A Pilot and Phase II Study to Assess the Safety, Tolerability and Efficacy of Pembrolizumab Plus Chemotherapy in Metastatic Triple Negative Breast Cancer Patients
Phase: PHASE1
Conditions: Triple Negative Breast Cancer
Sponsor: Providence Health & Services

 
 
                                       
 
 
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Protocol Number:  
PHS IRB: 16-001 
Title:   
A Pilot and Phase II Study to Assess the Safety, Tolerability 
and Efficacy of Pembrolizumab Plus Chemotherapy in 
Metastatic Triple Negative Breast Cancer Patients 
 
 
Version Date:  
January 9, 2018 
 
Previous Version:  
July 7, 2017 
 
 
Sponsor:  
Providence Portland Medical Center 
Earle A. Chiles Research Institute 
Robert W. Franz Cancer Research Center 
4805 NE Glisan Street, Room 2N35 
Portland, OR  97213 
503-215-6805 
Principal Investigator: 
David Page, MD 
 
Earle A. Chiles Research Institute 
4805 NE Glisan Street, 2N87 
Portland, OR 97213 
503-215-5696 
FAX 503-215-5695 
David.Page2@Providence.Org 
 
 
Co-Investigators: 
 
 
Alison Conlin, MD 
Todd Crocenzi, MD 
Brendan Curti, MD 
John Godwin, MD 
Rom Leidner, MD 
Rui Li, MD, PhD 
Rachel Sanborn, MD 
Walter J. Urba, MD, PhD 
Herschel Wallen, MD 
 
Anupama Acheson, MD 
Nicholas Barber, MD 
Regan Duffy, MD 
Stacy Lewis, MD 
Christine Lin, MD 
Christie Moore, MD 
Heather McArthur, MD 
 
Responsible Research Nurses: 
Nicole Moxon, RN 
 
 
 
 
 
Providence Portland Medical Center 
 
 
 
 
 
Robert W. Franz Research Center 
4805 NE Glisan Street, 2N35 
 
 
 
 
 
Portland, OR 97213 
 
 
 
 
 
503-215-2691 

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Fax 503-215-6725 
 
 
 
 
 
Nicole.moxon@providence.org 
 
Staci Mellinger, RN 
 
 
 
 
 
Providence Portland Medical Center 
 
 
 
 
 
Robert W. Franz Research Center 
4805 NE Glisan Street, 2N35 
 
 
 
 
 
Portland, OR 97213 
 
 
 
 
 
503-215-2642 
 
 
 
 
 
Fax 503-215-6725 
 
 
 
 
 
Staci.Mellinger@providence.org 
 
 
 
 
 
 
 
 
Responsible Data Manager: 
Amanda Seino 
 
 
 
 
 
Providence Portland Medical Center 
 
 
 
 
 
Robert W. Franz Research Center 
4805 NE Glisan Street, 2N35 
 
 
 
 
 
Portland, OR 97213 
 
 
 
 
 
(503) 215-2818 
 
 
 
 
 
Fax 503-215-6725 
 
 
 
 
 
Amanda.Seino@providence.org 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
 
 
Protocol Number: 
PHS IRB 16-001 Version January 9, 2018 
 
 
Protocol Title: 
A Pilot and Phase II Study to Assess the Safety, Tolerability and Efficacy of 
Pembrolizumab Plus Chemotherapy in Metastatic Triple Negative Breast 
Cancer Patients 
 
 
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.  
 
 
 
 
 
 
 
David Page, MD 
 
 
 
 
 
 
 
 
 
 
 
Investigator Name (print)  
 
Investigator Signature 
 
Date 
 

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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ........................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................... 11 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 11 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................... 18 
4.1 
Design ........................................................................................................................................ 18 
4.2 
Intervention ................................................................................................................................ 18 
4.3 
Estimated Duration of Subject Participation ......................................................................... 19 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ................................................................................ 19 
5.1.5  Clinical supplies disclosure .................................................................................................... 21 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................ 22 
6.1 
Subject Inclusion Criteria ........................................................................................................ 22 
6.2 
Subject Exclusion Criteria ....................................................................................................... 24 
7.0 
RECRUITMENT PLAN................................................................................................................ 25 
8.0 
PRETREATMENT EVALUATION ............................................................................................. 25 
9.0 
TREATMENT / INTERVENTION PLAN ................................................................................... 26 
9.1 Monitoring of Dose Administration .......................................................................................... 26 
9.3.2 Resynchronization of Pembrolizumab with chemotherapy following scheduling delay
 ............................................................................................................................................................ 32 
9.4 Discontinuation of Study Therapy after CR ........................................................................... 33 
9.6 Supportive Care Guidelines ..................................................................................................... 34 
9.8 
Diet ......................................................................................................................................... 37 
9.9 
Use in subjects with childbearing potential....................................................................... 37 
9.10 
Use in Pregnancy ................................................................................................................. 37 
9.12  
Clinical Criteria for Early Trial Termination ....................................................................... 38 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 39 
10.1.1 Informed Consent ................................................................................................................. 44 
10.1.7 Adverse Event (AE) Monitoring .......................................................................................... 45 
10.1.15 Withdrawal/Discontinuation .............................................................................................. 48 
10.1.16 Visit Requirements ............................................................................................................. 49 
11.0 
TOXICITIES/SIDE EFFECTS ..................................................................................................... 49 
11.1 Summary of toxicities of investigational agents ...................................................................... 49 

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11.1.1 Weekly paclitaxel ..................................................................................................................... 49 
11.3 Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor 
and to Merck ..................................................................................................................................... 51 
11.4 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ............................. 52 
11.5 Immediate Reporting of Adverse Events to the Sponsor and to Merck .......................... 52 
11.6 Evaluating Adverse Events .................................................................................................... 54 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 57 
CT scan with contrast of the chest, abdomen, and pelvis ................................................................. 58 
MRI scans .................................................................................................................................................. 58 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................ 62 
14.0 
BIOSTATISTICS .......................................................................................................................... 63 
15.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES ........................................................................................................................................ 65 
15.1 
Research Participant Registration ......................................................................................... 65 
15.2 
Randomization .......................................................................................................................... 65 
16.0 
DATA MANAGEMENT ............................................................................................................... 65 
16.1 
Data collection .......................................................................................................................... 65 
16.1 
Quality Assurance .................................................................................................................... 65 
16.2 
Monitoring .................................................................................................................................. 65 
18.0 
INFORMED CONSENT PROCEDURES ................................................................................. 66 
19.0 
REFERENCES ............................................................................................................................. 67 
 
 
 

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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Name of Investigational drug:  Pembrolizumab 
Title of Study:  A Pilot and Phase II Study to Assess the Safety, Tolerability and Efficacy of 
Pembrolizumab Plus Chemotherapy in Metastatic Triple Negative Breast Cancer Patients 
Study Centers: Providence Portland Medical Center, Cedars-Sinai Medical Center 
Study Period: 12 months (Pilot); 12 months (Phase II) 
Phase of Development: Pilot/ Phase 
II 
Objectives:  
Primary objectives: 
Pilot phase: 
 
To establish the safety and tolerability of pembrolizumab when administered in combination with 
either 
of 
two 
chemotherapy 
regimens 
(weekly 
paclitaxel 
or 
capecitabine) 
in 
unresectable/metastatic triple negative breast cancer (MTNBC) patients 
 
Optional phase II expansion cohort(s): 
 
To estimate the week 13 objective response rate (ORR), as measured by RECIST v1.1, of 
pembrolizumab when administered in combination with chemotherapy in MTNBC 
 
Secondary objectives: 
Pilot phase: 
 
To evaluate the week 13 ORR based on RECIST v1.1 and immune related RECIST criteria 
 
Optional phase II expansion cohort(s): 
 
To evaluate the week 13 ORR based on immune-related RECIST criteria 
 
To evaluate the safety and tolerability of pembrolizumab plus chemotherapy 
 
Exploratory objectives (both cohorts):  
 
To evaluate immunologic biomarkers that may correlate with activity of pembrolizumab plus 
chemotherapy in MTNBC, or prospectively identify MTNBC patients likely to respond to 
treatment 
Study Design: This will be a pilot feasibility design followed by optional phase II expansion cohorts. It 
will be conducted to determine the safety and tolerability of pembrolizumab plus chemotherapy in 
subjects with MTNBC for whom chemotherapy is indicated, and to estimate the efficacy of 
pembrolizumab plus chemotherapy. 
 
