Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to a previously administered agent. 
 
- 
Note:  Subjects with alopecia or ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
 
- 
Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
 
7.   Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
 
8.  Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided they 
are stable (without evidence of progression by imaging for at least two weeks prior to the 
first dose of trial treatment and any neurologic symptoms have returned to baseline), have 
no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 
days prior to trial treatment. 
 
9.  Has an active autoimmune disease requiring systemic treatment within the past 3 months or 


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a documented history of clinically severe autoimmune disease, or a syndrome that requires 
systemic steroids or immunosuppressive agents.   Subjects with vitiligo or resolved 
childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent 
use of bronchodilators or local steroid injections would not be excluded from the study.   
Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not 
be excluded from the study. 
 
10.   Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
Lymphangitic spread of the NSCLC is not exclusionary. 
 
11.   Has an active infection requiring intravenous systemic therapy. 
 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
 
13. Has  known  psychiatric  or  substance  abuse  disorders  that  would  interfere  with 
cooperation with the requirements of the trial. 
 
14. History  or  presence  of  clinically  relevant  cardiovascular  abnormalities  such  as 
uncontrolled hypertension, congestive heart failure NYHA classification of 3 (Refer to 
APPENDIX 12.4), unstable angina or poorly controlled arrhythmia as determined by the 
investigator. Myocardial infarction within 6 months prior to enrollment. 
 
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of  the  trial,  starting  with  the  pre-screening or  screening visit 
through 120 days after the last dose of trial treatment. 
 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2.  
 
17. Known hypersensitivity to afatinib or the excipients of any of the trial drugs 
 
18. Prior history of receiving afatinib. 
 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
21. Has received a live vaccine within 30 days of planned start of study therapy (See Section 
5.5.2). Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
22. The presence of poorly controlled gastrointestinal disorders that could affect the  
absorption  of  the  afatinib  (e.g.  Crohn’s  disease,  ulcerative  colitis, chronic diarrhea, 


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malabsorption). 
 
23. Receiving drugs known to be strong inducers or inhibitors of P-glycoprotein that are known 
to interact with afatinib including, but not limited to: ritonavir, cyclosporine A, 
ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, 
saquinavir, and amiodarone.  Because the l i s t s  of these agents are constantly changing, it is 
important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information.  As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions  with  other  agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product. The subject 
must stop the strong inducer or inhibitor of P-glycoprotein 7 days before or 5 half lives 
before study drug administration (whichever timepoint is longer). 
 
24. Major surgery within 4 weeks before starting study treatment or scheduled for surgery during 
the projected course of the study. 
 
25. Radiotherapy within 4 weeks prior to enrollment, except as follows: 
 
i.) Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to 
enrollment, and 
 
ii.) Single dose palliative treatment for symptomatic metastasis outside above allowance to 
be discussed with sponsor-investigator prior to enrolling. 
26. Meningeal carcinomatosis. 
27. Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment. 
28. Any history of or concomitant condition that, in the opinion of the Investigator, would 
compromise the patient’s ability to comply with the study or interfere with the evaluation of 
the efficacy and safety of the test drug. 
 
5.1.4 Trial Treatments 
 
The treatment to be used in this trial is outlined below in Table 3. Each cycle is 21 days in length.  
Table 3 Trial Treatments 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
MK-3475 
200 mg 
Q3W 
IV infusion 
Day 1 of each cycle 
Experimental 


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Afatinib* 
20 mg, 30 mg, 
or 40 mg 
Once daily 
Oral 
Day 1-21 of each 
cycle 
Experimental 
The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.1.5.3. 
*Cohort B begins in Cycle 3 
 
Table 4: Dose De- Escalation Schema 
Dose Level 
Number of Patients 
Afatinib  
(Daily) 
MK-3475  
(q3 weeks) 
0 
3+ 
40 mg D1 
200 mg D1 
-1 
3+ 
30 mg D1 
200 mg D1 
-2 
3+ 
20 mg D1 
200 mg D1 
Each cycle is 21 days in length. 
 
Dose De-Escalation 
This treatment will start at dose level 0 (Bold). Afatinib is an oral agent that will be given once 
daily for 21 days per cycle starting on day 1 of each cycle before administration of MK- 
3475. It should be taken in the morning with 200 mL of water. Tablets should be taken 1 
hour before or 2 hours after meals. MK-3475 will be given once every 3 weeks at a fixed 
dose of 200 mg. Treatment will be administered until progression or toxicity or withdrawal of 
consent as defined in this protocol. 
 
Cohort A (Arm A): Dose Expansion 
 
This treatment will start at the MTD determined in the dose de-escalation portion of this trial. 
Afatinib is an oral agent that will be given once daily for 21 days per cycle starting on day 1 of 
each cycle before administration of MK-3475. It should be taken in the morning with 200 mL of 
water. Tablets should be taken 1 hour before or 2 hours after meals. MK-3475 will be given 
once every 3 weeks. Treatment will be administered until progression or toxicity or 
withdrawal of consent as defined in this protocol. 
 
Cohort B (Arm B): Dose Expansion 
 
This treatment will start at the MTD determined in the dose de-escalation portion of this trial. 
MK-3475 will be administered on Day 1 of each cycle, which is q21d in length. Afatinib is an 
oral agent that will be given once daily for 21 days per cycle starting on Cycle 3 Day 1 of each 
cycle starting prior to administration of MK-3475 on day 1. It should be taken in the morning 
with 200 mL of water. Tablets should be taken 1 hour before or 2 hours after meals. MK-
3475 will be given once every 3 weeks. Treatment will be administered until progression or 
toxicity or withdrawal of consent as defined in this protocol. 
 
After the MTD is reached, Cohort A will complete first to further assess toxicity at the MTD of 
the combination, followed by enrollment in Cohort B. Cohort Assignment is further defined in 


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Section 5.2. 
 
 
 
5.1.5    Dose Selection/Modification 
 
5.1.5.1   Dose Selection 
 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale. 
 
MK-3475 will be provided by Merck at no cost to the patient. 
 
Afatinib will be provided by Boehringer Ingelheim at no cost to the patient. 
 
Subjects will take a single oral dose of afatinib daily starting on Day 1 of each cycle, until the 
development of progressive disease or unacceptable adverse events. 
 
See section 5.1.5 for Dose Modifications for afatinib and MK-3475. See Table 6 for dose 
reduction for afatinib. 
 
5.1.5.2 
Dose De-Escalation 
 
Dose Level 
Number of Patients 
Afatinib  
(Daily) 
MK-3475  
(q3 weeks) 
0 
3+ 
40 mg D1 
200 mg D1 
-1 
3+ 
30 mg D1 
200 mg D1 
-2 
3+ 
20 mg D1 
200 mg D1 
 
 
Figure 1: Dose De-Escalation Schema 
 


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This is a phase I study. A minimum of 9 patients (if trial is terminated early due to unacceptable 
toxicity and a maximum of 38 patients (18 patients in the dose- de-escalation cohort plus 10 in 
each of the two expansion cohorts) are anticipated for this trial. Analysis of safety and 
biomarkers will be limited to patients who receive active treatment. 
 
The dose-de-escalation phase will establish a MTD recommended dose of MK-3475 in expansion 
cohorts (A +B). 
 
We plan to enter 3 patients at Dose Level 0. If 0/3 or 1/3 patients experience a DLT on level 
0, an additional 3 patients will be accrued to Level 0, where 2 or more DLTs will terminate 
that study arm and we will proceed to dose level -1. 
 
If 2 or more patients have DLTs at level 0, patients will be accrued at level -1. If 1/3 patients 
experience a DLT on level -1, an additional 3 patients will be accrued to Level -1, where 2 or 
more DLTs will require termination of that study arm while 1 DLT out of 6 will result in 
proceeding with dose level -1 as the MTD for the dose expansion cohorts. 
 
If 2 or more patients have DLTs at level -1, patients will be accrued at level -2. If 1/3 patients 
experience a DLT on level -2, an additional 3 patients will be accrued to Level -2, where 2 or 
more DLTs will require termination of the study while 1 DLT out of 6 will result in 
proceeding with dose level -2 as the MTD for the dose expansion cohorts. 
 
The phase I dose de-escalation portion of the trial will be closed when the maximum tolerated 
dose level (MTD) or dose level 0 is reached and six patients have been treated at that dose level. 
 
Dose modifications for patients that experience DLT is described in section 5.1.5.3.  Once the 
dose is decreased, there will be no dose re-escalation allowed for an individual patient. 
 
 
The recommended phase II dose (RP2D) will be determined by the overall assessment of the 
MTD and toxicities observed in the de-dose escalation and dose expansion portion of this study. 
 
Treat 3 subjects 
at dose level 
If (0 or 1)/3 
subjects with DLT 
If ≥2/3 subjects 
with DLT 
Treat 3 more 
subjects 
If (0 or 1)/6 DLT, 
stop, MTD reached 
If ≥2/6 subjects  
with DLT 
Stop, lower dose and 
enroll 3 subjects 


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5.1.5.3   Dose Modification 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. MK-3475 will be withheld for MK-3475-
related toxicities and severe or life- threatening AEs as per Table 5. See Section 5.6.1 and Events 
of Clinical Interest Guidance Document for supportive care, including use of corticosteroids. 
 
 
 
 
 
 
 
 
Table 5: Dose modification guidelines for MK-3475 related adverse events. 
 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 Toxicity does not resolve within 12 weeks of last 
dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are 
clinically and metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-
1. Therapy with 
pembrolizumab can be 
continued while endocrine 
replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab Therapy with pembrolizumab can be continued 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
can be continued while 
thyroid replacement therapy is 
instituted 
while thyroid replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1 Permanently discontinue if toxicity develops 
despite adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or 
equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be 
premedicated  for the next scheduled dose; Refer to Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons  
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for interruption 
should be documented in the patient's study record. 
 
Treatment related toxicities will be managed by treatment interruptions and subsequent dose 
reductions of afatinib according to the schedule described in Table 6. Dose reductions will apply 
to individual patients only. Once the dose has been reduced, it cannot be increased later. 
 
To prevent the development of more severe adverse events, treatment related diarrhea, nausea 
and vomiting or rash should be managed early and proactive as described in Section 5.6. 
 


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Table 6. Dose reduction scheme for Afatinib 
 
 
AE Type and CTCAE Grade 
Action 
Dose Reduction Scheme 
Events related to study drug (afatinib): 
 
• Diarrhea 
Grade 2 persisting for 2 or more 
consecutive days (48 hours) despite 
adequate anti-diarrheal 
medication/hydration 
• Reduced renal function to ≥ Grade 2 
as measured by serum creatinine, 
proteinuria or decrease in glomerular 
filtration rate  of more than 50% from 
baseline 
• Any drug related AE Grade ≥3 
 
 
• Pause treatment until patient 
has recovered to Grade ≤1 or 
baseline.1 
 
 
• Resume treatment at reduced 
dose according to schedule 
opposite. 
 
 
• If patient has not recovered 
to Grade ≤1 or baseline1 
within 14 days study  
treatment must be 
permanently discontinued.2 
 
 
• If patient was receiving 
40 mg, resume treatment at a 
dose of 30 mg. 
• If patient was receiving 
30 mg, resume treatment at a 
dose of 20 mg. 
• If patient was receiving 
20 mg, discontinue afatinib. 
Acute onset and/or unexplained 
worsening of pulmonary systems 
(dyspnea, cough, fever) 
Pause afatinib while clinical 
assessment to exclude ILD is 
completed. 
If ILD is ruled out as a cause of 
symptoms, grade symptoms 
and relatedness and report as 
AEs. If AEs are not related, 
resume afatinib at current dose. 
If AEs are drug related, follow 
directions in row above. 
 
If ILD is confirmed, 
discontinue afatinib 
1  Baseline is defined as the CTCAE Grade at the start of treatment. 
2  In the event that the patient is deriving obvious clinical benefit according to the investigator’s judgment, 
further treatment with afatinib will be decided by the investigator. 
 
 
In the event of any unrelated adverse events, the investigator may choose to interrupt the 
afatinib for up to 14 days, but no dose reduction should occur.  If afatinib is interrupted for 
more than 14 days, the decision to continue with afatinib will be made by the investigator. 
 
 
 
 
 


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5.1.6    Timing of Dose Administration 
 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
 
All trial treatments may be administered on an outpatient basis. 
MK-3475 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target  infusion  timing  to  be  as  close  to  30  minutes  as  possible.    
However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
Afatinib is an oral agent that will be given once daily for 21 days per cycle starting on day 1 of 
each cycle before administration of MK-3475. It should be taken in the morning with 200 mL of 
water.  
 
The medication should be taken at the same time each day (± 2 hours) without food (at least one 
hour before or at least 2 hours after a meal). 
 
Missed doses of afatinib can be made up during the same day.  Otherwise, the dose must be 
skipped and patients should take the next scheduled dose at the usual time. Patients with emesis 
must not take a replacement dose. A missed dose of afatinib should not be taken within 12 
hours of the next dose. 
5.1.7    Trial Blinding/Masking 
 
This is an open-label trial; therefore, the Sponsor-Investigator and subject will know the 
treatment administered. 
 
5.2    Treatment Allocation 
 
Patients will be enrolled into the dose de-escalation protocol until the MTD is reached. Then 
patients will be enrolled into 2 cohorts for the dose expansion at the recommended expansion 
dose and RP2D. Cohort (Arm) A: will be concurrent MK-3475 + afatinib at initiation of 
treatment and Cohort (Arm) B: will be lead in MK-3475 for 2 cycles followed by concurrent 
MK-3475 and afatinib. The recommended dose for the dose expansion cohorts and RP2D dose 
will be informed by the MTD determined in the de-dose escalation phase and assessment of 
the overall toxicity at the treated dose levels. 
 
After the expansion dose (MTD) is determined, for the expansion phase we will enroll and 
complete Cohort A: Afatinib + MK-3475 (Concurrent) to further define toxicities at the MTD in 
the dose expansion. After completion of Cohort A, we will enroll patients into Cohort B (lead-in 
MK-3475 followed by combination afatinib and MK-3475 commencing at cycle #3). 
 


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5.3    Definition of Dose Limiting Toxicities (DLT) 
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.0. The 
occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
judged by the Investigator to be possibly, probably or definitely related to study drug (either 
afatinib or MK-3475) administration: 
1.          Grade 4 non-hematologic toxicity (not laboratory). 
 
2.          Grade 4 hematologic toxicity lasting ≥14 days. 
 
3.          Grade 3 non-hematologic toxicity (not laboratory) lasting > 3 days despite optimal 
supportive care with maximal supportive care for diarrhea and rash. See description of 
maximal supportive care for diarrhea and rash attributed to afatinib below. 
 
4.          Any Grade 3 or Grade 4 non-hematologic laboratory value if: 
 
• Medical intervention is required to treat the patient, or 
 
• The abnormality leads to hospitalization, or 
 
• The abnormality persists as > grade 3 for >1 week. 
 
5.          Febrile neutropenia Grade 3 or Grade 4: 
 
• Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 
degrees F) for more than one hour 
 
• Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 
degrees F) for more than one hour, with life-threatening consequences and urgent 
intervention indicated. 
 
6.          Thrombocytopenia <25,000/mm3 if associated with: 
 
• A bleeding event which does not result in hemodynamic instability but requires 
an elective platelet transfusion, or 
 
• A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit 
 
• Grade 5 toxicity (i.e. death). 
 
7.         Diarrhea is an expected adverse event from afatinib. Diarrhea attributed to afatinib 
will be considered a DLT if grade 3 despite maximal medical management for > 72 
hours. Maximal medical management will be defined as anti-diarrheal management that 
includes: loperamide, diphenoxylate and atropine, and tincture of opium. Grade 4 
diarrhea will be considered a DLT. 


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8. 
Acneiform rash is an expected adverse event from afatinib. Acneiform rash attributed to 
afatinib will be considered a DLT if grade 3 despite maximal medical management for 
> 72  hours.  Maximal medical management will  be  defined  as  oral  antibiotic,  
preferably doxycycline, cleocin solution or cream and topical steroids. In addition an 
asymptomatic/minimally symptomatic classic acneiform rash will only be considered a DLT 
if it covers ≥ 50% BSA. Grade 4 rash will be considered a DLT. 
 
9.  
To be evaluable for a DLT, 80% of dose must have been administered in cycle 1 unless a 
DLT occurred. 
 
10.  
Delay in starting cycle 2 of ≥ 14 days due to toxicity related to afatinib and/or MK-3475 
5.4    Attribution of Adverse Events 
Investigators are required to assess whether there is a reasonable possibility that afatinib and/or 
MK-3475 caused or contributed to the adverse event.  The following general guidance may be 
used. 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
      • Unrelated – The AE is clearly NOT related to the study treatment. 
If an adverse event is attributable (either definite, probable or possible) to MK-3475 and/or 
afatinib that requires the drug be held the other drug may be continued if it the adverse event is 
not attributable to that drug (either unlikely or unrelated) with approval of the treating physician 
and primary investigator. Exceptions include pneumonitis and grade 2 and above enterocolitis 
(as defined in this protocol) where both MK-3475 and afatinib must be held. 
 