Eligible patients will have RECIST1.1-measurable MTNBC, as defined by estrogen receptor negativity 
(defined by IHC<1%) and HER2-receptor negativity (defined by IHC 0-1 (or) IHC 2 and ISH 
HER2/CEP17<2.0).  
 
In the pilot phase, patients will be enrolled to one of two experimental arms, which will be selected by 
the treating investigator (arm A: pembrolizumab + weekly paclitaxel; arm B: pembrolizumab + 
capecitabine). First and second line therapy is allowed, and patients must not have previously received 
the same chemotherapeutic agent(s), either in the metastatic setting, or in the (neo)adjuvant setting 
(unless ≥12 months from consent). Subjects will receive pembrolizumab via IV infusion at 200mg every 
three weeks (Q3W), and continue treatment Q3W until progression of disease, initiation of alternative 
cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur, up to 24 months. 
Patients will concurrently receive one of two chemotherapy regimens, and continue treatment until 
progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to 
discontinue chemotherapy occur. Chemotherapy dose delays and modifications will be allowed at the 
discretion of the treating investigator, per section 9. Furthermore, at the discretion of the treating 
investigator, chemotherapy may be discontinued with ongoing dosing of pembrolizumab after week 7.  
 

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Patients will be evaluated by physical exam and routine blood tests every three weeks during the study 
period. CT or MRI will be performed during screening, at week 13 and subsequently at 12 week intervals 
as per the standard of care for MTNBC. Safety will be evaluated routinely using the CTCAE 4.0 toxicity 
reporting criteria. Tumor measurements and determination of tumor response will be performed 
according to RECIST 1.1. Subjects may continue to receive pembrolizumab beyond radiographic 
progression in the absence of clinical deterioration, and after discussion with the Principal Investigator.  
 
Figure 1.0-1: Protocol Schema 
 
Table 1.0-1: Therapeutic agents, by arm 
Study 
arm 
Drug 
Dose 
Cycle 
Frequency 
Route
Regimen 
All 
Pembrolizumab 
200mg 
Q3W 
IV infusion 
Day 1 of each 3 week cycle 
A 
Paclitaxel 
80mg/m2 
Q3W 
IV infusion 
Day 1, 8, and 15 of each 3 week 
cycle 
B 
Capecitabine 
2000mg  
Q2W 
Oral 
BID, Days 1-7 of each 2 week 
cycle 
 
The primary endpoint of the pilot phase is to establish safety and tolerability of chemotherapy plus 
pembrolizumab. For each subject, the therapy will be deemed tolerable if the following criteria are met:  
 
Subjects receive at least 7 weeks of pembrolizumab (2 cycles) and remain free of serious 
adverse events and grade III/IV treatment-associated adverse events requiring discontinuation 
of pembrolizumab during that period; 
 
Subjects receive at least 7 weeks of chemotherapy within an acceptable therapeutic 
dosing/scheduling range without chemotherapy discontinuation or chemotherapy dosing delay 
≥21 days. Shorter chemotherapy delays (<21 days) and dose modifications are acceptable if 
they conform to guidelines specified in section 9.3.3.  
 
In previously reported phase II/III studies, 78-91% of patients treated with chemotherapy (weekly taxol 
or oral capecitabine) tolerated therapy without requiring dose discontinuation. Accordingly, we will deem 
the therapy safe if at least 60% of evaluable patients in the pilot phase (i.e. 9 or more out of 14 patients) 
are able to tolerate therapy. Assuming that all 14 patients are evaluable for safety/tolerability, there is a 
.49 probability that the therapy will be deemed safe if we assume a .6 true safety/tolerability probability.  
If the true probability is assumed to be .7 and .8, the probability of deeming the therapy tolerable is .78 
and .96 respectively. The rate of grade I/II toxicities, grade III/IV toxicities, and chemotherapy dose delays 
and modifications will be reported as additional, descriptive measures of tolerability. 
 

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Subjects who clinically progress prior to week 13 will be included as treatment failures in the 
determination of ORR. Subjects who are enrolled but do not initiate the first infusion of therapy will be 
replaced and not included in the determination of safety/tolerability or ORR. Subjects who withdraw 
consent prior to week 13, and therefore are not evaluable for ORR, will be replaced and not included in 
the determination of ORR. Subjects will be included in the determination of safety/tolerability only if they 
remained evaluable for safety/tolerability for at least 6 weeks from the first dose. 
 
In addition to safety/tolerability, clinical efficacy will also be assessed in the pilot cohort, as measured by 
RECIST1.1 ORR and immune-related RECIST ORR. If the therapy is deemed tolerable and if an efficacy 
futility boundary is exceeded in the pilot cohort, clinical efficacy and safety/feasibility may be further 
evaluated via an expansion cohort(s) of one or more treatment arms. For a treatment arm to be eligible 
for expansion, RECIST1.1 overall response in the pilot stage must exceed ≥4/14 objective responses 
(OR). This boundary is modeled after a Simon 2-stage optimal design, whereby the first Simon stage is 
the pilot phase arm (n=14), and the second Simon stage is the expansion cohort (n=30). This design is 
powered, with a type I error rate of 10% and type II error rate of 10%, to discriminate between ORR of 
25% (the estimated response rate for chemotherapy alone for each of the chemotherapy regimens based 
on historical trials) versus 45%. Safety/feasibility will continue to be assessed in the expansion cohort(s) 
using the same criteria as in the pilot phase. 
 
For a study arm to be eligible for expansion in an optional phase II cohort, the arm must meet both 
safety/tolerability and efficacy criteria. If these criteria are met, the decision to open an expansion cohort 
will be determined by a committee consisting of study site principal investigators and Merck 
representatives. The decision will be based upon: safety/tolerability of the treatment in the pilot study; 
efficacy observed in the pilot study; feasibility of accrual (which will be estimated during the pilot study); 
immunologic correlatives data; resources, and other considerations. 
 
All subjects will be followed for at least 18 weeks from the start of therapy to evaluate for delayed 
toxicities.  Patients with ongoing clinical benefit will be eligible to receive pembrolizumab for up to 2 years 
from the first dose. The study will terminate after the primary endpoints (safety/tolerability and 13-week 
ORR) have been achieved for all enrolled patients. Based upon the observed ORR and available 
resources, the committee may elect to prolong the study to assess for 1-year and/or 2-year progression 
free survival. This study will accrue a minimum of 28 subjects (or fewer if an arm closes prematurely for 
unanticipated excess toxicity), and up to 88 subjects if both cohorts are expanded. If one of the two arms 
expand, the estimate for total accrual is 58 subjects. Additional subjects may be enrolled to replace 
subjects that are inevaluable for efficacy.  
 
Based upon conservative estimates of enrollment of 1-2 subjects per month across each of two sites, 
the accrual time for the pilot phase is estimated to be 1 year, and accrual time for the expansion phase 
is estimated to be 1 year. Tumor biopsies for research purposes will be mandatory for all patients. 
Biopsies will be obtained at baseline (or archival if there is no intervening anti-neoplastic therapies) and 
at 6 weeks following initiation of therapy +/- 1 week. Peripheral blood samples will be obtained in all 
patients at baseline at specified follow-up weeks at the time of routine standard-of-care blood 
assessments.  
 
Tumor biopsies and peripheral blood will be used to conduct laboratory immunologic assessments, which 
will be used to support clinical findings in the trial. Furthermore, these findings will be correlated with 
clinical outcome in an exploratory manner in order to identify predictive makers for response, and to 
further our understanding of pembrolizumab when administered in conjunction with chemotherapy in 
MTNBC. 

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Diagnosis and Main Criteria for Inclusion in the Study:  
Inclusion Criteria 
1. Willing and able to provide written informed consent; 
2. ≥ 18 years of age on day of signing informed consent. 
3. HER2-negative breast cancer (defined by IHC 0-1 (or) IHC 2 and ISH HER2/CEP17<2.0); 
4. ER and PR-negative breast cancer (defined by IHC<1%); 
5. Measurable metastatic or unresectable disease based on RECIST 1.1. 
6. Indicated for treatment with either weekly paclitaxel or oral capecitabine as first or second-line 
chemotherapy in the metastatic or unresectable setting 
7. Consent for tumor biopsies and blood draws for research purposes. 
8. Consent for use of available archived tissue for research purposes. 
9. Performance status of ECOG 0 or 1. 
10. Adequate organ function, defined as: 
 
Absolute Neutrophil Count ≥ 1,500/mm3. 
 
Platelet count ≥ 100,000/mm3. 
 
Serum creatinine ≤ 1.5 x ULN or CrCl ≥60 mL/min.  
 
AST and ALT ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with liver metastases. 
 
Bilirubin ≤ 1.5 × ULN or Direct bilirubin ≤ ULN (except subjects with Gilbert’s Syndrome, 
who will be allowed in consultation with the Principal Investigator). 
 
 
INR/PT and PTT ≤1.5 X ULN unless on anticoagulant therapy and PT/PTT within 
therapeutic range. 
11. Women of childbearing potential must avoid becoming pregnant while on treatment, and men 
must avoid fathering a child while on treatment. 
 
Exclusion Criteria 
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 (inhaled 
steroids are permitted). 
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 4 weeks prior to study, Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. Denosumab is allowed. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. Note:  Subjects with ≤ Grade 2 neuropathy and 
alopecia are an exception to this criterion and may qualify for the study. 
7. Has received the assigned chemotherapy regimen previously in the metastatic setting, or has 
received the assigned chemotherapy regimen previously in the (neo)adjuvant setting within 12 
months of consent 
8. If subject received major surgery, they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy. 
9. Has a known additional malignancy that progressed or required active treatment in the last 5 
years (history of synchronous breast cancer is allowed at the discretion of the principal 
investigator) 
10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 
Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least four weeks prior to the first dose of trial 
treatment and any neurologic symptoms have returned to baseline), have no evidence of new 

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or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment. This exception does not include carcinomatous meningitis which is excluded 
regardless of clinical stability. 
11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy 
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
12. Has history of/active pneumonitis requiring treatment with steroids or history of/active interstitial 
lung disease. 
13. Has an active infection requiring systemic therapy. 
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the 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. 
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after the 
last dose of trial treatment. 
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or has participated 
in a pembrolizumab Merck-sponsored study. 
18. Has a known history of Human Immunodeficiency Virus (HIV).  
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected). 
20. Has received a live vaccine within 30 days of planned start of study therapy. Note:  Seasonal 
influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however 
intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Number of Subjects: n=28 for pilot phase, n=30 for each phase II cohort 
 
 
 

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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 Primary Objectives 
 
Pilot phase: 
To establish the safety and tolerability of pembrolizumab when administered in 
combination with either of two chemotherapy regimens (weekly paclitaxel or capecitabine) 
in unresectable/metastatic triple negative breast cancer (MTNBC) patients 
 
Optional phase II expansion cohort(s): 
To estimate the week 13 objective response rate (ORR), as measured by RECIST v1.1, 
of pembrolizumab when administered in combination with chemotherapy in MTNBC 
 
2.2 Secondary Objectives: 
 
Pilot phase: 
To evaluate the week 13 ORR based on RECIST v1.1 and by immune related RECIST 
criteria 
Optional phase II expansion cohort(s): 
 
To evaluate the week 13 ORR based on immune-related RECIST criteria 
 
To evaluate the safety and tolerability of pembrolizumab plus chemotherapy 
 
2.3 Exploratory Objectives 
 
To evaluate immunologic biomarkers that may correlate with activity of pembrolizumab 
plus chemotherapy in MTNBC, or prospectively identify patients likely to respond to 
treatment 
 
3.0 
BACKGROUND AND RATIONALE 
An estimated 90% of deaths attributable to breast cancer are a consequence of metastases, with 
more than 40,000 deaths caused by metastatic breast cancer each year in the United States 
alone, for which the triple negative breast cancer (TNBC) subtype is disproportionately 
represented. Despite notable therapeutic innovations, patients with MTNBC have a median 
survival of only 2–3 years. 
 
Combining standard-of-care cytotoxic therapy with a novel immunomodulatory agent, 
pembrolizumab, may enhance therapeutic efficacy and lead to improved patient outcomes. The 
primary goal of this protocol is evaluate the safety/tolerability of combining pembrolizumab with 2 
of the most common cytotoxic regimens used in MTNBC. If this approach is safe, we will also 
estimate the efficacy of this approach in one or more expansion cohorts. These expansion cohorts 
will provide preliminary data, either in support or against, further evaluation of the combination 
chemotherapy/pembrolizumab approach in a larger, randomized trial.  
 
3.1 TNBC 
TNBC is clinically defined as lacking estrogen receptor (ER), progesterone receptor (PR) 
and HER2 receptor expression by immunohistochemistry (Society 2012).  Although TNBC 
comprises 15-20% of incident breast cancers, it is over-represented among those with 
metastatic disease and is responsible for a disproportionately higher number of breast 
cancer deaths.  Histologically, TNBC is poorly differentiated, more often an interval breast 
cancer (i.e., diagnosed between screening mammograms), and, when recurrent, it 

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preferentially relapses in visceral sites, including the lungs, liver, and brain.  For TNBC 
patients, the risk of recurrence and death is significantly and dramatically higher in the first 
3 to 5 years after diagnosis compared to women with ER/PR+ tumors.  Currently, with an 
absence of a clinically relevant target, there are no targeted therapeutic approaches, 
leaving only nonspecific conventional chemotherapies as the mainstay of treatment for 
TNBC. While effective for some, cytotoxic therapy is not curative for any patient with 
metastatic disease. 
 
3.1.1 Standard-of-care cytotoxic therapies for TNBC 
The National Comprehensive Cancer Network (NCCN) endorses numerous single-agent 
cytotoxic chemotherapy regimens for TNBC, including anthracyclines (doxorubicin or 
pegylated doxorubicin), taxanes (paclitaxel or docetaxel), anti-metabolites (gemcitabine 
or capecitabine), and other microtubule inhibitors (vinorelbine or eribulin). 
 
Weekly Paclitaxel 
Of these agents, the taxanes and anthracyclines are the most clinically active, however 
anthracycline use in the metastatic setting is limited by constraints on cumulative dosing, 
and frequent anthracycline use in the adjuvant setting. Single agent taxane regimens are 
among the most frequently-employed therapies for metastatic TNBC. Weekly paclitaxel 
(Mauri, Kamposioras et al. 2010) is well tolerated and improves survival over every three 
week regimens, and therefore is a frequently employed regimen, with impressive first-line 
objective response rates (ORRs, 18%-49%).(Miller, Wang et al. 2007, Seidman, Berry et 
al. 2008, Fountzilas, Dafni et al. 2009, Brufsky, Valero et al. 2012, Miles, Dieras et al. 
2013) In contemporary practice, the response rate is likely closer to 20-30%, likely owing 
to increased use of paclitaxel in the (neo)adjuvant setting. 
 