5.5    Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck and/or Boehringer Ingelheim.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the subject's primary physician.   
5.5.1    Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.   


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All concomitant medications received within 28 days before the first dose of trial treatment and  
30  days  after  the  last  dose  of  trial  treatment  should  be  recorded.    Concomitant 
medications administered after 30  days  after  the  last  dose  of  trial  treatment should be 
recorded for SAEs and Event(s) of clinical interest. ECIs guidance document attached within the 
appendices. 
 
5.5.2    Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 
• Antineoplastic systemic chemotherapy or biological therapy 
 
• Immunotherapy not specified in this protocol 
 
• Chemotherapy not specified in this protocol 
 
• Investigational agents other than MK-3475 and afatinib 
 
• Radiation therapy 
 
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the Investigator’s discretion. 
 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. 
 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor-
Investigator. 
 
• Strong  inducers  or  inhibitors  of  P-glycoprotein  that  are  known  to  interact  with 
afatinib including, but not limited to: ritonavir, cyclosporine A, ketoconazole, 
itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and 
amiodarone. Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information. 
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Subjects  
may  receive  other  medications  that  the  investigator  deems  to  be  medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. There are no 
prohibited therapies during the Post-Treatment Follow-up Phase. 


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In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with afatinib around one week prior to the surgery, and to restart treatment after complete 
wound healing. If afatinib is interrupted for more than 14 days, the decision to continue will be 
made by the Sponsor-Investigator. 
5.6    Rescue Medications & Supportive Care 
5.6.1    Supportive Care Guidelines 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.   Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
• 
Diarrhea/Colitis:    
Both   afatinib   and   MK-3475   can   cause   diarrhea.   Subjects   should additionally 
be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).    
o All  subjects  who  experience  diarrhea/colitis  should  be  advised  to  drink  liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. Diarrhea 


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should be managed aggressively with anti-diarrheal agents such as: loperamide, 
diphenoxylate/atropine and tincture of opium if necessary.For Grade 2 diarrhea/colitis 
that persists greater than 3 days, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
 
• Management of Acneiform Rash – Afatinib as with other EGFR-inhibitors can cause a 
classic acneiform rash. Acneiform rash attributed to afatinib ≥ grade 2 should be  
managed  aggressively  with  cleocin  solution  and  appropriate anti-biotics such  as 
doxycycline. Management for grade 1 acneiform rash per investigator’s discretion. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
• For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
• Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g., propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
• Grade 3-4 hyperthyroidism  
• Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 


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• Hepatic: 
• For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
• Treat with IV or oral corticosteroids 
• For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
• For Grade 2 events, treat with corticosteroids. 
• For Grade 3-4 events, treat with systemic corticosteroids. 
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. 
 
 
Table 7 shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of MK-3475. Please also see Events of Clinical Interest Appendix attached at 
end of protocol for further details. 
 
 
 


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Table 7.  Infusion Reaction Treatment Guidelines  
 
NCI CTCAE Grade 
Treatment 
Premedication at  
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines,  NSAIDS, narcotics, 
IV fluids); prophylactic medications 
indicated for < =24 hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids Antihistamines NSAIDS 
Acetaminophen Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held 
until symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose. Subjects who develop 
Grade 2 toxicity despite adequate 
premedication  should be permanently 
discontinued from further trial 
treatment administration. 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with: 
 
Diphenhydramine  50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen  500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening;  pressor or 
ventilatory support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids Antihistamines NSAIDS 
Acetaminophen Narcotics Oxygen 
Pressors Corticosteroids Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
Hospitalization  may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration 
 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. For Further information, please refer to the Common Terminology Criteria 
for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 
 


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5.6.2 Rescue medication for Afatinib 
 
Rescue medications to reverse the actions of afatinib are not available. There is no specific 
antidote for overdosage with afatinib. Potential adverse events should be treated symptomatically. 
Common adverse events of treatment with afatinib with specified management recommendations 
and/or requirements include diarrhea, and rash/acne, paronychia. To improve tolerability and the 
probability of clinical benefit, patients should receive prompt and appropriate supportive care at 
the first signs of symptoms. Suggested treatments for AEs are described below. 
5.6.3    Management of Eye Complications of Afatinib 
 
Patients who present with symptoms of keratitis, such as acute or worsening eye inflammation, 
lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly 
to an ophthalmic specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment with 
afatinib should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of 
continuing treatment with afatinib should be carefully considered. Afatinib should be used with 
caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens 
use is a risk factor for keratitis and ulceration. 
5.6.4    Management of expected adverse events 
 
Dermatologic adverse events, mucositis/stomatitis and diarrhea are the most common side- 
effects associated with treatment with afatinib. Treatment of these side-effects should be 
proactive and should be started as early as possible after onset of symptoms. 
 
5.6.5    Management of diarrhea and hydration status following treatment with afatinib 
 
Diarrhea occurs at a high frequency and generally begins within 2 weeks of exposure to 
afatinib. Although usually mild to moderate, diarrhea may lead to dehydration and compel 
treatment modification or discontinuation, so early management is essential (Table 10). At the 
time of initiation of treatment with afatinib patients should be given a supply of loperamide to 
keep with them at all times or access to afatinib should be confirmed; and patients should be 
counselled on the appropriate use. 
 
 
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhea. (5) 
 
 
 
 
 
 
 
 


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Table 10: Grade specific treatment recommendations for afatinib related diarrhea 
 
Severity 
(CTCAE 
Grading) 
Description 
Intervention Concerning 
Afatinib Treatment 
Specific Intervention 
Mild  
(Grade 1) 
Increase of < 4 stools per 
day over baseline; mild 
increase in ostomy output 
compared with baseline 
Continue same dose 
Stop laxatives and advise patient to drink 
at least 8-10 glasses of water of clear 
fluids per day; 
4 mg (2 tablets) of loperamide to be taken 
immediately, followed by 2 mg (1 tablet) 
after each loose stool until bowel 
movements cease for 12 hours  
Moderate 
(Grade 2) 
Increase of 4-6 stools per 
day over baseline; IV fluids 
indicated < 24 hours; 
moderate increase in 
ostomy output compared 
with baseline; not 
interfering with ADL 
Continue same dose unless 
Grade 2 diarrhea continues 
for ≥ 2 days (48 hours) in 
which case treatment must 
be interrupted until 
recovered to ≤ Grade 1 
followed by dose reduction 
Continue loperamide; assess for 
dehydration and electrolyte imbalance; 
consider IV fluids and electrolyte 
replacement 
Severe 
(Grade 3) 
Increase of ≥ 7 stools per 
day over baseline; 
incontinence; IV fluids >24 
hours; hospitalization; 
severe increase in ostomy 
output compared with 
baseline; interfering with 
ADL 
Dose interruption until 
recovered to ≤Grade 1 
followed by dose 
reduction* 
See Grade 2; plus: 
an infectious process should be ruled out 
with stool cultures; aggressive iv fluid 
replacement 
≥ 24 hours; hospitalization to monitor 
progress; consider prophylactic antibiotics 
if patient is also neutropenic; 
Life 
threatening 
(Grade 4) 
Life-threatening 
consequences (e.g. 
hemodynamic collapse) 
Dose interruption until 
recovered to ≤Grade 1 
followed by dose 
reduction* 
See Grade 3 
 
* If despite optimal supportive care and a treatment interruption, diarrhea does not resolve 
to CTC AE Grade ≤1 within 14 days, treatment with afatinib must be permanently discontinued. 
In the event that the patient is deriving obvious clinical benefit according to the investigator’s 
judgment, further treatment with afatinib will be decided in agreement between the company 
supporter and the investigator. 
 
5.6.6 Management recommendations for dermatological AEs following treatment with 
afatinib 
 
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 11 and grade-specific treatment 
recommendations are summarized in Table 12 and 13. For dose adjustment of afatinib refer to 
Table 6. 
 
Specific interventions should be reassessed at least after 2 weeks or at any worsening of 


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symptoms, in which case the specific intervention should be adjusted and, depending on own 
clinical experience, early involvement of a dermatologist should be considered. (4). 
 
 
Table 11: General recommendations for prophylaxis while receiving afatinib 
 
 
Personal hygiene 
• Use of gentle soaps and shampoos for the body, e.g. pH5 neutral bath and shower 
formulations and tepid water. 
• Use of very mild shampoos for hair wash. 
• Only clean and smooth towels are recommended because of potential risk of 
infection. The skin should be patted dry after a shower, whereas rubbing the skin 
dry should be avoided. 
• Fine cotton clothes should be worn instead of synthetic material. Shaving has to be 
done very carefully. 
• Manicure, i.e. cutting of nails, should be done straight across until the nails no 
longer extend over the fingers or toes. Cuticles are not allowed to be trimmed 
because this procedure increases the risk of nail bed infections 
Sun protection 
• Sunscreen should be applied daily to exposed skin areas regardless of season. 
Hypoallergenic sunscreen with a high SPF (at least SPF30, PAPA free, UVA/UVB 
protection), preferably broad spectrum containing zinc oxide or titanium dioxide  
are recommended 
• Patients should be encouraged to consequently stay out of the sun.  
• Protective clothing for sun protection and wearing a hat should be recommended. 
Moisturizer 
treatment 
• It is important to moisturize the skin as soon as anti-EGFR therapy is started. 
• Hypoallergenic moisturizing creams, ointments and emollients should be used 
once daily to smooth the skin and to prevent and alleviate skin dryness. 
• Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral oil based) and 
topical acne medications 
Prevention of 
paronychia 
• Patients  should  keep  their  hands  dry  and  out  of  water  if  ever possible. 
• They should avoid friction and pressure on the nail fold as well as picking or 
manipulating the nail. 
• Topical application of petrolatum is recommended around the nails due to its 
lubricant and smoothing effect on the skin. 


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Table 12:  Grade specific treatment recommendations of skin reactions to afatinib 
 
Severity 
Description 
Specific intervention 
ACNEIFORM RASH 
Mild  
(Grade 1) 
Macular or papular eruptions or 
erythema without associated symptoms 
Consider topical antibiotics, e.g. 
clindamycin 2% or topical erythromycin 1% cream of 
metronidazole 0.75% or topical nadifloxacin 1%; 
Isolated scattered lesion: cream preferred 
Multiple scattered areas: lotion preferred 
Moderate 
(Grade 2) 
Macular or papular eruptions with 
pruritus or other associated symptoms; 
localized desquamation or other lesions 
covering <30% of BSA 
Topical treatment as for Grade 1 plus short term topical 
steroids, e.g., prednicarbate cream 0.02% plus an oral 
antibiotic (for at least 2 weeks) e.g. Doxycycline 100mg 
b.i.d. or Minocycline hydrochloride 100mg b.i.d 
Severe  
(Grade 3) 
Severe, generalized erythroderma or 
macular, popular or vesicular eruption; 
desquamation covering ≥30% of BSA; 
associated with pain, disfigurement, 
ulceration or desquamation 
Topical and systemic treatment as for 
Grade 2. 
Consider referral to dermatologist 
Consider systemic steroids 
Life 
threatening 
(Grade 4) 
Generalized exfoliative, ulcerative, or 
bullous dermatitis 
See Grade 3 
Systemic steroids are recommended 
EARLY AND LATE XEROTIC SKIN REACTIONS - PRURITUS 
Mild  
(Grade 1) 
Mild or localized 
Topical polidocanol cream. Consider oral antihistamines, 
e.g. diphenhydramine, dimethindene, cetirizine, 
levocetirizine, desloratidine, fexofenadine or clemastine) 
Moderate 
(Grade 2) 
Intense or widespread 
See Grade 1 plus oral antihistamines; Consider topical 
steroids, e.g., topical hydrocortisone 
Severe  
(Grade 3) 
Intense or widespread and interfering 
with activities of daily living (ADL) 
See Grade 2. 
XEROSIS (DRY SKIN) 
Mild  
(Grade 1) 
Asymptomatic 
Soap-free shower gel and/or bath oil. Avoid alcoholic 
solutions and soaps. Urea- or glycerin-based moisturizer. 
In inflammatory lesions consider topical steroids (e.g., 
hydrocortisone cream) 
Moderate 
(Grade 2) 
Symptomatic, not interfering with 
ADL 
See Grade 1. 
In inflammatory lesions consider topical steroids (e.g., 
hydrocortisone cream) 
Severe  
(Grade 3) 
Symptomatic, interfering with ADL 
See Grade 2. 
Topical steroids of higher potency (e.g., prednicarbate, 
mometasone furoate) Consider oral antibiotics 


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FISSURES 
Mild  
(Grade 1) 
Asymptomatic 
Petroleum jelly, Vaseline® or Aquaphor for 
30 minutes under plastic occlusion every night, 
followed by application of hydrocolloid dressing; 
antiseptic baths (e.g. potassium permanganate 
therapeutic baths, final concentration of 1:10,000, or 
povidone-iodine baths) 
Topical application of  aqueous silver nitrate solutions 
to fissures 
Moderate  
(Grade 2) 
Symptomatic, not interfering 
with 
See Grade 1. 
Consider oral antibiotics. 
Severe  
(Grade 3) 
Symptomatic, Interfering with 
ADL 
See Grade 2. 
1 If Grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, the investigator may 
choose to pause treatment up to 14 days followed by a reduction in the dose of afatinib according to the dose 
reduction scheme in Table 6. 
 
 
5.6.7 Management of mucositis/stomatitis 
 
General and grade specific recommendations are described in Table 13. For dose adjustment 
refer to Section 5,2 and for restrictions on concomitant therapies refer to Section 5.6. 
 
Treatment is supportive and aimed at symptom control. These may include atraumatic cleansing 
and rinsing with non-alcoholic solutions such as normal saline, diluted salt and baking soda 
solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one quart of water 
every four hours); avoidance of agents containing iodine, thyme derivatives and prolonged use of 
hydrogen peroxide; dietary maneuvers such as promotion of soft, non irritating foods like ice-
creams, mashed/cooked vegetables, potatoes and avoidance of spicy, acidic or irritating foods 
such as peppers, curries, chillies, nuts and alcohol. If the patient is unable to swallow foods or 
liquids, parenteral fluid and/or nutritional support may be needed. Examples of some of the 
agents suggested in Table 13 include: topical analgesics –viscous lidocaine 2%; mucosal coating 
agents - topical kaolin/pectin; oral antacids, maltodextrin, sucralfate; topical antifungals – 
nystatin suspension. (adapted from (8)). 
 
 
 
 
 
 


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Table 13: Grade specific treatment recommendations of study-drug related mucositis/stomatitis 
 
 
Severity  
(CTCAE 
Grading) 
Description 
Treatment Recommendations 
Intervention Concerning 
Afatinib Treatment/Dose 
Modification 
Mild  
(Grade 1) 
Minimal 
symptoms; 
normal diet 
Oral rinses with agents such as non-
alcoholic mouthwash,normal saline, 
diluted salt and baking soda solution. 
No change. 
Moderate  
(Grade 2) 
Symptomatic, 
but  can  eat and 
swallow 
modified diet 
Addition of topical analgesic 
mouth treatments, topical 
corticosteroids, antiviral therapy if 
herpetic infection confirmed, 
antifungal therapy preferably topical 
on a case by case basis. 
Maintain dose if 
tolerable; Hold dose if 
intolerable until recovery 
to grade ≤1, then  restart  
at  the same dose. 
Severe  
(Grade 3) 
Symptomatic 
and unable to 
adequately 
aliment or 
hydrate orally 
Same as for Grade 2; institute 
additional symptomatic therapy 
(topical or systemic) as clinically 
indicated . 
Hold dose until 
recovery to  grade ≤1 or 
baseline, then restart at the 
reduced dose according to 
Section 5.2. 
Life threatening 
(Grade 4) 
Symptoms 
associated 
with life- 
threatening 
consequences 
Same as for Grade 2; institute 
additional symptomatic therapy 
(topical or systemic) as clinically 
indicated 
Hold dose until 
recovery to  grade ≤1 or  
baseline,  then restart at 
the reduced dose 
according to Section 5.2 
 
5.7    Diet/Activity/Other Considerations 
 
5.7.1    Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
Patients should be advised to avoid any foods known to aggravate diarrhea. 
 
5.7.2    Contraception 
 
MK-3475 a n d  a f a t i n i b  may have adverse effects on a fetus in utero.   Furthermore, it is 
not known if MK-3475 has transient adverse effects on the composition of sperm.    
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   


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Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:   
(1) practice true abstinence† from heterosexual activity, if this is the preferred and usual 
lifestyle 
OR  
(2) use (or have their partner use) highly effective methods of contraception during 
heterosexual activity.   
 