Oral Capecitabine 
An alternative and frequent first-line systemic therapy is oral capecitabine, owing to its 
convenience of administration (oral), relative tolerability, and respectable clinical activity 
(overall response rate of 18-30% in randomized trials).(Oshaughnessy, Blum et al. 2001, 
Fumoleau, Largillier et al. 2004, Brufsky, Valero et al. 2012, Miles, Dieras et al. 2013) The 
traditional dosing schedule is 1255mg/m2 twice daily, two weeks on, one week off. 
However, mathematical modeling and phase II clinical trials demonstrate similar efficacy 
and improved tolerability with fixed 1500mg-2000mg twice daily dosing delivered one 
week on, one week off, and is therefore an acceptable and frequently employed 
regimen.(Traina, Dugan et al. 2010, Gajria, Feigin et al. 2011, Gajria, Gonzalez et al. 2012) 
 
3.1.2 Immune augmentation in TNBC 
Recently published studies suggest that distant metastatic invasion of TNBC may be 
potentially induced by immune/inflammatory deregulation. Among a set of 45-gene 
signature that was found to be statistically predictive in distant disease recurrence in 
TNBC, ten genes are found to be within TGF-β signaling pathway, associated with immune 
suppressed phenotype.(Kuo, Chang et al. 2012) In BC patients, either decreased number 
of effector CD8(+) T cells, or increased number of regulatory T-cells, was associated with 
adverse tumor characteristics such as lymph node metastasis, higher stage, and Ki-67 
immunopositivity. (Miyashita, Sasano et al. 2014) Corroborating these findings, across 
multiple large adjuvant and neoadjuvant datasets, the quantity of tumor infiltrating 
lymphocytes in early stage triple negative breast cancers has been associated with 
improved survival, and increased likelihood of response to chemotherapy.(Salgado, 
Denkert et al. 2014) Functional assays demonstrate that adequate activation of tumor 
infiltrating lymphocytes (TILs) derived from BC tissue could restore the appropriate 

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antitumor immune responses. This emerging data underscores the potential of a 
therapeutic strategy that immune-mediated anti-tumor responses.  
 
In light of these data, an immunomodulatory agent, pembrolizumab 10mg/kg q2wk, was 
evaluated in a phase Ib cohort of metastatic TNBC pts. Pembrolizumab is a therapeutic 
blocking antibody targeting programmed death 1 (PD-1), a surface receptor found on 
chronically antigen-exposed T-cells associated with downregulation of T-cell cytotoxic 
activity.(Topalian, Drake et al. 2012) In this population (median prior treatments = 2.5), the 
overall response rate was 18.5% by RECIST1.1, with an additional 25.9% with stable 
disease (figure 3.2.1-1). Responses were durable, with the median duration of response 
not reached (median follow-up 9.9mo). The treatment was safe (grade III/IV tox: 15.6%).7 
In a similar phase Ib cohort of the anti-programmed death ligand 1 (PD-L1) antibody, 
MPDL3470A, an objective response rate of 33% was observed in evaluable TNBC 
patients.(Emens, Braiteh et al. 2014) 
 
Figure 3.2.1-1: Waterfall plot of objective responses to pembrolizumab in TNBC 
 
 
3.1.3 Rationale and safety of combining cytotoxic therapy with immune 
augmentation 
Response rates to anti-PD-1 in TNBC, while respectable, are lower than observed in 
melanoma and Hodgkin’s lymphoma. Novel strategies may be required to optimize 
efficacy of immunotherapy in MTNBC. Furthermore, co-administration of pembrolizumab 
with chemotherapy in an earlier-line setting (when functional status and immune 
competency is preserved) might enhance efficacy.  
 
Chemotherapy may induce immunogenic cell death, facilitating effective presentation of 
tumor-associated antigens to T-cells, which may in turn be primed for activation by 
concurrent administration with anti-PD-1 therapy.(Zitvogel, Apetoh et al. 2008) Several 
groups have demonstrated that the combination of chemotherapy plus checkpoint 
blockade results in synergistic regression of tumors in a TNBC murine 4T1 model and 
other models.(Lesterhuis, Salmons et al. 2013) 
 
Two of the most prescribed regimens are weekly paclitaxel and oral capecitabine. Each 
of these regimens have been associated with favorable immunomodulatory effects, and 
therefore each of these regimens has the potential for synergy with immunotherapy (table 
3.1.3-1).  
 

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Table 3.1.3-1: Immunologic effects of chemotherapeutic regimens  in metastatic TNBC 
Regimen 
Immunologic Effects 
Paclitaxel 
 T-cell activation; T-reg depletion14 
 Enhanced NK and T-cell function14 
 Myeloid derived suppressor cell (MDSC) depletion15 
Capecitabine 
 T-cell activation 
 Induction of heat-shock proteins/antigen presentation16 
 T-reg and MDSC depletion15 
 
Additionally, chemotherapy may induce inflammation and interferon gamma in the tumor 
microenvironment, which may induce adaptive expression of PD-L1 by the tumor.(Sistigu, 
Yamazaki et al. 2014, Tumeh, Harview et al. 2014)  
 
3.1.3.1 Prior Safety and Efficacy Data of combining immune modulation with 
chemotherapy in humans 
In a phase I-III clinical trials, immunologic checkpoint agents (including anti-PD-1 agents) 
have been combined safely with chemotherapy.(Robert, Thomas et al. 2011, Lynch, 
Bondarenko et al. 2012, Reck, Bondarenko et al. 2013, Weber, Hamid et al. 2013, Antonia, 
Brahmer et al. 2014) In a phase II study of ipilimumab with carboplatin plus paclitaxel in 
non-small-cell lung cancer, the phased combination of carboplatin/paclitaxel followed by 
the addition of ipilimumab, improved immune-related progression free survival compared 
to chemotherapy alone (HR 0.72, p=0.05), and toxicities were acceptable enough to 
support further study, with grade III/IV immune related toxicity rates of 15% compared to 
6% with chemotherapy alone.(Lynch, Bondarenko et al. 2012) In a similar study in small 
cell lung cancer, progression free survival was highest with chemotherapy followed by the 
addition of ipilimumab (HR=0.64, p=0.03), with similar grade III/IV immune-related toxicity 
rates of 17%, compared to 9% with chemotherapy alone.(Reck, Bondarenko et al. 2013) 
In melanoma, a phase I study of ipilimumab versus ipilimumab plus chemotherapy 
(carboplatin/paclitaxel or DTIC) demonstrated no pharmacokinetic or pharmacodynamic 
interactions.(Weber, Thompson et al. 2009) Finally, in a large phase III study of DTIC 
versus DTIC plus ipilimumab, the combination improved overall survival, however the 
combination led to greater grade III/IV adverse events compared to chemotherapy alone 
(56% versus 28%).(Robert, Thomas et al. 2011) The adverse events were similar in nature 
to ipilimumab alone, however with greater rates of elevated liver function values. 
 
Compared to ipilimumab, relatively few trials combining anti-PD-1 plus chemotherapy 
have been reported. However, a phase 1 dose de-escalation trial evaluated the safety of 
the anti-PD-1 antibody nivolumab, when combined with platinum-based doublet 
chemotherapy (gemcitabine/cisplatin or pemetrexed/cisplatin or paclitaxel/carboplatin). 
(Antonia, Brahmer et al. 2014) Chemotherapy was given for 4 cycles, and thereafter 
nivolumab was continued. Grade III/IV adverse events were reported in 45% of patients, 
however there were no DLTs reported. Encouraging one year overall survival rates of 59-
87% were reported. 
 
In summary, sufficient previous data exist to suggest that the combination of 
pembrolizumab plus chemotherapy will be safe in metastatic triple negative breast cancer 
at the standard chemotherapy dose levels. However, a pilot study is necessary to confirm 

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safety/tolerability of combining pembrolizumab to therapeutic doses of systemic 
chemotherapy.  
 
3.2 Background of therapeutic agents 
3.2.1 Pembrolizumab 
3.2.1.1 Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis 
and long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  
The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
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.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced 
in a variety of cell types, including non-hematopoietic tissues as well as in various tumors.  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor.  PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 

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ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in 
the United Stated for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilimumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. 
 
3.2.1.2 Non-Clinical Toxicology Summary of results 
In the 1-month and 6-month toxicology study in cynomolgus monkeys, pembrolizumab 
administered once a week and once every other week respectively, intravenously up 
to 200 mg/kg resulted in no adverse treatment related effects. The exposure multiple 
based on a predicted AUC 0-tau of 4464 µg/day/mL at the maximum anticipated human 
clinical dose of 10 mg/kg Q2W or Q3W is 15-fold at 200 mg/kg, the NOAEL for the 
6-month monkey study.  Additionally, in the tissue cross-reactivity study of 
pembrolizumab with human and monkey tissues demonstrated the expected on-target 
staining of the membranes of mononuclear leukocytes in both species.   Off-target 
cross-reactivity staining was also noted in both species but was limited to cytoplasm 
of various cell types/tissues and the stroma (extracellular  connective  tissue  matrix), 
and  was  considered  related  to  the experimental method artifacts, i.e. tissue 
processing for IHC, that are well recognized limitations  of  tissue  cross-reactivity  
studies  and,  thus  not  considered  toxicologically relevant. 
 
No reproductive or developmental toxicity studies are planned with pembrolizumab.  
Therefore, inclusion of women of childbearing potential in clinical trials should be in 
accordance with  the  study  protocol  and  applicable  regulatory  guidance  (e.g.,  
ICH  M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization for Pharmaceuticals). 
 
3.2.1.3 Clinical Summary of Results 
As of 18-Oct-2013, 1,000 patients have been treated with pembrolizumab at several 
dose- schedules, including 10 mg/kg every 2 weeks.  Pembrolizumab has been generally 
well tolerated, as expected based on preclinical findings and other anti-PD-1 
monoclonal antibodies.   As of 18-Oct-2013 no serious infusions reactions have been 
reported in PN001, however, since t h e  p o t e n t i a l  e x i s t s  i n  a n t i -PD-1 
m o n o c l o n a l  a n t i b o d i e s , investigators should be vigilant to this possibility. 
Less than 1% of patients thus far assayed had confirmed positive ADA samples and 
among these, no or no clear impact on exposure has been observed. There is no 
contraindication to further clinical investigation with pembrolizumab. Pharmacokinetics 
were as expected, based on pembrolizumab being an IgG mAb and based on 
preclinical data, which support dosing once every 2 or 3 weeks. pembrolizumab  
monotherapy  induces  an  ORR  of  25%/27%  in  patients  with  ipilimumab- exposed 
melanoma by central independent RECIST and oncology review/investigator 
assessed irRC, respectively.   Pembrolizumab monotherapy induces an ORR of 
39%/43% in patients with ipilimumab-naive melanoma by central independent RECIST 
and oncology review/investigator assessed irRC, respectively.  These responses are 
remarkably durable. The preliminary 1-year survival rate for patients, many of whom 
have had multiple therapies, including ipilimumab, who receive pembrolizumab is 81%.  
Pembrolizumab monotherapy induces an ORR of 21%/24% in patients with 
previously-treated NSCLC by central independent RECIST/investigator assessed irRC, 
respectively, with these responses also remarkably durable.   Preliminary data suggest 
higher levels of PD-L1 expression in tumors of NSCLC are associated with 
increased activity (ORR 67% by investigator assessed irRC/57% by central 
independent RECIST); additional data are required to define the optimal PD-L1 cut 

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point. 
   
The most commonly reported treatment emergent AEs experienced are fatigue 
(43.8%), nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhea (22.3%) and rash 
(21.5%).  Immune-related adverse events were reported in 21.4% of melanoma 
patients; most of these events (15.8%) were considered drug-related by the investigator.  
The most commonly reported, immune-related adverse events across the  dose-
schedules  are  rash  (3.2%),  pruritus  (2.9%),  vitiligo  (2.9%),  hypothyroidism (2.7%), 
arthralgia (2.2%), diarrhea (2.2%), and pneumonitis (1.9%).   Review of the overall 
benefit:risk ratio of pembrolizumab favors enrollment of eligible patients into clinical 
trials of pembrolizumab. 
    
3.2.1.4 Rationale for dose selection and schedule 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no 
dose-limiting toxicities were observed.  This first in human study of MK-3475 showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 
mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in 
Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent data from 
other clinical studies within the MK-3475 program has shown that a lower dose of MK-
3475 and a less frequent schedule may be sufficient for target engagement and clinical 
activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21 days).  This early PK and pharmacodynamic data provides scientific 
rationale for testing a Q2W and Q3W dosing schedule. 
  
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose 
regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, 
there are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 

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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. 
 
3.2.2 Chemotherapeutic regimens 
This study will evaluate the safety of pembrolizumab when combined with standard-of-
care, frequently administered chemotherapy regimens, weekly paclitaxel or oral 
capecitabine. The clinical efficacy and toxicity profiles of these two regimens are well-
described in the literature and in the Providence/Cedars-Sinai chemotherapy guidelines. 
  
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
4.1.1 Pilot phase 
This is a pilot study of pembrolizumab in combination with chemotherapy (either 
weekly paclitaxel or oral capecitabine). It will be conducted to determine the 
safety/tolerability of these combinations in subjects with metastatic or unresectable 
TNBC. The treatment arm will be determined by the treating investigator. 
 
4.1.2 Phase II expansion cohorts 
Based upon the safety/tolerability and efficacy of therapy observed in the pilot cohorts, 
the trial may expand one or more of the treatment cohorts to enroll additional patients, 
so that the anti-tumor activity and safety/tolerability of the combination may be further 
estimated. Statistical methods for evaluating efficacy, and criteria for expanding the 
cohorts, are described in detail in sections 10 and 14. 
 
4.2 
Intervention 
Eligible patients will have measurable disease by RECIST v1.1 criteria and will meet the 
criteria for triple negative breast cancer based upon biopsy assessment. A research 
biopsy must occur prior to initiation of the first dose of investigational therapy unless 
archival tissue with sufficient material is available for analysis, and as long as no 
intervening systemic therapy has been administered (1 tumor-bearing tissue block, or 18 
5-micron FFPE slides). 
 
All subjects will receive chemotherapy (as per the standardized dosing schedule described 
in section 5.0), and pembrolizumab via IV infusion at 200mg every three weeks (q3w). 
 

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Pembrolizumab will be continued q3w until progression of disease, initiation of an 
alternative cancer therapy, unacceptable toxicity, or another reason to discontinue 
treatment occur, up to 24 months. Subjects may continue to receive pembrolizumab 
beyond radiographic disease progression in the absence of clinical deterioration, and after 
discussion with the Principal Investigator. 
 
Chemotherapy will be continued as per section 5 and 9 until at least week 7, at which point 
chemotherapy may be discontinued if clinically indicated at the discretion of the treating 
investigator for reasons such as toxicity or chemotherapy intolerance. Chemotherapy 
dose/schedule modifications may be conducted in accordance with the guidelines 
described 
in 
section 
9.0. 
The 
rationale 
for 
allowing 
chemotherapy 
modification/discontinuation is to simulate real-world conditions whereby clinicians can 
tailor chemotherapy to the individual patient to optimize palliation and minimize toxicities. 
 