Highly effective methods of contraception for men and women are‡: 
• Male sterilization (vasectomy).  For female patients, the vasectomized male partner 
should be the only partner 
• Female sterilization 
• intrauterine device (IUD) (copper or hormonal) 
• vasectomy of a female subject’s male partner  
• Contraceptive subdermal implant (Nexplanon) 
• Hormonal birth control (i.e., contraceptive pill, patch, ring or injection) for subject or 
for  male patient’s female partner 
 
Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-


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only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
 
Unacceptable methods for men and women: 
• Abstinence at certain times of the cycle only, such as during the days of ovulation, 
after ovulation (based on symptoms or temperature) 
• Pre-ejaculatory withdrawal 
• Condom with spermicidal foam/gel /film/cream/suppository 
• Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites 
in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to the Sponsor-Investigator, Merck and Boehringer Ingelheim.  If there is any 
question that a subject will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
 
5.7.3    Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with MK-3475 and afatinib, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the company supporters and 
Investigator to Merck and Boehringer Ingelheim without delay and within 24 hours to the 
Sponsor and within 2 working days to Merck if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to 
the mother or newborn).  The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
company supporters.   If a male subject impregnates his female partner the study personnel at 
the site must be informed immediately and the pregnancy reported to the Sponsor-Investigator 
and to Merck and followed as described above and in Section 7.2.2. 
 


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5.7.4    Use in Nursing Women 
 
It is unknown whether MK-3475 is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment. 
 
5.8    Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the company supporter if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.   
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other 
Procedures. 
 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression by RECIST 1.1 
 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved by the primary investigator in 
consultation with the sponsor. 
 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with MK-3475 or 35 administrations of 
study medication, whichever is later 
Note: 24 months of study medication is calculated from the date of first dose. 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be  
followed  for  30  days  for  adverse  event  monitoring.   Subjects who discontinue for reasons 
other than progressive disease will have post-treatment follow- up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 
follow-up.   
 


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5.8.1 Discontinuation of Study Therapy after CR  
 
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 24 weeks with pembrolizumab and had at least two treatments 
with pembrolizumab beyond the date when the initial CR was declared.  Subjects who then 
experience radiographic disease progression may be eligible for up to one year of additional 
treatment with pembrolizumab via the Second Course Phase at the discretion of the investigator 
if no cancer treatment was administered since the last dose of pembrolizumab, the subject meets 
the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects 
will resume therapy at the same dose and schedule at the time of initial discontinuation.  
Additional details are provided in Section 7.1.5.5. 
 
5.9    Subject Replacement Strategy 
 
Patients who consent for the study and do not receive MK-3474 or afatinib on study will be 
replaced. 
 
Patients who receive <80% of the MK-3475 and afatinib infusion in Cycle 1 (e.g., because the 
infusion had to be discontinued due to an infusion reaction) and did not experience a DLT will 
not be taken into account in the assessment of the overall DLT rate for the particular dose 
level cohort and will need to be replaced. 
 
5.10  Clinical Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
 
1.   Quality or quantity of data recording is inaccurate or incomplete 
 
2.   Poor adherence to protocol and regulatory requirements 
 
3.   Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
 
4.   Plans to modify or discontinue the development of the study drug 
 
In the event of Merck and Boehringer Ingelheim decision to no longer supply study drug, 
ample notification will be provided so that appropriate adjustments to subject treatment can be 
made. 


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6.0  TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles1.9 
End of Treatment 
 
 
Main Study 
Screening (Visit 1) 
1 
2 
3 
4 
To be repeated beyond 8 cycles 
Discontinuation Visit/Safety 
Follow Up Visit/PFS follow up 
5 
6 
7 
8 
Scheduling Window (Days)2: 
-30 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics  and Medical History 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
NSCLC Disease Details and Prior Treatment 
X 
 
 
 
 
 
 
 
 
 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs and Weight12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Zubrod Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test – Urine or Serum β-HCG3,6 
X 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT4,6 
X5 
 
 
 
 
 
 
 
 
 
CBC with Differential6 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive  Serum Chemistry Panel (see 
6
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis6 
X5 
T3, FT4 and TSH6 
X5 
 
X 
 
X 
 
X 
 
X 
X 
 


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Trial Period: 
Screening Phase 
Treatment Cycles1,9 
End of Treatment 
Treatment Cycle/Title: 
Main Study 
Screening (Visit 1) 
1 
2 
3 
4 
To be repeated beyond 8 
cycles
Discontinuation Visit/Safety 
Follow Up Visit 
  5 
  6 
  7 
  8 
Scheduling Window (Days)2 
-30 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
Efficacy Measurements 
Tumor Imaging7 
X 
 
 
X 
 
 
X 
 
 
 
Brain Imaging (MRI or CT Scan)13 
X 
Tumor Biopsies/Archival  Tissue Collection/Correlative Studies Blood 
Tissue Collection10 
X  
(must be within 60 days) 
 
 
X 
 
 
 
 
 
 
EGFR Mutation Testing8 
X 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection11 
X 
 
 
X 
 
 
X 
 
 
X 


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1. In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified. 
Treatment cycles are 3 weeks (21-days); however the MK-3475 treatment cycle interval may be increased due to toxicity according to the dose modification 
guidelines provided. If treatment cycles are increased all procedures except imaging will be completed according to the Cycle number and not weeks on 
treatment, imaging will be performed every 6 weeks (± 3 days) from the first dose of trial treatment regardless of any treatment delays. Weekly (D8 and D15 
+/- 3 days) follow up visits for the first cycle when starting afatinib is recommended (when afatinib is added (Cohort A C1D1 and Cohort B C3D1). 
2. In general, the window for each visit is ± 3 days unless otherwise specified. 
3. For women of reproductive potential, a urine or serum pregnancy test will be performed within 72 hours prior to first dose of trial treatment. If 
urine pregnancy results cannot be confirmed as negative, a serum pregnancy test, performed by the local study site laboratory, will be required. 
Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines. 
4. Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy. 
5. Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. 
6. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. 
7. The initial tumor imaging will be performed within 30 days prior to the first dose of trial treatment. Scans performed as part of routine clinical management 
are acceptable for use as the screening scan if they are of diagnostic quality and performed within 30 days prior to the first dose of trial treatment. On-study 
imaging will be performed every 6 weeks (42 -7 days) after the first dose of trial treatment or more frequently if clinically indicated. The timing for imaging 
studies should follow calendar days and should not be adjusted for delays in cycle starts or extension of MK-3475/afatinib cycle frequencies. The same 
imaging technique should be used in a subject throughout the trial. CT including the chest, abdomen and pelvis or PET-CT is required for the baseline 
assessment. 
8. Provide documentation of the subject’s tumor EGFR mutation from a CLIA certified laboratory. 
9. MK-3475 can be administered for up to 2 years. For the dose de-escalation and Cohort (Arm) A (concurrent afatinib and MK-3475) both drugs will be 
administered as outlined in this protocol starting with cycle #1. For cohort B. MK-3475 will be initiated with cycle #1 and afatinib will commence in 
combination with MK-3475 starting with cycle #3. 
10. Tumor biopsy for immune and EGFR biomarker analysis will be performed prior to Cycle 1 of treatment either on archival tissue or fresh biopsy (within 60 
days). Repeat biopsy will be performed prior to initiation of cycle 3 (42 days (-7 days)) 
11.  Correlative blood draws for immune correlates will be performed prior to cycle 1 (- 3 days), prior to cycle 3 (-3 days), prior to cycle 6 (-3 days) and at 
progression (+/- 5 days). Correlative blood draws for plasma tumor cfDNA will be performed at baseline, every 2 cycles (+/- 3 days) and at progression (+/- 
5 days). 
12.  Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only. 
13.  Contrast enhanced MRI brain or CT head is recommended. If contrast is contraindicated, a non-contrast enhanced study may be performed. 
 


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7.0  TRIAL PROCEDURES 
7.1    Trial Procedures 
 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor- 
Investigator and/or Merck and/or Boehringer-Ingelheim for reasons related to subject safety. In 
some cases, such evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis 
C, etc.), and thus local regulations may require that additional informed consent be obtained 
from the subject.  In these cases, such evaluations/testing will be performed in accordance with 
those regulations. 
7.1.1    Administrative Procedures 
 
7.1.1.1   Informed Consent 
 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
7.1.1.1.1  General Informed Consent 
 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion. 
 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.   The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available that 
may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent form 
or addendum to the original consent form that captures the subject’s dated signature or by the 
subject’s legally acceptable representative’s dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level. 
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor-Investigator requirements. 


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7.1.1.2   Inclusion/Exclusion Criteria 
 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial. 
 
7.1.1.3   Medical History 
 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history. 
 
7.1.1.4   Prior and Concomitant Medications Review 
 
7.1.1.4.1  Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 
days before starting the trial.  Treatment for the disease for which the subject has enrolled in this 
study will be recorded separately and not listed as a prior medication. 
 
7.1.1.4.2  Concomitant Medications 
 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
 
7.1.1.5   Disease Details and Treatments 
 
7.1.1.5.1  Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
 
7.1.1.5.2  Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
7.1.1.5.3  Subsequent Anti-Cancer Therapy Status 
 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up. 


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7.1.1.6   Trial Compliance (Medication/Diet/Activity/Other) 
 
The study medication will be given in accordance with the protocol and the instructions of a site 
investigator. 
 
The appropriate number of afatinib tablets for 3 weeks of treatment will be provided to patients 
to be self-administered at home. 
 
Patients will be asked to bring the remaining trial medication at the end of each 3 week to the 
investigator site for a compliance check. The remaining film-coated tablets will be counted by 
the investigator/site staff and recorded at the investigator site. Discrepancies between the 
number of tablets remaining and the calculated number of tablets the patients should have 
taken must be documented and explained. At the end of each 3 week, any remaining medication 
will be collected. If the patient is eligible for further treatment, a new bottle of study medication 
must be dispensed. 
 
The investigator can withdraw a patient from the study in the event of serious and persistent 
non-compliance which jeopardizes the patient’s safety or render study results for this patient 
unacceptable. Patients who do not attend a minimum of 75% of scheduled study visits, unless 
due to exceptional circumstances, should be discussed with the company supporter and be 
evaluated for compliance. 
7.1.2    Clinical Procedures/Assessments 
 
7.1.2.1   Adverse Event (AE) Monitoring 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 12.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment. 
 
For subjects receiving treatment with MK-3475 all AEs of unknown etiology associated with 
MK-3475 exposure should be evaluated to determine if it is possibly an event of clinical 
interest (ECI) of a potentially immunologic etiology (termed immune-related adverse events, or 
irAEs).    See the separate ECI guidance document in the appendix (Section 12.9) regarding the 
identification, evaluation and management of potential irAEs. 
 
Refer to section 7.2 for detailed information regarding the assessment and recording of AEs. 
 
7.1.2.2   Full Physical Exam 
 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.   Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed during screening, 


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7.1.2.3   Directed Physical Exam 
 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration. 
 
7.1.2.4   Vital Signs 
 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment (on day 1 prior to MK-3475) and at treatment 
discontinuation as specified in the Trial Flow Chart (Section 6.0).  Vital signs should include 
temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at 
screening only. 
 
7.1.2.5   Eastern Cooperative Oncology Group (ECOG/Zubrod) Performance Scale 
 
The  investigator  or  qualified  designee  will  assess  ECOG  status  (see  Section  12.1)  at 
screening, prior to the administration of each dose of trial treatment and discontinuation of trial 
treatment as specified in the Trial Flow Chart.    
 
7.1.2.6   Tumor Imaging and Assessment of Disease 
 
 
For the purposes of this study, patients should be re-evaluated for response after cycle 2 (6 
weeks) and then every 2 cycles (6 weeks). In addition to a baseline scan, confirmatory scans 
should also be obtained at least 4 weeks following initial documentation of objective response. 
 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in 
this study. 
 
* As published in the European Journal of Cancer: 
 
• PET-CT At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and  can  be  
used  interchangeably with  conventional CT  in  accurately measuring cancer lesions 
over time.  Note, however, that the PET portion of the CT introduces additional data  
which  may  bias  an  investigator if  it  is  not  routinely or  serially performed. 
 
• Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for 
body scans). 
 


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Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with MK-3475 and afatinib. 
 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.   (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
 
Evaluable Non-Target Disease Response.   Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 
mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
 
Note:  Tumor lesions that are situated in a previously irradiated area are measurable if there is 
evidence of growth post-radiation such as increase in size on CT or increase in FDG avidity on 
PET. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
 
Non-measurable disease.   All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non- measurable) since they are, by 
definition, simple cysts. 
 
 


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‘Cystic  lesions’  thought  to  represent  cystic  metastases  can  be  considered  as 
measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion that can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to 
be included in the sum, then only the short axis is added into the sum.  The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note:   the appearance of one or more new lesions is 
also considered progressions). 
 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
 
 
 


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Evaluation of Non-Target Lesions 
 
Complete Response (CR):    Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
 
Non-CR/Non-PD:   Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
 
Progressive Disease (PD):   Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.   It must be representative of overall disease status change, not a 
single lesion increase. 
 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
 
Evaluation of Best Overall Response 
 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
 
 
 


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For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non- PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
 
PR 
Non-CR/Non- PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: Patients  with  a  global  deterioration  of  health  status  requiring  discontinuation  of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ’Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is  increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign  
this category when no lesions can be measured is not advised 
 
 
 
 
 


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Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements. 
 
 
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
 
Response Review 
 
Response review will be done by the investigator. 
 
 
7.1.3    Laboratory Procedures/Assessments 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.   
 
7.1.3.1 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in the trial flow 
chart (Section 6) and section 12.7. The total amount of blood/tissue to be drawn/collected over 
the course of the trial (from pre- trial to post-trial visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per subject. 
 
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment. After Cycle 1, pre-dose laboratory procedures 
can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment. 
 


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7.2    Correlative Studies 
Correlative Studies 
Study-specific correlatives are outlined below. Remaining extra plasma and tissue after these 
studies are performed may be used for additional research studies focusing on molecular 
pathways of resistance to EGFR-directed therapy and additional immune markers. 
A Study ID number will be assigned to each patient and will be used in sample coding instead 
of the name.  The key linking the number with the patient identity and clinical outcomes will 
be kept by Dr. Riess and his research staff. This will be kept in a locked location. 
 
7.2.1    EGFR-directed Correlative Studies 
7.2.1.1    Plasma EGFR-mutant DNA 
 
Molecular Studies: Blood 
• Plasma DNA/RNA detection of EGFR and PD-L1 
Prior to each cycle of treatment, two tubes of blood (1 for RNA and 1 for DNA) will be collected 
for EGFR and PD-L1 DNA and RNA quantification. Tubes will be provided in a collection kit 
from Liquid Genomics. The assay will be performed by Liquid Genomics, which has validated 
DNA and RNA assays for EGFR mutations and PD-L1 RNA levels. Please see Appendix 12.6 
for tube collection and shipping instructions. 
Please be sure to order kits from Liquid Genomics at the time of study activation (if not already 
available at the site). 
 
7.2.1.2    EGFR-Activating Mutations and Mechanisms of Resistance to EGFR-TKIs on 
Biopsied Tumor Specimens 
 
7.2.1.3   Standard-of-Care Baseline Biopsy  
Biopsy of a patient’s tumor upon progression with erlotinib to examine EGFR-resistance 
mechanisms such as EGFR T790M and rule out small cell histologic transformation is 
considered standard-of-care. The biopsied tissue performed at baseline will be sent to 
Foundation Medicine (for patients at UC Davis) or equivalent CLIA-certified assay for 
confirmation of EGFR-mutation status and determination of EGFR-T790M resistance 
mutation, following usual clinical procedures. If tissue permits, other mechanisms of resistance 
will be examined, prioritizing MET amplification, HER2 amplification, PIK3CA specific and 
pathway mutations, and MEK pathway mutations. (Biopsy must be performed within 60 days 
of consent). 
 
 
 


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7.2.2    Repeat Biopsies for EGFR-mutation Status and Immune Correlates 
In all patients following consent, two biopsies will be attempted on study: one prior to 
initiation of study treatment and one after cycle #2 of treatment before initiation of cycle 3. 
This will be approximately week 5-6 on study (see study calendar). Patient consent for 
biopsies will be a study requirement. 
 
Biopsies will be performed by a qualified professional and will be tailored to the available 
disease targets. Potential biopsies could include image-guided core biopsy, or limited surgical 
or pulmonary interventional biopsy. Image-guided tumor biopsies will be obtained with the 
help of the Interventional Radiology or Radiology team by a percutaneous approach or by the 
assistance of our surgical or pulmonary colleagues. Alternative biopsy techniques (e.g. 
transbronchial, skin punch biopsy) will be considered if indicated after discussion with the 
principal investigator. When a core biopsy is performed, it is preferred that a core biopsy 
system be used to obtain at least 3 core biopsies not less than 22 gauge in diameter and 1 cm 
in length (6 core biopsies is ideal). 
 