Patients will be evaluated by physical exam and routine blood tests every three weeks 
during the study period. Research bloods will be obtained periodically as per the schedule 
in section 10. CT CAP with or without PET or bone scan will be performed during 
screening, and then at 12 week intervals. Additional scans will be conducted if there is a 
clinical indication, for example to evaluate the etiology of a new symptom. Tumor 
measurements and determination of tumor responses will be performed according to 
RECIST 1.1, and according to immune related RECIST as a secondary endpoint. 
  
Patients who have ongoing response to pembrolizumab will discontinue after 24 months, 
but will continue clinic visits, routine blood work, and q12w imaging assessments as per 
standard-of-care. Any patient with a prior response to pembrolizumab, who discontinues 
for a reason other than toxicity/progression, may resume treatment for an additional 12 
months upon disease progression. 
 
Exploratory research studies to evaluate the effect of this therapy will be performed in 
patients using research blood draws, and tumor biopsy at baseline and week 7 +/- 1 week 
for research purposes. 
   
 
4.3 
Estimated Duration of Subject Participation 
Subjects may be treated for up to 24 months, with the option to resume treatment for an 
additional 12 months upon disease progression, unless there is another reason to 
discontinue treatment. All subjects will be followed for at least 18 weeks from the start of 
therapy to evaluate for delayed toxicities. The study will terminate after the primary 
endpoints (safety/tolerability and 13-week ORR) have been ascertained for all patients. 
Based upon the observed ORR and available resources, the committee may elect to 
prolong the study to assess for 1-year and/or and 2-year progression free survival. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
The treatments to be used in this trial is outlined below in table 5.0-1 
 
 
 
 
 
 
 
 

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Table 5.0-1: Trial Treatment 
Study 
arm 
Drug 
Dose 
Cycle 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
All 
Pembrolizumab 
200mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experiment
al 
A 
Paclitaxel 
80mg/m2 
Q3W 
IV infusion 
Day 1, 8, and 15 
of each 3 week 
cycle 
FDA 
approved 
B 
Capecitabine 
2000mg 
Q2W 
Oral 
BID, Days 1-7 of 
each 2 week cycle 
FDA 
approved 
 
Trial treatment should begin as close as possible to the date on which treatment is 
allocated/assigned. 
 
5.1 Pembrolizumab 
5.1.1 Formulation, packaging, and storage 
Drug will be provided by Merck as summarized in Table 5.1-1. Clinical supplies will be 
affixed with a clinical label in accordance with regulatory requirements. 
 
Table 5.1-1 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
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. 
 
5.1.2 Preparation 
The pharmacy manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
 
5.1.3 Administration 
Pembrolizumab will be administered as a 30 minute IV infusion. Given the variability 
of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e. infusion 
time is 30minutes -5 minutes/+10 minutes). The reason for any delay in infusion 
outside of the protocol specified window should be documented and recorded in the 
case report form (CRSs). Central venous catheters (CVCs) or vascular access devices 
(VADs) may be used to administer treatment. Pembrolizumab will be administered 
following completion of infusion of standard-of-care chemotherapy (i.e. following 
completion of paclitaxel). 
 
5.1.4 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. 
  

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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. 
 
5.1.5 
Clinical supplies disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 
and/or designee are not blinded to treatment. Drug identity (name, strength) is included 
in the label text; random code/disclosure envelopes or lists are not provided. 
 
5.2 
Weekly paclitaxel 
Paclitaxel is a taxane originally derived from the bark of the Pacific yew tree (Taxus 
Brevifolia), and is one of the most active and commonly used agents for the treatment of 
breast carcinoma. Paclitaxel binds to the dimeric tubulin preventing microtubule 
disassembly by stabilizing microtubules so that the spindle cannot be dismantled. This 
microtubule disruption halts mitosis, interferes with other critical interphase functions, and 
subsequently leads to cell death. 
  
5.2.1 
Formulation, packaging, and storage 
Paclitaxel is supplied as 30mg (5mL), 100mg (16.7mL), and 300mg (50mL) multi-use 
vials. Commercial supply for paclitaxel will be utilized for this study. Paclitaxel is a clear 
colorless to slightly yellow viscous solution. Paclitaxel is supplied as a non-aqueous 
solution intended for dilution with a suitable parenteral fluid prior to intravenous 
solution. Each mL of sterile nonpyrogenic solution contains 6mg paclitaxel, 527mg of 
purified Cremophor® EL and 49.7% of v/v dehydrated alcohol. 
 
Unopened vials of paclitaxel injection are stable until the date indicated on the package 
when stored between 20-25°C. Neither freezing nor refrigeration adversely affects the 
stability of the product. Upon refrigeration components in the paclitaxel vial may 
precipitate, but will re-dissolve upon reaching room temperature with little or no 
agitation. 
 
5.2.2 
Preparation 
Prior to infusion paclitaxel should be diluted in 0.9% sodium chloride injection or 5% 
dextrose injection or 5% dextrose and 0.9% sodium chloride, or 5% dextrose in ringers 
lactate, to a final concentration of 0.3 to 1.2 mg/mL. Paclitaxel must be prepared in 
glass, prolypropylene, or polyolefin containers and non-PVC containing (nitroglycerin) 
infusion sets. Prepared solutions are stable at room temperature (20-25°C) and 
protected light, up to 72 hours. In-line filtration with micropore no greater than 0.22 
micron filter is required. Chemo dispensing pin devices or similar devices with spikes 
should not be used with paclitaxel vials since they can cause the stopper to collapse 
resulting in loss of sterile integrity. 
 
5.2.3 
Administration 
Intravenous paclitaxel should be administered over approximately 60 minutes. 
Paclitaxel will be administered intravenously on a weekly schedule at a dose of 
80mg/m2. Doses may be modified as per section 9.0. 

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5.3 
Capecitabine  
5.3.1 
Formulation, Packaging, and Storage 
The commercial formulation will be used, as per standard-of-care. Capecitabine is a 
white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20ºC 
and is supplied as biconvex, oblong film-coated tablets for oral administration. Each 
peach-colored tablet contains either 150mg or 500 mg capecitabine. Capecitabine 
tablets will be stored at room temperature (15° to 30°C) in the container in which they 
are provided.  
 
5.3.2 
Dosage Regimen and Administration  
Commercially supplied capecitabine will be administered at total daily dose of 4,000 
mg (2,000 mg BID). The dose of capecitabine will be fixed, not calculated on the basis 
of body surface area. Capecitabine will be administered as intermittent therapy given 
on days 1-7 in 14-day cycles.  
 
Capecitabine will be taken orally. The total daily dose should be taken as two divided 
doses approximately 12 hours apart, within 30 minutes after the ingestion of food, 
ideally after breakfast and the evening meal. Tablets should be swallowed with 
approximately 200 ml of water (not fruit juices). Tablets are not scored and should not 
be split.  
 
5.3.3 
Dispensing and Accountability of Medication  
 
Commercially supplied drug will be dispensed by the patient’s pharmacy as per the 
standard-of-care. The patient will also have the option to keep a diary or calendar to 
document each dose of capecitabine taken while on study. Doses may be modified as 
per section 9.0. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
 
Be willing and able to provide written informed consent/assent for the trial. 
 
Be  18 years of age on day of signing informed consent. 
 
HER2-negative breast cancer (defined by IHC 0-1 (or) IHC 2 and ISH 
HER2/CEP17<2.0); 
 
ER and PR-negative breast cancer (defined by IHC<1%); 
 
Measurable metastatic or unresectable disease based on RECIST 1.1. 
 