If a site is deemed appropriate for biopsy with minimal risk to the participant by agreement 
between the investigators and biopsy team, a biopsy will be attempted.  The  use  of  imaging  
to  facilitate biopsies will be decided by members of the Interventional  Radiology or 
Radiology team and may include an ultrasound  (US), a computer  tomography  (CT) scan, 
or a magnetic  resonance  imaging (MRI) scan. Should a CT scan be needed for biopsy, the 
number of scans for each procedure will be limited to the minimum number needed to safely 
obtain a biopsy. Tumor biopsies and local anesthesia will be administered only if they are 
considered to be of low risk to the participant, as determined by the investigators and/or the 
interventionist. 
 
Tissue Study Requirements on Treatment Listed in Order of Priority 
Test 
Institution or 
commercial entity 
Baseline Biopsy 
(slides) 
On Treatment Biopsy 
(Prior to Cycle 3) 
Standard-of-Care 
Genomic Testing in 
CLIA Certified Lab 
Investigator Choice 
Per SOC Guidelines 
X 
PD-L1 and QIF 
Yale Translational 
Immuno-Oncology 
5 slides minimum, 10 
slides optimal 
5 slides minimum,  
10 slides optimal 
Next Generation 
Sequencing with 
Mutational Load* 
Broad Institute 
10 slides minimum 20 
slides optimal. 
(RNA later processing 
if available) 
10 slides minimum, 
20 slides optimal. 


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RPPA for on target 
EGFR-inhibition 
(EGFR, p-EGFR, 
pERK, ERK, pAKT, 
AKT), caspase 3 
cleavage 
Theranostics 
3-5 unstained slides 
3-5 unstained slides 
* Companion blood draw in kit for germline DNA comparison 
 
7.2.2.1    Standard-of-Care Genomic Testing 
 
Tumor biopsy at baseline will be sent for standard molecular testing at a CLIA-certified lab for 
confirmation of EGFR activating mutation and to detect the presence or absence of an EGFR-
T790M mutation as well as other resistance mechanisms to EGFR-TKI. When possible, the 
post-TKI specimen will be compared to the diagnostic block to identify treatment-induced 
differences in molecular profiles. 
 
7.2.2.2    PD-L1 and Evaluation of TILS 
The PD-L1 immunohistochemistry will be performed in 3-5 µm-thick histology preparations 
obtained from conventional biopsy formalin-fixed, paraffin-embedded (FFPE) tissue samples.  
The tumor PD-L1 protein will be tested using the FDA-approved Dako 22C3 assay using 
chromogenic immunohistochemistry in the Yale Pathology Labs or UC Davis under CLIA 
laboratory conditions. The scoring procedure will include the determination of the percentage of 
positive cells in the tumor by a surgical pathologist using bright field microscopy. The score will 
be semi-quantitative and determined based on the percentage of positive cells. 
 
The level of major TIL subtypes, TIL activation/proliferation and expression of major immune 
inhibitory receptors will be evaluated using multiplexed quantitative immunofluorescence (QIF) 
performed in 3-5 µm-thick histology preparations obtained from formalin-fixed, paraffin-
embedded (FFPE) tissue samples, as previously reported (Schalper KA, Brown J, Carvajal-
Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, et al. Objective measurement and clinical 
significance of TILs in non-small cell lung cancer. J Natl Cancer Inst. 2015;107.). We will 
perform three multiplexed QIF panels containing the following markers: Panel #1: 
DAPI/CD4/CD8/CD20; Panel #2: DAPI/CD3/Granzyme-B/Ki-67; and Panel #3: 
DAPI/CD3/PD-1/TIM-3/LAG-3.  The Yale group has already performed validation of the 
antibodies and combined these markers into multiplexed QIF panels. Simultaneous 
measurements of the targets will be performed using multispectral imaging and the AQUA® 
method providing continuous fluorescence marker scores. Eventually, quantification of positive 
cells for each marker will also be performed using the Vectra multispectral imaging platform 
with the cell phenotyping tool of the InForm® software; and reported as cell density (number of 
cells/area unit).See section 7.2.4 for processing and shipping information for the PD-L1 and QIF 
samples. 
 
 


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7.2.2.3    Next-Generation Sequencing with Mutational Load and Reverse-phase protein 
arrays (RPPA) 
 
Next-Generation Sequencing (DNA and RNA - if sufficient tissue available) of the Stand Up 2 
Cancer (SU2C) Customized Gene Panel which is the standard for the Lung Cancer dream team 
with a focus on resistance mechanisms to EGFR-TKI and quantifying mutational load will be 
performed at the Broad Institute. This will be performed at baseline biopsy unless tissue amount 
is inadequate where it will be performed on the on-treatment biopsy. When requested, the Broad 
Institute Samples lab will ship sample collection kits to research site.  A companion blood 
collection tube will also be provided and should be collected at baseline for germline mutation 
testing. 
 
Kits are specific for Material Type collected 
i. Labels – FFPE or Frozen Tumors 
ii. Labels – Blood or Buffy Coat Samples 
iii. Matrix Kits – DNA or RNA analytes 
 
1. Researcher fill kit & provides Sample Kit Metadata spreadsheet (example provided). 
2. Kits are shipped back to the Broad Institute Samples lab per instructions provided in the kits.  
(See Attached Documents). Specimens should be coded with a unique identifier (ie., 
Institution, Clinical Trial Number, patient number and biopsy number in sequence (ie. for 
patient 1, UCD250-001-01 (baseline biopsy), UCD250-001-02 (on-treatment biopsy), 
UCD250-001-03 (post progression biopsy). 
 
Sample Processing & Data Generation will proceed.  (Turnaround Time is expected to be 5-6 
weeks for Exome runs). RNA sequencing will be batched so timeline will be more variable. 
 
7.2.3    Immunology Correlates 
 
Immune correlates will be performed by Yale University Translational Immuno-Oncology or 
the Human Immune Monitoring Core (HIMC) at UC Davis as outlined below. 
 
PD-L1 expression will be assayed using Merck’s proprietary 22C3 antibody that is FDA 
approved as a companion diagnostic for pembrolizumab for quantifying PD-L1 expression for 
MK-3475 trials in NSCLC and melanoma including Garon, Edward B. Naiyer A. Rizvi. 
“Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer.” nejm.org.  The New 
England Journal of Medicine. April 19, 2015. 
 
7.2.3.1    Biopsied tumor for PD-L1 Quantification 
 
PD-L1 expression by immunohistochemistry at baseline and in repeat biopsy specimens to 
assess for changes in PD-L1 expression in response to treatment will be conducted  by UC 
Davis or Yale Translational Immuno-Oncology using the FDA approved DAKO 22C3 


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antibody and  by quantitative IHC. 
 
7.2.3.2    Biopsied tumor for Tumor Infiltrating Lymphocytes and Subsets and RT-PCR for 
Immune Markers 
 
In baseline and on treatment biopsies, the HIMC at UC Davis or Yale University Immunology 
Core will quantify changes in tumor infiltrating lymphocytes and immune subsets using IHC for 
T-cell subsets that include CD4, CD8, and Foxp3. Real time-PCR for immune markers (if tissue 
size permits) including CD3, PD-1, GranzB, Perforin, IL-2, IFNg, Tim3, LAG3, CTLA-4, Foxp3 
will be performed if adequate tissue is available. 
 
7.2.4    EGFR & Immunology Biopsy Processing   
 
Tumor  tissue  obtained  at  each  biopsy  time  point  will  be  collected  by  a representative 
of the study team. At the first biopsy, one of the cores will be submitted directly to Pathology 
for  clinical  interpretation  and  report  as  well  as  standard  of  care  molecular  studies.  The 
remaining cores will be delivered to UC Davis Research Pathology, Pavilion Room 2P524 (or 
corresponding local research lab at other trial sites) and divided into 2 components.  
 
At least two core biopsies not less than 22 gauge in diameter and 1cm in length or tissue the 
equivalent of core biopsies sufficient to generate at least 20 cut slides should be paraffin 
embedded and stored in research pathology until ready for processing and shipping. Ideally, 6 
cores per biopsy timepoint should be obtained. At the first timepoint 2 cores should be used for 
histologic confirmation and standard molecular testing.  2 cores should be paraffin embedded for 
IHC of PD-L1 and other markers of the tumor immune microenvironment. At UC Davis, this 
FFPE specimen may also be stored in the laboratory of Dr. Philip Mack or the UC Davis 
HIMC for storage until sent for further testing. 
 
If available, two additional cores should be immediately stored in 2ml of RNAlater 
solution (Life Technologies) (the tissue portion should be processed into pieces, each less 
than 0.5cm3) for comprehensive DNA/RNA sequencing at the Broad Institute. The Samples in 
RNAlater solution should be kept refrigerated until processed at HIMC.  This should be 
delivered to the Human Immune Monitoring Core with the contact information listed below. If 
not enough cores are obtained DNA/RNA sequencing can be sent of the initial FFPE 
tissue 
 
Specimens in RNA Later should be shipped on cool packs (Monday – Thursday only) to: 
 
Human Immune Monitoring Core (Maverakis Laboratory) 
Department of Dermatology 
UC Davis School of Medicine 
IRC Bldg., Room 1630 
2921 Stockton Blvd.  
Sacramento CA 95817 


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LAB: 916-734-2156 
 
Tissue from the  second  biopsy  timepoint will  be divided  into  the  2 research  components  
with  the  procedures  outlined above.  Component  1:  at least 2  cores  or enough tissue for 20 
cut slides as specified for initial biopsy for  FFPE  for  PD-L1 and additional IHC quantification  
by  UC Davis or Yale  and  2: remaining cores in RNA later solution then FFPE for 
DNA/RNA sequencing. (If no cores were available for processing with RNA later in the 
initial biopsy, the repeat biopsy should all go through FFPE and not through an RNA later 
step).    A research H&E slide will also be generated and reviewed by a research 
pathologist to confirm presence of tumor.  
 
If there is limited tissue for the baseline biopsy priority should be given to pathologic 
assessment and molecular  testing  at Response  Genetics  per standard of care and then  PD-
L1  testing  by  the  central  vendor.  For the repeat biopsy priority should be given for PD-L1 
and additional IHC testing by the central vendor and UC Davis HIMC. 
 
RPPA will be performed at Theranostics using their established procedures for FFPE samples 
under their CAP-accredited CLIA laboratory.  Our previous experience with this resource is that, 
for phosphorylation states of intracellular signaling molecules, the assay is highly quantitative 
and correlates with Western blotting analysis conducted at UC Davis.  The following analytes 
will be performed, listed in order of priority (although measured simultaneously): pEGFR, 
totalEGFR, pERK, totalERK, pAKT, totalAKT, caspase 3 cleavage. 
 
7.2.4.1 Immunohistochemistry and Quantitative Immunofluorescence 
 
Immunohistochemistry and Quantitative Immunofluorescence: Staining for PD-L1, relevant 
immunoproteins and tumor infiltrating immune cells will be performed by the SU2C Immune 
Core at Yale University as outlined below. Tissue samples will be collected from participants 
who have been properly consented and who have agreed to participate in the research study. 
Tumor tissues are optimally suitable for IHC/QIF studies if fixed in 10% neutral buffered 
formalin (NBF) for 16-24 hours and processed into paraffin blocks using clinical-grade 
pathology laboratory conditions. 
1.  Select the tumor block and obtain one Hematoxylin & Eosin (H&E) stained slide for 
review by site pathologist to confirm diagnosis and ensure presence of tumor cells.  For in 
situ analyses, there is no lower limit in the amount of tumor cell content.   
 
a. Samples with few tumor cells (<100-200 cells) may be insufficient for PD-L1 
immunostaining but should still be submitted for the QIF studies of TILs and other 
stromal markers. 
 
3. If pathologist review is not possible or available at the site, the H&E slides or a digital 
version may be sent directly to Yale Pathology for initial assessment. 
 
3. Obtain 5 additional serial 4-5µm thick sections from the reviewed paraffin block and 
place each section in a positively-charged glass histology slide.  Tissues should be cut and 


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processed using conventional, clinical-grade in-house histology protocols.  Paraffin dipping 
of slides after sectioning is not recommended.  
4. Collect 5 freshly cut (<5 days) unstained serial section slides from each case, label each 
preparation using the SU2C coding system and place them in a conventional plastic histology 
slidebox.  Make sure slides are in a firm position to avoid damage during transportation and 
cover with paper towel prior to packing to prevent movement within the box.  If possible, 
also include the sectioning order on the label for each slide. 
 
a.  Whenever feasible, blocks should be processed in batches, and shipped together within 
a 5-day period after sectioning. 
 
5. Include H&E stained preparation together with the 5 unstained sections in the slidebox.  
This slide will be digitalized and become available for review within the SU2C group.  
Specimens should be coded with a unique identifier (ie. institution, trial number, patient 
number and biopsy number in sequence (ie. for UC Davis patient 1, UCD250-001-01 
(baseline biopsy), UCD250-001-02 (on-treatment biopsy), UCD250-001-03 (post 
progression biopsy). 
 
6. Seal the slidebox using Parafilm and/or a plastic envelope and wrap with bubble wrap 
prior to shipping.  Include detailed sender information (with email) and ship using overnight 
service to: 
 
Attention to: Nikita Mani (nikita.mani@yale.edu).   
Backup contact should Nikita be out is Ila Datar (ila.datar@yale.edu) 
Address: BML112/BML113 
   
Department of Pathology 
    
Yale School of Medicine 
    
310 Cedar Street 
    
New Haven, CT  06510 
Phone 1:  203-737-4205 
Phone 2:  203-785-3588 
 
A confirmation of sample reception will be sent via email to the sender within 72 hours.  
 
7. 
 Slides will be stained for IHC and the QIF panels within 5 working days from reception 
in the lab or stored in appropriately until use and batched to accommodate projects in single 
experimental runs (whenever possible). 
 
8. 
Results of the analyzed markers will be provided as continuous scores using fluorescence 
intensity scores and/or phenotype cell counts.  The turnaround time will depend on the amount of 
slides and project volume.   
 
 


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7.2.5    Immunology Peripheral Blood Processing 
  
7.2.5.1  Peripheral blood Analysis of Changes in Immune Cell Subsets, T-Cell  Repertoire, 
and Cytokines 
 
 
Flow cytometry for immune cell subsets. (primarily T-cell subsets) will be performed in the 
Human Immune Monitoring Core (HIMC) at UC Davis. Expression levels determined by MFIs 
for markers will be compared at baseline and on treatment. 
 
These: subsets will include: 
 
• T cell subset panel: CD4, CD8, CD3, CD25, CD127, Foxp3 (ICS) 
 
• T  cell  differentiation  panel:  CD4, CD8, CD3, CD45RA, CCR7 (extras: CD45RO, 
CD44) 
 
• T  cell  exhaustion  panel: CD4, CD8, CD3, PD-L1, PD-1, TIM3, (extras: LAG3, 2B4, 
CD160) 
 
• T cell activation panel: CD4, CD8, CD3, HLA-DR, Fas, GranzB (ICS), CD28 (extras: 
ICOS, CD40L, FasL) 
 
Luminex Assay for measurement of cytokines (25 plea) in plasma and supernatant after 
activation with CD3+ CD28 or PMA+Ionomycine will also be performed in the HIMC at UC 
Davis. (http://tools.lifetechnologies.com/content/sfs/manuals/LHC0009_Protocol.pdf). 
 
7.2.5.2   Peripheral Blood Collection for Changes in Immune Subsets 
 
From each patient, at the relevant time points indicated in the study calendar, blood will be 
withdrawn directly into two 10 mL lavender-topped (EDTA coated) tubes. Samples will be 
stored and assays run at the Human Immune Monitoring Core (Director: Emanual Maverakis 
laboratory at UC Davis). 
 
Contact information listed below: 
 
Human Immune Monitoring Core (Maverakis Laboratory) 
UC Davis School of Medicine 
IRC Bldg., Room 1630 
2921 Stockton Blvd. Sacramento CA 95817 
LAB: 916-734-2156 
 
The HIMC laboratory (Director: Emanual Maverakis, MD) is a research laboratory at UC 
Davis with both immunology expertise and the appropriate equipment to carry out the 
proposed studies. These studies will include: Luminex Cytokine Assays to determine changes 


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in cytokine profiles in response to treatment and Flow Cytometry to detect changes in 
immune cell subsets. 
 
The tubes should be centrifuged as soon as possible at approximately 800 x g for 10 minutes. 
Plasma should be transferred to a 15 mL conical tube and centrifuged a second time at 1000 – 
1500 x g for 10 minutes.  After the second centrifugation, aliquot plasma in 500 ul aliquots 
into labeled cryovials. For peripheral blood mononuclear cell (PBMC) preparation, replace the 
plasma removed with an equal amount of PBS (Ca and Mg free) in the original lavender-top 
tubes, and then slowly layer it on top of the 15ml of Ficoll in a 50ml conical tube, followed 
by centrifugation at 800 x g for 20 minutes with the break off. The buffy coat, a whitish layer 
of cells between the PBS and Ficoll layers above the red blood cell layer, should be collected 
and transferred into a new 50ml tube, washed once with 50ml of PBS, re-suspended in an 
appropriate volume of freezing medium and then transferred  into labeled cryovials 
(107/ml/vial).  All cryovials are then to be frozen as rapidly as possible, and stored in a -70 
degree freezer until batch analysis is feasible by the HIMC. 
 
Sites other than UC Davis may store per SOP until ready for shipment to UC Davis HIMC. 
Please contact Maverakis lab prior to shipment. 
 
 
7.3   Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse  events  which  are  present  at  the  time  of  discontinuation/withdrawal should  be 
followed in accordance with the safety requirements outlined in Section 5.4 Attribution of 
adverse events and Section 7.5 - Assessing and Recording Adverse Events.  Subjects who a) 
attain a CR or b) complete 24 months of treatment with MK-3475 may discontinue treatment.  
After discontinuing treatment following assessment of CR, these subjects should return to the 
site for a Safety Follow-up Visit and then proceed to the Follow-Up Period of the study. 
 
7.4    Visit Requirements 
 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
 
7.4.1   Screening 
 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
 
Approximately  30  days  prior  to  enrollment,  potential  subjects  will  be  evaluated  to 
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be  obtained prior  to  performing any  protocol specific procedure. Results of a test 
performed prior to the subject signing consent as part of routine clinical management are 
acceptable in lieu of a screening test if performed within the specified time frame. Screening 
procedures are to be completed within 30 days prior to the first dose of trial treatment except for 
the following: 
 
Laboratory tests are to be performed within 10 days prior to the first dose of trial treatment. For 
women of reproductive potential, a urine pregnancy test will be performed within 72 
hours prior to first dose of trial treatment. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test, performed by the local study site laboratory, will be 
required.  
 
Tumor imaging must be performed within 30 days prior to the first dose of trial treatment. 
 
7.4.2   Treatment Period 
 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
 
7.4. 3   Post-Treatment Visits 
 
7.4.3.1  Safety Follow-Up Visit 
 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1  
or  until the beginning of  a new anti-neoplastic therapy, return to baseline, or it is deemed 
that further recovery is unlikely, whichever occurs first.  SAEs that occur within 30 days of the 
end of treatment or before initiation of a new anti-cancer treatment should also be followed and 
recorded.  
 
7.4.3.2   Follow-up Visits 
 
Every effort should be made to collect information regarding disease status until the start of new 
anti-neoplastic therapy, disease progression, death, end of the study.  Information regarding 
post-study anti-neoplastic  treatment  will  be collected if new treatment is initiated. 
 
7.4.3.2.1  Survival Follow-up 
 
Once  a  subject  experiences  confirmed  disease  progression  or  starts  a  new  anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 


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7.5    Assessing and Recording Adverse Events 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol- 
specified procedure, whether or not considered related to the medicinal product or protocol- 
specified procedure.   Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s and/or BIPI product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency  or  severity  from  expected  levels  are  not  to  be  considered  adverse  events. 
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator  medication)  or  marketed,  manufactured  by,  licensed  by,  provided  by  or 
distributed by Merck for human use. 
 
Adverse events may occur during the course of the use of Merck product in clinical trials or  
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and 
from withdrawal. 
 
Progression of the cancer under study is not considered an adverse event. 
 
All adverse events that occur after the consent form is signed but before treatment allocation must 
be reported by the investigator if they cause the subject to be excluded from the trial, or are the 
result of a protocol-specified intervention, including washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
 
From the time of treatment allocation through 30 days following cessation of treatment, all 
adverse events must be reported by the investigator.  Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets. The reporting timeframe for 
adverse events meeting any serious criteria is described in section 7.5. The investigator will 
make every attempt to follow all subjects with non-serious adverse events for outcome.  
 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of  archival  tissue  status)  as  long  as  that  subject  has  not  undergone any 
protocol-specified procedure or intervention.   If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs will 
be captured according to guidelines for standard AE reporting. 
 
All adverse events, serious and non-serious, will be collected, documented and reported to the 


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company supporter by the investigator on the appropriate CRFs / SAE reporting forms (BI and 
Merck SAE report form). 
 
For each adverse event, the investigator will provide the onset date, end date, CTC AE grade, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined 
below. 
 
Adverse events with onset within first administration of afatinib therapy and 28 days after last 
administration of afatinib will be considered as on treatment. All AEs, including those persisting 
after end of study treatment must be followed up until they have resolved or have been 
sufficiently characterized or the principal investigator decides to not further pursue them. Serious 
and non-serious adverse events occurring later than 28 days after last administration of trial 
drugs will only be reported in case they are considered drug-related or trial (procedure) related. 
 
7.5.1    Definition of an Overdose for This Protocol and Reporting of Overdose to Merck 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (>5 times the indicated dose). No specific information is available on the 
treatment of  overdose of  MK-3475.  Appropriate supportive treatment should be provided if 
clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.   
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the company supporter and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
 
7.5.2    Reporting of Pregnancy and Lactation to Merck and BIPI 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial. 
 
Pregnancy and lactations that occur after the consent form is signed but before treatment 
allocation must be reported by the investigator if they cause the subject to be excluded from the 
trial, or are the result of a protocol-specified intervention, including but not limited to washout or 


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discontinuation of usual therapy, diet, placebo treatment or a procedure.   
 
Pregnancies and lactations that occur from the time of treatment allocation through 120 days 
following cessation of treatment, or 30 days following the cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier must be reported by the investigator. All 
reported pregnancies must be followed to the completion/termination of the pregnancy.  
Pregnancy outcomes of spontaneous abortion, missed  abortion,  benign  hydatidiform mole,  
blighted  ovum,  fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).   If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. Report pregnancy to BIPI only if it is associated with the 
SAE (including an outcome that meets SAE criteria).  
 
Such events must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX  215 993-1220) as well as Boehringer Ingelheim. 
 
7.5.3    Immediate Reporting of Adverse Events to Merck and BIPI 
 
7.5.3.1   Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event 
 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
Merck for collection purposes. 
 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
 
Refer to Table 12.7 for additional details regarding each of the above criteria. 
 
For the time period beginning when the consent form is signed until treatment allocation, any 
serious adverse event, or follow up to a serious adverse event, including death due to any cause 
other than progression of the cancer under study (Section 7.2.3.3 for additional details) that 
occurs to any subject must be reported within 2 working days to Merck Global Safety if it causes 
the subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
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or a procedure. 
 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
 
For the time period beginning at treatment allocation, through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anti-cancer 
therapy, whichever is earlier, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of cancer under study (reference Section 
7.5.4 for additional details), whether or not related to Merck product, must be reported within 2 
working days to Merck Global Safety. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to Merck Global Safety. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number: +1-215-993-1220 
 
Assessment of safety laboratory parameters 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
The investigator shall report all SAEs and non serious AEs relevant to a reported SAE by fax 
from the time the informed consent is signed until the trial specified observational period (please 
specify) using BI IIS SAE form to BIPI Unique Entry Point in accordance with the following 
timelines: 
 
• within five (5) calendar days upon receipt of initial  and follow-up SAEs containing at 
least one fatal or immediately life-threatening event; 
• within ten (10) calendar days upon receipt of any other initial and follow-up SAEs. 
 
BI Unique Entry point: 
Boehringer Ingleheim Pharmaceuticals, Inc 
900 Ridgebury Road 
Ridgefield, CT 06877 


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Fax: 1-203-837-4329 
 
 
7.5.3.2   Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
 
For the time period beginning when the consent form is signed until treatment allocation, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 2 working days 
to Merck Global Safety if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck 
product, must be reported within 24 hours to Merck Global Safety. 
 
Events of clinical interest for this trial include: 
 
1. an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to Merck, that is not associated with clinical 
symptoms or abnormal laboratory results. 
 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
 
*Note:   These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for  an  underlying  etiology.     
 
7.5.4    Protocol-Specific Exceptions to Serious Adverse Event Reporting 
 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.5.3 .- Immediate Reporting of Adverse Events to Merck and BIPI, unless there is 
evidence suggesting a causal relationship between the drug and the event. Any such event will be 
submitted to Merck Global Safety within 2 working days either by electronic or paper media  
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 


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ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE within 
2 working days of determination that the event is not progression of the cancer under study 
 
All the reports specified in this section will also be submitted to BIPI according to SAE reporting 
timeframe in section 7.5.3.1.  
 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
7.5.5 Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
7.5.6    Sponsor-Investigator Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable laws and regulations. 
 
7.5.7    Safety Reporting Requirements for IND Exempt Studies 
 
For Investigator Sponsored IND Exempt Studies there are some reporting requirements for the 
FDA in accordance with the guidance set forth in 21 CFR 314.80. 
 
Post-marketing 15-Day ‘Alert Report’ 
The Sponsor-Investigator is required to notify the FDA of each adverse drug experience that is 
both serious and unexpected and is assessed by the investigator to be possibly related to study 
treatment as soon as possible but in no case later than 15 calendar days of initial receipt of the 
information.  An unexpected adverse event is one that is not already described in the Investigator 
Brochure.  Such reports (2 copies) are to be submitted to the FDA at the following address: 
Central Document Room, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. 
 
All 15-Day Alert Reports submitted to the FDA by the Sponsor-Investigator must also be faxed 
to Merck. 
 
 
8.0  STATISTICAL ANALYSIS PLAN 
 


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8.1    Statistical Analysis Plan Summary 
 
This is a phase I/Ib study. A minimum of 9 patients, if trial is terminated early due to 
unacceptable toxicity and a maximum of 38 patients (18 patients in the dose de-escalation cohort 
plus 10 in each of the two expansion cohorts) are anticipated for this trial. Analysis of safety and 
biomarkers will be limited to patients who receive active treatment. 
 
The dose de-escalation phase will establish a MTD recommended dose of MK-3475 in 
combination with lead in MK-3475 followed by the combination or concurrent afatinib/MK- 
3475. 
 
We plan to enter 3 patients at Dose Level 0. If 0/3 or 1/3 patients experience a DLT on level 
0, an additional 3 patients will be accrued to Level 0, where 2 or more DLTs will terminate 
that study arm and we will proceed to dose level -1. 
 
 
If 2 or more patients have DLTs at level 0, patients will be accrued at level -1. If 1/3 patients 
experience a DLT on level -1, an additional 3 patients will be accrued to Level -1, where 2 or 
more DLTs will require termination of that study arm while 1 DLT out of 6 will result in 
proceeding with dose level -1 as the MTD for the dose expansion cohorts. 
 
If 2 or more patients have DLTs at level -1, patients will be accrued at level -2. If 1/3 patients 
experience a DLT on level -2, an additional 3 patients will be accrued to Level -2, where 2 or 
more DLTs will require termination of the study while 1 DLT out of 6 will result in 
proceeding with dose level -2 as the MTD for the dose expansion cohorts. 
 
The phase I de-dose escalation portion of the trial will be closed when the maximum tolerated 
dose level (MTD) or dose level 0 is reached and six patients have been treated at that dose level. 
 
Please see section 5.1.4.2 for further details. 
 
 
All patients at a given dose level who have not experienced DLT, must be observed for a 
minimum of 21 days or until completion of their first cycle of therapy before the dose level can 
be escalated. Treatment will continue in an individual patient at the same dose level if no DLT is 
observed and if benefit is observed. There will be no dose escalation allowed for an individual 
patient. 
 
 
The recommended phase II dose (RP2D) will be determined by the overall assessment of the 
MTD and toxicities observed in the de-dose escalation and dose expansion portion of this study. 
 
The baseline assumption is that single agent afatinib yields a response rate of 10% in this setting, 
and a response rate of 10% or less would not warrant further study. A response rate of 40% or 
greater would justify further study with a larger sample size. With 10 patients enrolled in cohort A 
expansion arm, we will declare this combination lacking promise if fewer than 3 patients respond, 
and potentially worthy of further study if 3 or more patients respond. If the true response rate is 
10%, the chance of having 3 or more patients respond is 7%. If the true response rate is 40%, the 


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chance of having 3 or more patients respond is 83%. 
 
If 3 or more patients respond, the response rate, toxicity, and progression-free survival will be 
evaluated to decide if larger randomized studies are warranted in this disease. Descriptive 
summaries will be provided for each of these summary measures (numbers and proportion 
responding, number and proportion with specific type and grade of toxicities, Kaplan-Meier plot and 
life-table summary of progression-free survival.) As stated earlier, a “pick the winner” approach 
between cohort A and cohort B based on toxicity: RR, PFS and changes in PDL1 expression will 
decide which dosing scheme to take further. It is assumed that a true RR >40% would be 
sufficient to recommend such development, provided safety and tolerability are also acceptable. 
 
8.2 
Correlative Statistical Analysis Plan 
 
Plasma EGFR-mutant DNA/RNA levels, PDL1 expression by IHC at baseline and in repeat 
biopsy specimens as well as the other EGFR and immune biomarkers proposed will be evaluated 
in exploratory manner. A focus is on comparison between changes in PD-L1 expression 
comparing arm A (concurrent afatinib/MK-3475) and arm B (lead in MK-3475). Descriptive 
associations with response rate and PFS will be performed. All molecular and other secondary 
evaluations will be considered for exploratory analyses and in view of the limited sample-size 
and the exploratory nature of these analyses, any p-values reported will not be adjusted for 
multiple comparisons, and any such analyses will be stated carefully as being hypothesis-
generating. 
 
Standard descriptive methods will be used to summarize the baseline levels and changes in 
baseline levels will allow us to examine whether observed patterns are consistent with 
hypothesized patterns. If the combination is not found to have sufficient activity, these patterns 
may help explain the lack of activity. If sufficient activity is found, then patients who experience 
an objective response will be compared to those who did not in terms of these correlates. 
 
 
 
9.0  LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
 
9.1 
Investigational Product: MK-3475 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
Clinical Supplies will be provided by Merck at no cost to subjects as summarized below. 
 
Product Descriptions 
 


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Product Name & Potency 
Dosage Form 
MK-3475 100 mg/ 4mL 
Solution for Infusion 
 
 
 
Instructions on preparation are provided with Merck pharmacy manual. 
9.1.1 Packaging and Labeling Information 
 
Clinical  supplies  will  be  affixed  with  a  clinical  label  in  accordance  with  regulatory 
requirements. 
 
9.1.2    Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor- Investigator 
and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the 
label text; random code/disclosure envelopes or lists are not provided. 
 
9.1.3    Storage and Handling Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
 
9.1.4    Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 


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9.2    Investigational Product: Afatinib 
 
9.2.1    Packaging and Labeling Information 
 
Medication numbers will be unique to each bottle and will be used for tracking purposes 
only. 
 
Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20, 30 and 
40 mg. Tablets will be supplied in HDPE, child-resistant, tamper-evident bottles. 
 
Bottles/boxes will be labelled according to local regulations and will include the following as a 
minimum; 
 
• Study number [UCDCC#250 + 1200.237] 
• Product name (Afatinib) 
• Contents of the bottle (number of tablets) 
• Tablet strength (mg) 
• Batch number 
• Medication number 
• Use-by date 
• Storage information 
• Instructions for use 
• Sponsor-Investigator name and address 
• A statement that the medication is for clinical study use only 
• A caution statement 
 
A new bottle of medication will be dispensed on day 1 of each course, regardless of the 
number of tablets remaining in the bottle from the previous course. The patient will initially 
receive one bottle of 20, 30 or 40 mg tablets and in the event that dose reduction is necessary the 
patient will return to the clinic and new medication will be dispensed. 
 
9.2.2    Storage Conditions 
 
Afatinib must be stored in the original package in order to protect from light. Film-coated tablets 
are humidity-sensitive; therefore, bottles must be kept tightly closed to protect from moisture. 
Tablets must be stored according to label instructions. 
 
9.2.3    Drug Accountability 
 
Afatinib, which will be provided by Boehringer Ingelheim Pharmaceuticals, Inc, at no cost to 
subject, will be kept in a secure, limited access storage area under the storage conditions. Where 
necessary, a temperature log must be maintained to make certain that the drug supplies are 
stored at the correct temperature. 


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The responsible person must maintain records of the product’s delivery to the study site, the 
inventory at the site, the use by each patient, and the return to the Boehringer Ingelheim (BIPI) 
or alternative disposition of unused product(s). Returned or unused study drug will be destroyed 
at site per site’s SOP.  
 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and study patients. The 
responsible person will maintain records that document adequately that the patients were 
provided the doses specified by the clinical study protocol and reconcile all investigational 
product(s) received from Boehringer Ingelheim (BIPI). The responsible person must verify that 
all unused or partially used drug supplies have been returned by the clinical study patient. 
 