Indicated for treatment with either weekly paclitaxel or oral capecitabine, as first or 
second-line chemotherapy in the metastatic/unresectable setting (as determined by 
the consenting investigator); 
 
Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor 
lesion. Newly-obtained is defined as a specimen obtained during screening. Archival 
tissue is acceptable if no intervening anti-neoplastic therapy has been administered, 
and if sufficient material is available for analysis (see section 8.0 for requirements); 

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 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
Demonstrate adequate organ function as defined in  
 
Table 1, all screening labs should be performed within 10 days of treatment initiation.   
Table 1  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 without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤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 OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels 
> 1.5 ULN 
Except subjects with Gilbert’s Syndrome, who will be allowed in consultation with the 
Principal Investigator 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤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 if using in place of serum 
creatinine. 
 

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 
Female subjects of childbearing potential must 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. 
 
Female subjects of childbearing potential must avoid becoming pregnant while on 
treatment. Men must avoid fathering a child while on treatment. This exclusion is 
required due to the toxicities that chemotherapy and anti-PD-1 antibody may have on 
the forming fetus, spermatogenesis, or the nursing child. Also, because pregnancy 
may alter immune function, it may limit treatment efficacy.  
6.2 
Subject Exclusion Criteria 
 
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. 
 
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 (inhaled steroids are permitted). 
 
Has a known history of active TB   (Bacillus Tuberculosis) 
 
Hypersensitivity to pembrolizumab or any of its excipients. 
 
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study, 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. Denosumab is allowed. 
 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. Note:  Subjects 
with ≤ Grade 2 neuropathy and alopecia are an exception to this criterion and may 
qualify for the study. 
 
Has received the assigned chemotherapy regimen previously in the metastatic setting, 
or has received the assigned chemotherapy regimen previously in the (neo)adjuvant 
setting within 12 months of consent; 
 
If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
 
Has a known additional malignancy that progressed or required active treatment in the 
last 5 years (history of synchronous breast cancer is allowed at the discretion of the 
principal investigator). 
 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability. 
 
Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 

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immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment. 
 
Has history of/active pneumonitis requiring treatment with steroids or history of/active 
interstitial lung disease. 
 
Has an active infection requiring systemic therapy. 
 
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. 
 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
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. 
 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or has 
participated in a Merck-sponsored pembrolizumab study. 
 
Has a known history of Human Immunodeficiency Virus (HIV). 
 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
Has received a live vaccine within 30 days of planned start of study therapy. Note:  
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 
7.0 
RECRUITMENT PLAN 
This study will be available to all patients seen at Cedars-Sinai Medical Center (Los Angeles, 
California), Providence Portland Medical Center, and Providence St. Vincent Medical Center 
(Portland, Oregon), who meet the eligibility criteria outlined in section 6.0.   
Both Cedars-Sinai and Providence Cancer Center are referral centers for MTNBC. The inclusion 
of two referral sites was intended to hasten accrual while preserving the unique ability of these 
institutions to conduct extensive immunological monitoring of patients enrolled on study. Drs. 
Heather McArthur and David Page are longstanding collaborators, and will facilitate accrual across 
the two sites, respectively. Both Cedars-Sinai and Providence Medical Center are equipped with 
the necessary laboratory infrastructure (i.e. the Cedar-Sinai Immune Monitoring Facility and the 
Providence Health Immune Monitoring Unit) to conduct the immune monitoring exploratory studies 
described in section 12.0. 
 
The investigators take due notice of the NIH policy concerning inclusion of women and minorities 
in clinical research populations.  There will be no limitation to access with regard to race or gender.  
Patients will be required to read, agree to, and sign an IRB-approved informed consent form prior 
to registration on this trial. The registration procedure will be conducted as described in section 
15.0. Patients will not receive payment for their participation on this study. 
 
8.0 
PRETREATMENT EVALUATION 
To be completed within 28 days of starting pembrolizumab: 

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 
Those wishing to enroll in the study will sign a written informed consent prior to initiating 
any protocol specific evaluations or procedures. Signing of the Informed Consent Form 
can occur outside the 28-day screening period. All screening evaluations must be 
completed and reviewed to confirm that patients meet all eligibility criteria before 
treatment. Results of standard-of-care tests or examinations performed prior to obtaining 
informed consent and within 28 days prior to treatment may be used for screening 
assessments rather than repeating such tests. 
 
CT scan with contrast (chest, abdomen and pelvis). If patient is unable to receive CT 
contrast, or the abdominal/pelvic target lesion is indeterminate on CT scan, then MRI with 
contrast (abdomen and pelvis) plus CT chest without contrast may be performed. Non-
contrast CT CAP may be used if the target lesion(s) do not require contrast for accurate 
measurements. 
 
12-lead Electrocardiogram (EKG) 
 
History and physical examination, including height, weight, vital signs (temperature, pulse 
rate, respiration rate, blood pressure), and performance status (ECOG); 
 
Serum pregnancy test for all women of childbearing potential. If the test result is positive 
related to pregnancy, the patient will not be allowed to participate in this study. Note that 
urine or serum pregnancy test for all women of childbearing potential must be obtained 
within 72 hours of first dose. If the test result is positive related to pregnancy, the patient 
will not be allowed to participate in this study. 
 
CBC with differential and platelet count, serum chemistries (Na, Cl, BUN, Creatinine, K, 
CO2, and glucose), LFTs (AST, ALT, alkaline phosphatase, total bilirubin), calcium, 
albumin, total protein, lactate dehydrogenase, phosphorus, magnesium, uric acid, 
PT/INR/aPTT; T3, FT4 and TSH. 
 
Serology for HepBsAg, HepBcAb and hepatitis C antibody (negative test acceptable prior 
to screening period); 
 
Urinalysis 
 
Blood test for research purposes 
 
Perform baseline tumor biopsy for research purposes. Achival biopsy tissue may be used 
if sufficient tissue is available (at least 1 FFPE-preserved core containing tumor, or 18 
unstained FFPE 5-micron slides), and if no anti-neoplastic therapies administered 
between the biopsy and start of pembrolizumab. 
 
9.0 
TREATMENT / INTERVENTION PLAN 
The first day of dosing is considered Day 1. Subjects will receive pembrolizumab as an 
IV infusion, as well as chemotherapy according to the dosing and route described on table 5.0-1. 
Refer to ‘MK-3475 Drug Preparation Instructions’ manual. 
 
Investigational drug dosing should be administered on Day 1 of each cycle. Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons.  
 
Pembrolizumab will be administered as a 30 minute IV infusion (every effort should be made to 
target infusion timing to be as close to 30 minutes as possible.  However, given the variability of 
infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion 
time is 30 minutes: -5 min/+10 min). 
 
9.1 Monitoring of Dose Administration  
Subjects will be monitored during and after infusion with assessment of vital signs per 
institutional practice. 

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In the event of an infusion-related reaction, refer to section 9.7.8 for guidance. 
  
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, 
and study personnel must be trained to recognize and treat anaphylaxis. The study site must 
have immediate access to emergency resuscitation teams and equipment in addition to the 
ability to admit subjects to an intensive care unit if necessary. 
 
9.2 Concomitant Medications 
9.2.1 Permitted Concomitant Medication 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in Section 9.3.2. 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial, with the exception of steroids which are discussed in section 
9.3.1.1. If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy may be required. 
The investigator should discuss any questions regarding this with the Merck Clinical team. 
The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician.  
 