10.0  ADMINISTRATIVE AND REGULATORY DETAILS 
 
10.1  Confidentiality 
 
In order to maintain patient privacy, all study reports and communications will identify the 
patient by initials and the assigned patient number.   Data capture records and drug 
accountability records will be stored in secure cabinets in the UCD Office of Clinical Research.  
Medical records of patients will be maintained in strict confidence according to legal 
requirements.  The investigator will grant monitor(s) and auditor(s) from Merck/BIPI or its 
designees and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection process.  
The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
 
 
 
10.2  Good Clinical Practice 
 
The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. Master files should 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations. 
 
10.3  Patient Information and Informed Consent 
 
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either the patient or his guardian or legal representative prior to study participation.   The 
method of obtaining and documenting the informed consent and the contents of the consent will 
comply with ICH-GCP and all applicable regulatory requirement(s). In accordance with UCD 
OCR policy an original signed and dated participant Informed Consent document will reside in a 
secured location within the UCD OCR.  Copies of the signed and dated Informed Consent 
document will be provided to the study participant and UCD Health System Information 
Management for inclusion in the participant’s UCD Health System Medical Record or per 
participating site’s policies. 
 
10.4  Records and Retention 
 
The investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s). 
 
10.5  Data and Safety Monitoring 
 
In addition to the requirements for adverse event reporting as outlined in Section 7.5, this 
protocol is also subject to the UC Davis Cancer Center’s (UCDCC) Data and Safety Monitoring 
Plan. The UCDCC is committed to pursuing high-quality patient-oriented clinical research and 
has established mechanisms to ensure both scientific rigor and patient safety in the conduct of 
clinical research studies. The UCDCC relies on a multi-tiered committee system that reviews 
and monitors all cancer clinical trials and ensures the safety of its participants, in compliance 
with institutional and federal requirements on adverse event (AE) reporting, verification of data 
accuracy, and adherence to protocol eligibility requirements, treatment guidelines, and related 
matters. The Scientific Review Committee (SRC) assumes overall oversight of cancer 
studies, with assistance and input from two independent, but interacting, committees: the 
Quality Assurance Committee and the Data Safety Monitoring Committee. A multi-level review 
system strengthens the ability of the UCDCC to fulfill its mission in conducting high quality 
clinical cancer research. 
 
As per University of California Davis Cancer Center (UCDCC) Office of Clinical Research 
(OCR)  SOP  AM  506:  Protocol  Specific  Meetings,  the  principal  investigator  (PI)  and 
clinical research coordinator (CRC) meet at least monthly for ongoing study information, to 
discuss patient data and adverse events and to determine if dose escalation is warranted, 
when applicable.  Because this is a phase I study, a meeting and/or conference call will take 
place  when  the  last  subject  on  each  cohort  completes  DLT  (dose-limiting  toxicity) 
assessment.  The meeting and/or call will update the attendees of the current status of the 
study and will include investigators from all participating centers, and, if necessary, 
representatives from the drug provider or financial supporter.   All serious adverse events 
experienced by study subjects will be discussed and appropriate action taken.  If serious 
adverse events occur between these meetings and/or calls, all investigators will be informed by 
email. 
 
According to the UCDCC Data and Safety Monitoring Plan (DSMP),  any new serious 


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adverse events related to the drugs being used on this trial are reviewed monthly by the UCDCC 
Data and Safety Monitoring Committee (DSMC) and any applicable changes to the study are 
recommended to the PI, if necessary. 
 
The UCDCC Scientific Review Committee (SRC) determines if a UCDCC Data and Safety 
Monitoring Board (DSMB) is required.  If required, the DSMC will appoint a DSMB. The 
DSMB is responsible for reviewing study accrual logs, adverse event information and dose 
escalation meeting minutes (where applicable) to ensure subject safety and compliance with 
protocol defined guidelines. 
 
10.6  Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information. 
 
10.7  Quality Assurance and Control 
 
Quality assurance audits of select patients and source documents may be conducted by the UC 
Davis Comprehensive Cancer Center Quality Assurance Committee as outlined in the UC 
Davis Cancer Center Data and Safety Monitoring plan. 
 
 
Quality control will be maintained by the OCR Quality Assurance team according to OCR 
policy. 
 
 
 


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10.8  Registration Guidelines 
 
A.       Before registration, the site study coordinator should check to make sure that the 
corresponding Investigational Drug Service or equivalent has investigational product(s) in 
stock. 
 
B.        Registrations must be made through the Office of Clinical Research (OCR) of the 
University of California, Davis Comprehensive Cancer Center between the hours of 9am and 
3pm (Pacific Time), Monday through Friday (except holidays).  Documentation of current 
IRB approval of this protocol must be on file prior to registration of patients. 
 
C.        Pre-study laboratory tests, scans, and x-rays, must be completed prior to registration, 
within the time frame specified in the protocol.  The eligibility checklist must be completed. 
Patients must sign an informed consent prior to registration. 
 
D.        Patients may be registered up to 72 hours prior to treatment initiation. The signed 
consent, completed checklist and reports from all pre-study laboratory tests, scans and x-rays 
must be faxed to UC Davis OCR in order to register the patient. The UC Davis Protocol 
Coordinator will review these documents and fax a registration confirmation within 3 hours. 
 
E.        If the patient is to be registered the same day as the proposed treatment start date, the UC 
Davis Study Coordinator must be notified by fax 24 hrs prior to proposed treatment start date 
that the site has a patient to register. 
 
F.        The Study Coordinator will verify that the patient is eligible, that pre-study tests have 
been completed, and that the forms are complete.  The Study Coordinator will then register the 
patient and assign a patient accession number.  The Study Coordinator will fax back a 
registration confirmation including the patient accession number within 3 hours. 
 
G.        A patient failing to meet all protocol requirements may not be registered. If you have any 
questions regarding eligibility, contact the coordinating site PI or Study Coordinator. 
 
NOTE: Administration of study medication may not be initiated until the registration 
confirmation has been received. 
 
 
 


P r o d ucts :  M K- 3 4 7 5 / Af atini b 
P r o t oc ol V ersi o n 3. 0  
 
V e r sio n D ate : 0 9/ 1 0/ 1 8 
P a g e 8 4  of 1 3 3  
 
1 0. 9   D at a M a n a ge me nt 
 
All  data  will   be c ollecte d  usi n g U C  Da vis  data  c ollecti o n f or ms.  A n y a n d all  s o urce 
d oc u me ntati o n s h o ul d be mai ntai ne d.  
 
   S U B MI T  WI T HI N  2 4 H O U R S O F R E GI S T R A TI O N:  
Patie nt  Re gistrati o n  F or m  
 
   S U B MI T  WI T HI N  1 4 D A Y S O F R E GI S T R A TI O N:  I n---H o us e Pre---S tu d y E val u ati o n  F or m  
(I H---1 0 2) 
 
   S U B MI T  WI T HI N  7 D A Y S O F S C R E E NI N G  F AI L U R E:  Patie nt  Scree n  Fail ure  F or m  
 
   S U B MI T  WI T H  1 4 D A Y S O F C Y C L E  C O M P L E TI O N:  A d vers e E ve nt/ Dr u g Relati o ns hi p  
F or m  
 
   S U B MI T  WI T HI N  1 4 D A Y S O F E N D  O F E A C H  T R E A T M E N T  C Y C L E:  I n---H o us e 
Treat me nt  C ycle  F or m  (I H---2 0 1) 
 
   S U B MI T  WI T HI N  1 4 D A Y S O F E A C H  R E S P O N S E  A S S E S S M E N T:  T u m or Meas ure m e nt  
L o g  
 
   S U B MI T  WI T HI N  1 4 D A Y S O F O F F T R E A T M E N T:  
Off Tr eat me nt/I n  F oll o w- u p/ Off St u d y/ E x pirati o n  F or m  (I H---3 0 1) 
 
   S U B MI T  WI T HI N  1 4 D A Y S O F K N O W L E D G E  O F D E A T H  I F P A TI E N T I S S TI L L  O N 
S T U D Y  O R  3 0 –D A Y S I F O F F S T U D Y:   
Off Tr eat me nt/I n  F oll o w- u p/ Off St u d y/ E x pirati o n  F or m  (I H---3 0 1) 
 
   S U B MI T  WI T HI N  2 D A Y S O F K N O W L E D G E  O F P R O T O C O L  D E VI A TI O N:  N otice  of 
Pr ot oc ol De viati o n  
 
   S U B MI T  WI T HI N  1 4 D A Y S O F E A C H  R E Q UI R E D  F O L L O W
---U P E N C O U N T E R:  
F oll o w ---U p F or m  (I H---3 0 2) 
 
   A L L  S E RI O U S  A D V E R S E  E V E N T S  M U S T  B E  R E P O R T E D  A S O U T LI N E D  I N T H E  
P R O T O C O L.  
 
 
 
 
 


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11.0  LIST OF REFERENCES 
 
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associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800. 
 
 
3. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
 
4. 
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
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Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
 
6. 
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61. 
 
7. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400. 
 
8. 
Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81. 
 
9. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7. 
 
10.  Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19. 
 
11.  Diez  M,  Pollán  M,  Enriquez  JM,  Dominguez  P,  Santana  A,  Tobaruela  E,  et  al. 
Histopathologic  prognostic  score  in  colorectal  adenocarcinomas.  Anticancer  Res 
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12.  Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4. 
 
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51. 
 
14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival 


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of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and  
dendritic  cell  infiltration  after  interleukin-2 immunotherapy. Report  of  a  case. Tumori 
2008;94:426-30. 
 
15.  Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53. 
 
 
16.  Kloor   M.   Lymphocyte  infiltration   and   prognosis   in   colorectal   cancer.   Lancet 
2009;10(840):841. 
 
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters of  
aggressiveness  in  primary  cutaneous  melanoma.  Cancer  Immunol Immunother 
2008;57:97-106. 
 
18.  Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and  density of  tumour-infiltrating lymphocytes in  gastric cancer. Br J Cancer 
2008;99(10):1704-11. 
 
19.  Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al.   
Prognostic   significance  of   tumor-infiltrating  T-lymphocytes  in   primary   and 
metastatic  lesions  of  advanced  stage  ovarian  cancer.  Cancer  Immunol  Immunother 
2009;58:449-59. 
 
20.  Nishimura H,  Honjo  T,  Minato  N.  Facilitation of  β  selection  and  modification of 
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21.  Liotta F,  Gacci M,  Frosali  F,  Querci V,  Vittori G,  Lapini A,  et  al.  Frequency of 
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with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6. 
 
22.  Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value of 
tumour-infiltrating lynmphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-24. 
 
23.  Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
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24.  Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703. 
 
25.  Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ 
cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian  carcinoma. Cancer Immunol Immunother 
2010;59:909-19. 


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26.  Okazaki  T,  Maeda  A,  Nishimura  H,  Kurosaki  T,  Honjo  T.  PD-1  immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain- 
containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71 
 
27.  Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48. 
 
28. Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma:  prognostic 
factors. Cancer Control 2005;12(4):223-9. 
 
29.  Iannone R, Gergich K, Cong C, Kang P, Daud A, Dronca R, et al.  Efficacy and safety of 
MK-3475 in patients with advanced melanoma. Pigment  Cell  Melanoma Res 
2012;25:836-903. 
 
30.  Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of Anti-PD-1 antibody in cancer. N Engl J Med 
2012:doi: 10.1056/NEJMoa1200690. 
 
31.  Lyford-Pike S, Peng S, Young GD, et al.   Evidence for a role of the PD-1:PD-L1 
pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. 
Cancer Res 2013;73(2): Published online January 3. 
 
32.  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent R, Ford R, et al.  New 
response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). 
Eur J Cancer 2009;45(2):228-47. 
 
33.  Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al.  Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. 
Clin Cancer Res 2009;15(23):7412-20. 
 
34.  Blum JL, Jones SE, Buzdar AU, LoRusso PM, et al. Multicenter Phase II Study of 
Capecitabine in Paclitaxel-Refractory Metastatic Breast Cancer. J Clin Oncol 17: 485-
493, 1999 
 
35.  Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, et al. Gemcitabine plus 
vinorelbine monotherapy in patients with metastatic breast cancer previously treated 
with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer 
Research Group (GEICAM) trial. Lancet Oncol. 2007;8(3):219. 
 
36. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, et al.  Phase III Trial of 
Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front- 
Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193).   J Clin 
Oncol. 2003;21(4):588. 
 
37.  Stewart JSW, Ezra E.W. Cohen EEW, Licitra L, Van Herpen CML, et al. Phase III 
Study of Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous 


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Cell Carcinoma of the Head and Neck. J Clin Oncol. 2009;27(11):1864. 
 
38. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, et al.   Open-Label, 
Uncontrolled, Multicenter Phase II  Study  to  Evaluate the Efficacy and Toxicity of 
Cetuximab As a Single Agent in Patients With Recurrent and/or Metastatic Squamous Cell 
Carcinoma of the Head and Neck Who Failed to Respond to Platinum-Based Therapy. 
J Clin Oncol. 2007;25(16):2171. 
 
39.  Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, et al.  Phase III Trial of 
Vinflunine Plus Best Supportive Care Compared With Best Supportive Care Alone 
After a Platinum-Containing Regimen in Patients With Advanced Transitional Cell 
Carcinoma of the Urothelial Tract. J Clin Oncol. 2009;27(27):4454 
 
40.  Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, et al.  Phase II Study of 
Pemetrexed for Second-Line Treatment of Transitional Cell Cancer of the Urothelium. J 
Clin Oncol. 2006;24(21):3451. 
 
41.  Clopper C and Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 1934;26:404-413. 


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 12.0  APPENDICES 
 
12.1  ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- 
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden,   E.T.,  Carbone,   P.P.:  Toxicity   And  Response   Criteria   Of  The  Eastern  
Cooperative Oncology  Group.  Am  J  Clin  Oncol  5:649-655,  1982.  The  Eastern  Cooperative  
Oncology  Group, Robert Comis M.D., Group Chair. 


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12.2  Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)


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


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12.4  New York Heart Association Classification of Heart Failure 
 
 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of breath) 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased. 


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12.5  List of Potent Inhibitors and Inducers of P-glycoprotein (MDR1) 
 
Inhibitors 
Inducers 
Amiodarone 
Azithromycin  
Captopril  
Carvedilol  
Clarithromycin  
Conivaptan  
Cyclosporine  
Diltiazem  
Dronedarone  
Erythromycin  
Felodipine  
Itraconazole  
Ketoconazole  
Lopinavir  
Nelfinavir  
Ritonavir  
Quinidine  
Ranolazine  
Saquinavir  
Tacrolimus  
Ticagrelor  
Verapamil 
Carbamazepine 
Phenytoin 
Rifampicin 
St John’s Wort  
Phenobarbital Salt  
Tipranavir  
Ritonavir 
 
 
The  information  on  potent  inhibitors  and  inducers  of  P-glycoprotein may  evolve,  it  is 
important for the investigator to assess such status on concomitant. 
 
 
 
 
 
 


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12.6. Liquid Genomics Sample Requisition Form 
 
 
 


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12.7  Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
(β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
ProteinCr 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ (CO2 or 
biocarbonate) 
results are noted 
Free tyroxine (T4) 
Creatinine 
Urine or serum pregnancy test † 
Thyroid stimulating hormone (TSH) 
Uric Acid 
PK 
Calcium 
Chloride 
Blood for correlative studies 
Glucose 
Correlative Biopsies 
Phosphorus 
Potassium 
Sodium 
Magnesium 
Total Bilirubin 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
Total protein 
Blood Urea Nitrogen 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. 
‡ If considered standard of care in your region. 


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12.8  Evaluating Adverse Events 
 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
Grade 3 
Severe  or  medically  significant  but  not  immediately   life-threatening;  hospitalization   or  prolongation   or  hospitalization   indicated; 
disabling; limiting self-care ADL. 
Grade 4 
Life threatening consequences;  urgent intervention  indicated. 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
†Results in death; or 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
†Results in or prolongs an existing inpatient hospitalization  (hospitalization  is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization  is a precautionary  measure for continued observation. (Note: Hospitalization  [including hospitalization  for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
†Is a congenital anomaly/birth  defect (in offspring of subject taking the product regardless of time to diagnosis);or 
Is a new cancer; (that is not a condition of the study) or 
(For Merck Only. BIPI does not list criteria for overdose)Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is 
considered a serious adverse event. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization  may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken 
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s  signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below 
are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information. 
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration  of the Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational  medicinal product)? 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 


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Relationship to 
Merck product 
(continued) 
The following components  are to be used to assess the relationship  between the test drug and the AE: (continued) 
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED  FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES  IN THE PROTOCOL. 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable possibility 
Merck product relationship 
Subject  did  not  receive  the  Merck  product  OR  temporal  sequence  of the  AE  onset  relative  to administration  of the  Merck  product  is not 
reasonable OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an 
associated AE.) 


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Pembrolizumab Event of Clinical Interest Guidance Document 
 
 
 
 
 
12.9  Event of Clinical Interest Guidance Document 
 
 
PEMBROLIZUMAB PROGRAM 
(MK-3475) 
 
 
 
EVENT OF CLINICAL INTEREST  
 
GUIDANCE DOCUMENT 
 
 
 
Version 5.0 
 
For Instructional Purpose Only 
 
 
 
 
 
 
*Ensure that you are using the most current version of this document.  


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REVISION HISTORY LOG 
 
Version 
Effective 
Date* 
Revision 
Author 
Action 
1 
08-Aug-2012 Kevin Gergich 
Initial Release of guidance document for MK-3475 
2 
07-June-2013 Marty Huber, 
Kevin Gergich, 
Holly Brown 
Revised title, formerly was “MK-3475 Immune-Related 
Adverse Event Identification, Evaluation and 
Management 
Guidance Document for Investigators” 
Revised the format of irAE Guidance document, 
including layout, font, sectioning, etc. for consistency 
with Sponsor Events of Clinical Interest guidance 
documents. 
Modified Categories for irAEs: 
– 
Replaced GI with Colitis category. 
– 
Removed Neurologic category. 
– 
Added Renal category. 
Removed detail in the irAE Guidance document that can 
be located in the Investigator’s Brochure for MK-3475. 
Removed details regarding non-MK-3475 compounds. 
Added ECI reporting guidelines. 
Included a Table Events of Clinical Interest: Immune- 
Related Adverse Events that includes the key terms. 
– 
Also placed a pull-out quick-review sheet in the 
Appendix. 
Updated background, diagnosis and course of treatment 
details for irAEs. 


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3 
10-Sep-2014 Marty Huber, 
Kevin Gergich, 
Holly Brown 
Renamed the document: “Pembrolizumab Program (MK- 
3475) - Events of Clinical Interest Guidance Document”. 
Introduced generic name: pembrolizumab (MK-3475) 
and inserted throughout the document. 
Updated Overview – Section 1 
- Clarified the scope of the document and the reporting 
window for ECIs 
- Updated Table 1 with medDRA Preferred Terms for 
adverse events to correspond with reporting of terms to 
clinical database, rearranged the order, and updated the 
reporting criteria. 
-  Updated the dose modification/discontinuation section 
to clarify discontinuation and hold terminology. 
Updated Section 2 – ECI Reporting Guidelines 
 
 
 
 


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– Clarified that ECIs must be reported to Merck 
within 24 
hours regardless of attribution to study treatment or 
etiology. 
Updated Section 3 
–   For All Sections, removed the Course of Action 
for 
Grade 1 events. 
-   Section 3.1 Pneumonitis 
– 
Moved Pneumonitis to beginning of ECI 
Section 
– 
Updated management guidelines for Grade 2 
and 
Grade 3-4 events 
- 
Section 3.2 Colitis: 
- 
Updated AE terms and ECI criteria, updated 
course of action language for clarity 
- Section 3.3 Endocrine: 
- 
Updated ECI criteria and updated course of 
action language for clarity. 
- 
Added subsections for hypophysitis, 
hyperthyroidism and hypothyroidism to clarify 
management guidelines. 
- Section 3.4 Hematologic: 
- 
New section added. 
- Section 3.5: Hepatic: 
- 
Updated terms and added additional guidance 
for reporting of DILI ECI; updated course of action 
for clarity 
- Section 3.6 Neurologic: 
- 
New section added. 
- Section 3.7 Ocular: 
- 
Changed the name of this section from Eye to 
Ocular 
- 
Added the term “iritis”, updated ECI 
guidance, and updated course of action language for 
clarity


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- Section 3.11 Infusion Reactions: 
- 
New section added. 
- Section 3.12: Follow-up to Resolution: 
- 
New section added. 
- Section 4: 
- 
References updated. 
- Section 5: 
- 
ECI table updated for consistency with Table 
1. 
- Section 6: Appendix 2 – Past Medical History 
Related to 
Dermatologic Event:  New section added. 
4 
04-Dec-2014 Scot 
Ebbinghaus, 
Oswaldo 
Bracco, 
Holly Brown, 
Kevin Gergich 
- Table 1 
- 
Updated Endocrine (reported as ECI if  ≥ 
Grade 3 or ≥ Grade 2 and resulting in dose 
modification or use of systemic steroids to treat the 
AE) Section 
to include: 
- 
Hyperglycemia, if ≥Grade 3 and associated 
with ketosis or metabolic acidosis (DKA) 
- 
Created new section in Table 1 – Endocrine 
(reported as ECI) and added: 
- 
Type 1 diabetes mellitus (if new onset) 
- 
Hepatic: Clarified Transaminase elevations as: 
- 
Transaminase elevations (ALT and/or AST) 
- Section 3.2 Colitis 
- Updated the duration of diarrhea requirments under 
the Course of Action for Grade 2 and Grade 
3 
- Section 3.3 Endocrine 
- 
Clarified Course of Action for 
hyperthyroidism and hypothyroidism 
5 
18-Dec-2014 Holly Brown 
Kevin Gergich 
- Section 3.3 Endocrine 
- 
Updated the Course of Action for 
Hypophysitis
*Ensure that you are using the most current version of this document. 


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TABLE OF CONTENTS 
 
 
1. OVERVIEW ............................................................................................................................... 6 
2. ECI REPORTING GUIDELINES .............................................................................................. 8 
3. ECI CATEGORIES AND TERMS ............................................................................................ 8 
3.1 Pneumonitis .......................................................................................................................... 9 
3.2 Colitis .................................................................................................................................. 10 
3.3 Endocrine ............................................................................................................................ 12 
3.4 Hematologic ........................................................................................................................ 15 
3.5 Hepatic ................................................................................................................................ 16 
3.6 Neurologic........................................................................................................................... 18 
3.7 Ocular.................................................................................................................................. 19 
3.8 Renal ................................................................................................................................... 20 
3.9 Skin ..................................................................................................................................... 21 
3.9.1. Immediate Evaluation for Potential Skin ECIs ........................................................... 22 
3.10 Other ................................................................................................................................. 23 
3.11 Infusion Reactions ............................................................................................................ 24 
3.12 Follow-up to Resolution ................................................................................................... 26 
4. REFERENCES ......................................................................................................................... 27 
5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table ...................................... 28 
6. APPENDIX 2 – Past Medical History Related to Dermatologic Event ................................... 29 
7. APPENDIX 3 – Presentation of the Dermatologic Event ........................................................ 30 
8. APPENDIX 4 – Focused Skin Examination............................................................................. 32 


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1. OVERVIEW 
 
 
The purpose of this document is to provide study sites with guidance on the identification and 
management of 
Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) program. 
 
Based on the literature review [1-11], and consideration of mechanism of action of 
pembrolizumab, potential immune-related adverse events (irAEs) are the primary Event of 
Clinical Interest (ECI). Immune-related AEs are adverse events associated with the treatment of 
patients with immunotherapy treatments that appear to be associated with the immune therapy’s 
mechanism of action. Based on these potential irAEs, the sponsor has defined a list of specific 
adverse event terms (ECIs) that are selected adverse experiences that must be reported to 
Merck within 24 hours from the time the Investigator/physician is aware of such an occurrence, 
regardless of whether or not the investigator/physician considers the event to be related to study 
drug(s). In addition, these ECIs require additional detailed information to be collected and 
entered in the study database. ECIs may be identified through spontaneous patient report and / or 
upon review of subject data. Table 1 provides the list of terms and reporting requirements for 
AEs that must be reported as ECIs for MK-3475 protocols.  Of note, the requirement for 
reporting of ECIs applies to all arms, including comparators, of MK- 
3475 clinical trials 
 
Given that our current list of events of clinical interest is not comprehensive for all potential 
immune-related events, it is possible that AEs other than those listed in this document may be 
observed in patients receiving pembrolizumab. Therefore  any  Grade  3  or  higher  event  that  
the  investigator/physician considers  to  be immune-related should be reported as an ECI 
regardless of whether the specific event term is in Table 1 and reported to Merck within 24 
hours from the time the Investigator/physician is aware of such an occurrence. Adverse events 
that are both an SAE and an ECI should be reported one time as an SAE only, however the event 
must be appropriately identified as an ECI as well in in the database. 
 
 
 
 


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Table 1: Events of Clinical Interest 
Pneumonitis (reported as ECI if ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic 
steroids to treat 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis 
(DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset)  
 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids 
to treat the 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic Purpura 
(TTP) 
Idiopathic (or immune) 
Thrombocytopenia Purpura  (ITP) 
Disseminated Intravascular 
Coagulation (DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat 
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat 
Uveitis 
Iritis 
 
Renal (reported as ECI if ≥ Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 


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Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment 
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
 
 
Each of the events above is described within this guidance document, along with site 
requirements for reporting these events to the Sponsor.  The information collected should be 
entered into the narrative field(s) of the Adverse Event module in the database (please note, if 
narrative entry into the database is not available, please use the narrative text box on the 
1727/AER Form).   If additional Medical History or Concomitant Medications are reported, the 
Medical History and Concomitant Medication modules in the database must be updated. 
 
In addition, the guidelines include recommendations on the management of these ECIs. These 
guidelines are intended to be applied when the physician determines the events to be related to 
pembrolizumab. Note: if after the evaluation the event is determined not to be related, the 
physician is instructed to follow the ECI reporting guidance but does not need to follow the 
treatment guidance (below). Therefore, these recommendations should be seen as guidelines and 
the treating physician should exercise individual clinical judgment based on the patient.  For any 
question of dose modification or other treatment options, the specific language in the protocol 
should be followed.  Any questions pertaining to the collection of this information or 
management of ECIs should be directed to your local Sponsor contact. 
 
Dose Modification/Discontinuation 
 
The treatment guidance provides specific direction when to hold and/or discontinue 
pembrolizumab for each immune related adverse event.  Of note, when the guidance states to 
“discontinue” pembrolizumab this is the permanent discontinuation of treatment with 
pembrolizumab. “Hold” means to stop treating with pembrolizumab but resumption of treatment 
may be considered assuming the patient meets the criteria for resumption of treatment. 
 
 
2. ECI REPORTING GUIDELINES 
ECIs are selected non-serious and serious adverse experiences that must be reported to Merck  
within 24 hours regardless of attribution to study treatment.  The AEs listed in this document 
and any event that meets the ECI criteria (as noted) in Table 1 or in the respective protocol 


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(event term and Grade) must be reported regardless of physician-determined causality with study 
medication and whether or not considered immune-related by the physician (unless otherwise 
specified).   Physicians/study coordinators/designated site personnel are required to record these 
experiences as ECIs on the Adverse Experience electronic Case Report Forms (eCRFs) (or on 
paper) and to provide supplemental information (such as medical history, concomitant 
medications, investigations, etc.) about the event. 
 
– 
Please refer to the Data Entry Guidelines (DEGs) for your protocol. 
– 
Please refer to protocol for details on reporting timelines and reporting of Overdose and 
Drug Induced 
Liver Injury (DILI). 
 
3. ECI CATEGORIES AND TERMS 
This  section describes the  ECI  categories and  outlines subject management guidelines when an  
ECI  is reported. 
 
 
3.1 Pneumonitis 
 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to 
the Sponsor within 24 hours of the event: 
 
– 
Pneumonitis 
– 
Interstitial lung disease 
– 
Acute interstitial pneumonitis 
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a 
cardiology consultation should be considered. 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral 
infection.  It is important that patients with a suspected diagnosis of pneumonitis be 
managed as per the guidance below until treatment-related pneumonitis is excluded. 
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted. Management of the treatment of suspected pneumonitis with steroid treatment 
should not be delayed for a therapeutic trial of antibiotics.  If an alternative diagnosis is 
established, the patient does not require management as below; however the AE should be 
reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– 
Consider ID consult 


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– 
Conduct an in person evaluation approximately twice per week 
– 
Consider frequent Chest X-ray as part of monitoring 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent.  When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– 
Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the 
patient develops a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab. 
– 
Hospitalize patient 
– 
Bronchoscopy with biopsy and/or BAL is recommended. 
– 
Immediately  treat  with  intravenous  steroids  (methylprednisolone 125  mg  IV).  When  
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once per 
day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no less 
than 4 weeks. 
– 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 
48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional anti-
inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 
days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting at a 
higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional anti-
inflammatory measures, as needed 
– 
Add prophylactic antibiotics for opportunistic infections. 
 
 
3.2 Colitis 
 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of 
systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Colitis 
– 
Colitis microscopic 
– 
Enterocolitis 
– 
Enterocolitis hemorrhagic 
– 
Gastrointestinal perforation 
– 
Intestinal obstruction 
– 
Necrotizing colitis 
– 
Diarrhea 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 


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disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy.   However the AE should be reported regardless of etiology. 
 
Course of Action 
 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 
hours, abdominal pain, mucus or blood in stool): 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Symptomatic Treatment 
– 
For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood 
and/or mucus, 
o 
Consider GI consultation and endoscopy to confirm or rule out colitis 
o 
Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
– 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less 
than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– 
If symptoms worsen or persist > 3 days treat as Grade 3 
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Rule out bowel perforation. Imaging with plain films or CT can be useful. 
– 
Recommend consultation with Gastroenterologist and confirmation biopsy with 
endoscopy. 
– 
Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral 
steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours)   When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. Taper over 6 to 8 weeks in patients with diffuse and severe ulceration and/or 
bleeding. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
–  
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 
48 to 72 hours, consider treatment with additional anti-inflammatory measures as described in 
the literature [5]. Discontinue additional anti-inflammatory measures upon symptom relief and 
initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid 
reduction, initiate a retapering of 
steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and 
administer 
additional anti-inflammatory measures as needed. 
 
 
Grade 4 events: 


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–  
Report as ECI 
–  
Permanently discontinue pembrolizumab. 
–  
Manage as per Grade 3. 
 
 
 
3.3 Endocrine 
 
 
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require 
holding/discontinuation/ modification of pembrolizumab dosing, are considered ECIs and should 
be reported to the Sponsor within 24 hours of the event: 
 
– 
Adrenal insufficiency 
– 
Hyperthyroidism 
– 
Hypophysitis 
– 
Hypopituitarism 
– 
Hypothyroidism 
– 
Thyroid disorder 
– 
Thyroiditis 
 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection. However the AE should be reported regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism 
 
Grade 2-4 events: 
– 
Report as ECI if appropriate 
– 
Hold pembrolizumab 
– 
Rule out infection and sepsis with appropriate cultures and imaging. 
– 
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– 
Pituitary gland  imaging should be  considered (MRIs with  gadolinium and  selective 
cuts  of  the pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
– 
Treat with prednisone 40 mg p.o. or equivalent per day.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– 
Hypophysitis with  clinically  significant  adrenal  insufficiency  and  hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes 
adrenal crisis. 
– 
Consultation with an endocrinologist may be considered. 
 
 


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Hyperthyroidism and Hypothyroidism 
 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
– 
Report as ECI if appropriate (see Table 1) 
– 
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– 
Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
– 
Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is 
instituted. 
– 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy. 
– 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
– 
Consultation with an endocrinologist may be considered. 
 
Grade 3 hyperthyroidism events: 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Rule out infection and sepsis with appropriate cultures and imaging. 
– 
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by 
oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 hyperthyroidism events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab. 
– 
Manage as per Grade 3 
 
 
Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
 
The following AE terms are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
 
– 
Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA) 
– 
Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA). 
 


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Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt worsening 
of pre- existing diabetes associated with laboratorial evidence of beta cell failure. All attempts 
should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), T2DM 
decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or poorly 
controlled pre-existing diabetes (either T1DM or T2DM), but events meeting the above criteria 
should be reported as ECIs regardless of etiology. The patients may present with hyperglycemia 
(abrupt onset or abrupt decompensation) with clinical evidence of diabetic ketoacidosis or 
laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic 
acidosis, or low or undetected c-peptide. 
 
 
Course of Action 
 
T1DM should be immediately treated with insulin. 
 
T1DM or Grade 3-4 Hyperglycemia events: 
- 
Report as ECI if appropriate (see Table 1) 
- 
Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell failure, and resume pembrolizumab when patients are 
clinically and metabolically stable. 
- 
Insulin  replacement  therapy  is  recommended  for  Type  I  diabetes  mellitus  and  for  
Grade  3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
- 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
- 
Consultation with an Endocrinologist is recommended. 
- 
Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and 
insulin may be obtained. 
 
 
 
3.4 Hematologic 
 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic 
steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 
hours of the event: 
 
– 
Autoimmune hemolytic anemia 
– 
Aplastic anemia 
– 
Disseminated Intravascular Coagulation (DIC) 
– 
Haemolytic Uraemic Syndrome (HUS) 
– 
Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– 
Thrombotic Thrombocytopenic Purpura (TTP) 
– 
Any Grade 4 anemia regardless of underlying mechanism 
 


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All attempts should be made to rule out other causes such as metastases, sepsis and/or infection.    
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, 
haptoglobin, bone marrow biopsy or Coomb’s test, etc., should be considered to confirm the 
diagnosis. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Hold pembrolizumab 
– 
Prednisone 1-2 mg/kg daily may be indicated 
– 
Consider Hematology consultation. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
– 
Report as ECI 
– 
Hematology consultation. 
– 
Hold pembrolizumab  Discontinuation should be considered as per specific protocol 
guidance. 
– 
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– 
Report as ECI 
– 
Hematology consultation 
– 
Discontinue pembrolizumab for all solid tumor indications; refer to protocol for 
hematologic malignancies. 
– 
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
 
 
3.5 Hepatic 
 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification 
or use of systemic steroids to treat the AE), are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
 
– 
Autoimmune hepatitis 
– 
Hepatitis 
– 
Transaminase elevations 
 


 
 
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V ersi o n 5. 0  
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All atte m pts s h o ul d be ma de t o r ule o ut ot her ca us es s uc h as metastatic disease, i nfecti o n or 
ot her he patic diseases. H o we ver t he A E s h o ul d be re p orte d re gar dless of eti ol o g y. 
 
Dr u g I n d uce d Li ver I nj ur y ( DI LI)  
 
I n a d diti o n, t he e ve nt m ust be re p orte d as a Dr u g I n d uce d Li ver I nj ur y ( DI LI) E CI, if t he patie nt 
meets t he la b orat or y criteria f or p ote ntial DI LI defi ne d as:  
 
A n  ele vate d ala ni ne tr a ns a mi nase ( A L T) or as p art ate tra nsa mi nas e ( A S T) l a b val ue t hat is 
gr eater t ha n or e q u al t o t hree ti mes ( 3 X) t he u p per li mit of n or mal ( U L N) a n d  
  
An ele vate d t otal bilir u bi n la b val ue t hat is greater t ha n or e q ual t o t w o ti mes ( 2 X) U L N 
a n d 
 
At t he sa me ti me, a n al kali ne p h os p hatase ( A L P) l a b val ue t hat is less t ha n 2 X U L N, 
 
As  a res ult of wit hi n- pr ot oc ol-s pecific t esti n g or u nsc he d ule d testi n g. 
 
N ote  t hat a n y he p atic i m m u ne E CI meeti n g DI LI criteria s h o ul d o nl y be re p orte d o nce as a DI LI 
e ve nt.  
 
C o urse of  Acti o n  
 
Gra de 2 e ve nts:  
– 
Re p ort as E CI  
–  
H ol d pe m br oliz u ma b w he n A S T or A L T > 3. 0 t o 5. 0 ti mes U L N a n d/ or t otal bilir u bi n 
> 1. 5 t o 3. 0 ti mes 
U L N.  
–  
M o nit or li ver f u ncti o n tests m ore fre q u e ntl y u ntil ret ur ne d t o bas eli ne val u es (c o nsi der 
wee kl y).  
o 
Treat wit h 0. 5- 1 m g/ k g/ da y m et h yl pre d nis ol o ne or oral e q ui vale nt a n d w he n L F T ret ur ns 
t o gra d e 1 or b aseli ne, ta per ster oi ds o ver at least 1 m o nt h, c o nsi der pr o p h yl actic a nti bi otics f or 
o p p ort u nistic i nfecti o ns, a n d res u me p e m br oliz u ma b per pr ot o c ol 
– 
Per ma ne ntl y dis c o nti n ue f or i na bilit y t o re d u ce c ortic oster oi d d ose t o 1 0 m g or less of 
pre d nis o ne or e q ui vale nt per da y wit hi n 1 2 wee ks. 
–  
Per ma ne ntl y dis c o nti n ue pe m br oliz u ma b f or patie nts wit h li ver metastasis w h o be gi n 
treat me nt wit h 
Gra de 2 ele vati o n of A S T or A L T, a n d A S T or A L T i ncreas es ≥5 0 % relati ve t o baseli ne a n d 
lasts ≥1 wee k. 
 
Gra de 3 e ve nts:  
– 
Re p ort as E CI  
–  
Disc o nti n ue pe m br oliz u ma b w he n A S T or A L T > 5. 0 ti mes U L N a n d/ or t otal bilir u bi n 
> 3. 0 ti mes 
U L N.  
–  
C o nsi der a p pr o priate c o ns ultati o n a n d li ver bi o p s y t o esta blis h eti ol o g y of h e patic i nj ur y, 
if necessar y 


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– 
Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When 
symptoms improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or 
prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 weeks. 
– 
If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, 
oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not 
recommended due to its potential for hepatotoxicity. 
 
 
– 
Several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– 
Report as ECI 
– 
Permanently discontinue pembrolizumab 
– 
Manage patient as per Grade 3 above 
 
 
3.6 Neurologic 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
 
– 
Autoimmune neuropathy 
– 
Demyelinating polyneuropathy 
– 
Guillain-Barre syndrome 
– 
Myasthenic syndrome 
 
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Moderate (Grade 2) – consider withholding pembrolizumab. 
– 
Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
– 
Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
– 
Report as ECI 


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– 
Discontinue pembrolizumab 
– 
Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. If condition worsens consider IVIG or other immunosuppressive therapies as per 
local guidelines 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
 
 
 
3.7 Ocular 
 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of 
systemic steroids to treat the AE, is considered an ECI and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Uveitis 
– 
Iritis 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other ocular disease (e.g. glaucoma or cataracts). However the AE should be reported regardless 
of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Evaluation by an ophthalmologist is strongly recommended. 
– 
Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. 
– 
Discontinue  pembrolizumab  as  per  protocol  if  symptoms  persist  despite  treatment  
with  topical immunosuppressive therapy. 
 
Grade 3 events: 
– 
Evaluation by an ophthalmologist is strongly recommended 
– 
Hold pembrolizumab and consider permanent discontinuation as per specific protocol 
guidance. 
– 
Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day.   
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
 
 


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Grade 4 events: 
– 
Evaluation by an ophthalmologist is strongly recommended 
– 
Permanently discontinue pembrolizumab. 
– 
Treat with corticosteroids as per Grade 3 above 
 
 
3.8 Renal 
 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Nephritis 
– 
Nephritis autoimmune 
– 
Renal failure 
– 
Renal failure acute 
 
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids 
to treat the AE. 
 
All attempts should be made to rule out other causes such as obstructive uropathy, progression of 
disease, or injury due to other chemotherapy agents.  A renal consultation is recommended. 
However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Hold pembrolizumab 
– 
Treatment with prednisone 1-2 mg/kg p.o. daily. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3-4 events: 
– 
Discontinue pembrolizumab 
– 
Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent 
once per day. 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
 
 
 
 


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3.9 Skin 
 
Rash and Pruritus 
 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the 
Sponsor within 24 hours of the event: 
 
– 
Pruritus 
– 
Rash 
– 
Rash generalized 
– 
Rash maculo-papular 
– 
In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in 
the physician's judgment, should be treated as an ECI. Clinical significance is left to the 
physician to determine, and could possibly include rashes such as the following: 
o 
rash with a duration >2 weeks; OR 
o 
rash that is >10% body surface area; OR 
o 
rash that causes significant discomfort not relieved by topical medication or temporary 
cessation 
of study drug. 
 
Classic acneiform rash from afatinib < grade 3 need not be reported to sponsor. 
 
Other Skin ECIs 
 
The following AEs should always be reported as ECIs, regardless of grade, and should be 
reported to the 
Sponsor within 24 hours of the event: 
 
– 
Dermatitis exfoliative 
– 
Erythema multiforme 
– 
Steven’s Johnson syndrome 
– 
Toxic epidermal necrolysis 
 
Please note, the AE should be reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
– 
Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 
0.1% cream or hydrocortisone 1%) or urea-containing creams in combination with oral anti-
pruritics 
(e.g., diphenhydramine HCl or hydroxyzine HCl). 
– 
Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 


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Grade 3 events: 
– 
Hold pembrolizumab. 
– 
Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– 
Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg four times orally daily.  When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– 
Permanently discontinue pembrolizumab. 
– 
Dermatology consultation and consideration of biopsy and clinical dermatology 
photograph. 
– 
Initiate steroids at 1 to 2 mg/kg prednisone or equivalent.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
 
 
3.9.1. Immediate Evaluation for Potential Skin ECIs 
A. Photographs: 
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon 
as possible. Obtain appropriate consent for subject photographs if a consent form 
addendum is required by your IRB/ERC. 
– 
Take digital photographs of: 
o 
the head (to assess mucosal or eye involvement), 
o 
the trunk and extremities, and 
o 
a close-up of the skin lesion/rash. 
– 
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance. 
– 
The time/date stamp should be set in the 'ON' position for documentation purposes. 
– 
Photographs should be stored with the subject’s study records. 
– 
The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will 
provide guidance to the site, if needed. 
 
B. Past Medical History: 
Collect past medical history relevant to the event, using the questions in Appendix 2 (Past 
Medical History Related to Dermatologic Event) as a guide. Any preexisting conditions not 
previously reported (e.g., drug allergy) should be entered into the Medical History eCRF. 
 
C. Presentation of the Event: 
Collect information on clinical presentation and potential contributing factors using the questions 
in Appendix 
3 (Presentation of the Dermatologic Event) as a guide. This information should be summarized 
and entered in narrative format in the AE eCRF. Please use the available free-text fields, such as 
Signs and Symptoms. Note pertinent negatives where applicable to reflect that the information 


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was collected. Any treatments administered should be entered on the Concomitant Medication 
eCRF. 
D. Vitals Signs and Standard Laboratory Tests: 
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the 
Vital Signs eCRF.  Perform standard laboratory tests (CBC with manual differential and serum 
chemistry panel, including LFTs). 
E. Focused Skin Examination: 
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin 
Examination) as a guide. Information should be summarized and entered on the Adverse 
Experience eCRF as part of the narrative. 
F. Dermatology Consult 
Refer the subject to a dermatologist as soon as possible. 
– 
For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. 
– 
For clinically significant rash, the subject should be seen within 3-5 days. 
 
The  dermatologist  should  submit  a  biopsy  sample  to  a  certified  dermatopathology  
laboratory  or  to  a pathologist experienced in reviewing skin specimens. 
 
The site should provide the dermatologist with all relevant case history, including copies of 
clinical photographs and laboratory test results. 
 
 
3.10 Other 
The following AEs, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
 
– Myocarditis 
– Pericarditis 
– Pancreatitis 
– Any additional Grade 3 or higher event which the physician considers to be immune related 
 
All  attempts should be  made  to  rule  out  other  causes. Therapeutic specialists should be  
consulted as appropriate. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
– 
Withhold pembrolizumab. 
– 
Systemic corticosteroids may be indicated. 
– 
Consider biopsy for confirmation of diagnosis. 
– 
If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
– 
Hold pembrolizumab 


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– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
– 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may be 
restarted and the dose modified as specified in the protocol 
 
Grade 4 events: 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
– 
Discontinue pembrolizumab 
 
3.11 Infusion Reactions 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
– 
Allergic reaction 
– 
Anaphylaxis 
– 
Cytokine release syndrome 
– 
Serum sickness 
– 
Infusion reactions 
– 
Infusion-like reactions 
 
Please note, the AE should be reported regardless of etiology. 
 
Course of Action 
 
Refer to infusion reaction table in the protocol and below. 
 
 
 


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Infusion Reactions 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
Increase monitoring of vital signs 
as 
medically indicated until the 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS Acetaminophen Narcotics 
Increase monitoring of vital signs 
as medically indicated until the 
subject is 
deemed medically stable in the 
opinion of 
the investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may 
be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr 
Subject may be 
premedicated 
1.5h (± 30 minutes) prior 
to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg 
p.o. (or equivalent dose 
of antihistamine). 
 
Acetaminophen 500-
1000 mg p.o. (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS Acetaminophen Narcotics 
Oxygen 
Pressors Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov


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3.12 Follow-up to Resolution 
 
 
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated 
with information regarding duration and clinical course of the event. Information obtained from 
the consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. 
Free-text fields should be used to record narrative information: 
 
– 
Clinical course of the event 
– 
Course of treatment 
– 
Evidence supporting recovery 
– 
Follow-up to the clinical course 
 
Any treatments administered for the event should also be entered in the Concomitant Medication 
eCRF. 
 
 
 
 
 
 
 


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4. REFERENCES 
 
 
1.   Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.  Nature Reviews 
Cancer 2012; 12:252-264. 
 
2.   Weber JS Practical Management of Immune-Related Adverse Events from Immune Checkpoint 
Protein Antibodies for the Oncologist. American Society of Clinical Oncology 2012; 
1092-9118/10/1-10. 
 
3.   Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse Events and 
Kinetics of Response With Ipilimumab. J Clin Oncol 30. 2012. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750. 
 
4.   Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with 
Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010. 
 
5.   Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 
366:2443-2454. 
 
6.   Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 
Antibody in Patients with Advanced Cancer. N Engl J Med 2012; 366:2455-2465. 
 
7.   Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, phase 
II study comparing the tolerability and efficacy of ipilimumab administered with or without 
prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 
15:5591-5598, 2009. 
 
8.   Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the 
Management of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–66. 
 
9.   Phan GQ, Weber JS, and Sondak VK.  CTLA-4 Blockade with Monoclonal Antibodies in 
Patients with Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–
3021. 
 
10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse 
reactions— YERVOY Risk Evaluation and Mitigation Strategy 
(REMS). http://www.yervoy.com/hcp/rems.aspx 
 
11. Bristol-Myers Squibb: YERVOY   (ipilimumab) prescribing information revised March 2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf 
 
 
 


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5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table 
 
Pneumonitis (reported as ECI if ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic 
steroids to treat 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset)  
 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids 
to treat the 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic Purpura 
(TTP)
Idiopathic (or immune) 
Thrombocytopenia Purpura  (ITP) 
Disseminated Intravascular 
Coagulation (DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat 
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat 
Uveitis 
Iritis 
 
Renal (reported as ECI if ≥ Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 


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Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment 
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
 
 
 
 
 
 


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6. APPENDIX 2 – Past Medical History Related to Dermatologic Event 
 
Past Medical History: 
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the 
Medical History eCRF. 
 
1. Does the subject have any allergies? □ Yes □ No 
 
If yes, please obtain the following information: 
 
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No 
 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc):  ____ 
_______________________________________________________________________________ 
 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.?  
□ Yes □  No 
 
Describe the agent and type of allergic response: ________________________________________ 
_______________________________________________________________________________ 
 
c. Any allergy to food? □ Yes □ No 
 
Describe the food and type of allergic response: 
 
 
 
 
 
 
__________________________________________________________________________ 
 
d. Any allergy to animals, insects? □ Yes □ No 
 
Describe the allergen and type of allergic response:  
 
 
 
 
 
 
__________________________________________________________________________ 
 
e. Any other allergy? □ Yes □ No 
 
Describe the allergen and type of allergic response:   
_______________________________ 
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes □ No 
 
If so what kind?   _____________________________________________________________ 
 
3. Has the subject ever been treated for a skin condition? □ Yes □ No 
 
If so what kind?   _____________________________________________________________ 
 
4. Is the current finding similar to a past experience? □ Yes □ No 
 
 


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7. APPENDIX 3 – Presentation of the Dermatologic Event 
 
 
Presentation of the event: 
Collect information on clinical presentation and potential contributing factors. Key information 
should be summarized and entered on the Adverse Experience eCRF. Any treatments administered 
should be entered on the Concomitant Medication eCRF. 
 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
 
_________________________________________________________________________ 
 
2. Has the subject contacted any known allergens? □ Yes □ No 
 
If so what kind?   _____________________________________________________________ 
 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, 
personal care product, poison ivy, etc.)? □ Yes □ No 
 
If so what kind?   _____________________________________________________________ 
 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and 
supplement)? 
□ Yes □ No 
 
If so what kind?   _____________________________________________________________ 
 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
 
If so what kind?   _____________________________________________________________ 
 
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
 
If so what kind?   _____________________________________________________________ 
 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No 
 
If so who and what?  
 
_________________________________________________________________________ 
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g., 
Molluscum Contagiosum)? □ Yes □ No 
 
9. Has the subject had recent sun exposure? □ Yes □ No 
 
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 


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If so what kind?   ___________________________________________________________ 
 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No iii. Signs of dyspnea? □ Yes □ No 
iv. Fever, night sweats, chills? □ Yes □ No 
 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic 
catecholamine therapy? □ Yes □ No 
 
If so what kind?   ___________________________________________________________ 
 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No 
 
List medication(s) and dose(s):   _______________________________________________ 
_____________________________________________________________________________ 
 
13. Is the rash pruritic (itchy)? □ Yes □ No 
 
 
 
 
 


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8. APPENDIX 4 – Focused Skin Examination 
 
 
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience eCRF. 
 
Primary Skin Lesions Description 
Color:   
 
 
General description: 
 
 
 
 
Describe the distribution of skin reaction, skin eruption, or rash on the body: 
 
 
 
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
 
 
 
 
Any associated signs on physical