9.2.1.1 Concomitant Steroids for patients enrolled in the paclitaxel arm 
Paclitaxel 
Patients treated with paclitaxel are at risk for allergic reactions as a result the 
Cremophor diluent. The standard-of-care is to pre-medicate with steroids 
(dexamethasone 10mg IV) 30 minutes before infusion to reduce the risk of allergic 
reaction. Steroid use to prevent infusion reaction will be permitted at the discretion of 
the treating investigator. However to minimize immunosuppression associated with 
steroids, we advise discontinuing or tapering steroids after the second administration 
of paclitaxel in patients who experience no signs or symptoms suggestive of infusion 
reaction.  
 
9.2.2 Excluded Concomitant Medications 
Subjects must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator. 
 
The following medications are considered exclusionary during the study. The Principal 
Investigator must be notified if a subject receives any of these during the study. 
 
 
Any investigational anticancer therapy. 
 
Any concurrent chemotherapy (except as per study), immunotherapy, or biologic 
therapy. 
Note: 
concurrent 
use 
of 
bone-directed 
therapies 
(such 
as 
bisphosphonates or denosumab) are permitted; 
 
Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for 
diabetes and hormone replacement therapy) is acceptable.  
 
Immunosuppressive medications including, but not limited to systemic 
corticosteroids (>10 mg/day prednisone or equivalent, aside from described in 
9.3.1.1), methotrexate, azathioprine, and tumor necrosis factor alpha (TNF-α) 

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blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs, in subjects with contrast allergies is 
acceptable. In addition, use of inhaled and intranasal corticosteroids is permitted. 
 
9.3 Dose Modifications or Scheduling Delays 
9.3.1 Pembrolizumab Dose Modifications  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology.  These adverse events may occur shortly after 
the first dose or several months after the last dose of treatment. 
 
Pembrolizumab dose modifications will not be allowed. However, pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per Table 9.3.1-
1 below. See Section 5.6.1 and Events of Clinical Interest Guidance Document for 
supportive care guidelines, including use of corticosteroids to treat immune related AEs. 
 

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Table 9.3.1-1: Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 
Pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 
0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks 
of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-
related AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs and 
symptoms of pneumonitis 
 
Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment 
 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 
2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (ie, peritoneal signs and 
ileus). 
 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy 
to rule out colitis.  
 
Participants with diarrhea/colitis should 
be advised to drink liberal quantities of 
clear fluids.  If sufficient oral fluid intake 
is not feasible, fluid and electrolytes 
should be substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 

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AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
 
Monitor with liver function tests 
(consider weekly or more frequently until 
liver enzyme value returned to baseline 
or is stable 
Grade 3 or 4  
Permanently 
discontinue 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure 
Withhold 
 Initiate insulin replacement 
therapy for participants with 
T1DM  
 Administer anti-hyperglycemic 
in participants with 
hyperglycemia  
 
 
Monitor participants for hyperglycemia 
or other signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.   
 
 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidis
m  
Grade 2 
Continue  
 Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of 
care 
 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
 Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
 Based on severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 

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Grade 3 or 4 
Permanently 
discontinue 
 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 
2 
Withhold 
 Based on type and severity of 
AE administer corticosteroids  
 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may 
be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case 
of T1DM).   
 
 
 

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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 on a steroid 
taper (<12 weeks), or otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
 
9.3.2 Resynchronization of Pembrolizumab with chemotherapy following 
scheduling delay 
Treatment cycles will be defined by pembrolizumab dosing, with pembrolizumab 
being administered on day 1 of each cycle. In the setting of a delay in 
pembrolizumab dosing, an every-three week dosing interval should be re-
established upon resuming pembrolizumab.  
 
9.3.3 Chemotherapy dose modifications 
Subjects will be monitored for adverse events while receiving chemotherapy. Dose 
interruptions or reductions may be required, and are permitted. Chemotherapy 
dose modifications must be determined according to standard practice, with clinical 
determination guiding whether dose modification is necessary. Dose reductions 
should abide by the options delineated in table 9.3.4-2, but do not necessarily have 
to occur in the listed sequence. However, dose reductions should be permanent 
and should not be re-escalated. 
 
Table 9.3.3-2: Dose Modifications of Chemotherapeutic Agents 
 
Paclitaxel 
Capecitabine 
Baseline dose 
80mg/m2 
d 1,8,15 (q3w) 
2000mg BID 
(7d on, 7d off) 
Dose reduction 
option 1 
80mg/m2 
d 1,8 (q3w) 
1500mg BID 
(7d on, 7d off) 
Dose reduction 
option 2 
70mg/m2 
d,1,8 (q3w) 
1300mg BID 
(7d on, 7d off) 
Dose reduction 
option 3 
60mg/m2 
d,1,8 (q3w) 
1150mg BID 
(7d on, 7d off) 
Dose reduction 
option 4 
50mg/m2 
d,1,8 (q3w) 
1000mg BID 
(7d on, 7d off) 
Dose reduction 
option 5 
Discontinue 
Discontinue 
 
In addition to the recommended dose modifications, chemotherapy can also be 
interrupted. Any subject who requires dose de-escalation beyond the 
recommended guidelines, or requires sustained interruption of chemotherapy for 
greater than 20 days, should either be discontinued from study (or) should 
permanently discontinue the chemotherapy. Subjects discontinued from 
chemotherapy treatment may optionally remain on the study and receive treatment 
with pembrolizumab monotherapy. Such patients will be included in determining 
clinical responses. 
 
9.3.5 Special considerations for overlapping toxicities  

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Some toxicities, such as elevated LFTs, diarrhea, cytopenias, or rash, may be 
attributable to either chemotherapy or pembrolizumab. In these cases, both 
chemotherapy and pembrolizumab should be withheld as per the above defined 
criteria, with consideration of dose modification of the chemotherapy backbone 
upon resumption of therapy. 
  
9.4 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 9.6. 
 
9.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year 
of additional pembrolizumab therapy if they progress after stopping study treatment. 
This retreatment is termed the Second Course Phase of this study and is only available 
if the study remains open and the subject meets the following conditions: 
 
Either: 
o Stopped initial treatment with pembrolizumab after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, and 
o Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy, and 
o Received at least two treatments with pembrolizumab beyond the date 
when the initial CR was declared 
 
Or: 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months 
of study therapy for reasons other than disease progression or intolerability, 
and 
o Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their initial treatment with pembrolizumab, and 
o Did not receive any anti-cancer treatment since the last dose of 
pembrolizumab aside from the assigned chemotherapy backbone, and 
o Has a performance status of 0 or 1 on the ECOG Performance Scale, and 
o Demonstrates adequate organ function as detailed in inclusion criteria, and 
o Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might 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, and 
o Meets the following criteria regarding childbearing potential: 
 
Female subjects of childbearing potential must avoid becoming 
pregnant while on treatment. 
 
Male subjects must avoid fathering a child while on treatment. 
 
This exclusion is required due to the toxicities that chemotherapy and 
anti-PD-1 antibody may have on the forming fetus, spermatogenesis, 

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or the nursing child. Also, because pregnancy may alter immune 
function, it may limit treatment efficacy.  
 
Subjects who restart treatment will be retreated at the same dose and dose interval as 
when they last received pembrolizumab. Treatment will be administered for up to one 
additional year. Visit requirements are outlined in the schedule of assessments.  
 
9.6 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 and in greater 
detail in the ECI guidance document. 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 
is instructed to follow the ECI reporting guidance but does not need to follow the 
treatment guidance (as outlined in the ECI guidance document). Refer to Section 9 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. Suggested 
conditional procedures, as appropriate, can be found in the ECI guidance document. 
 
9.6.1 Management of 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. 
 
9.6.2 Management of Diarrhea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).   
 
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. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  

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o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids. 
   
9.6.3 When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  Management of Type 1 
diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
9.6.4 Management of 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. 
 
9.6.5 Management of 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. 
 
o Grade 2 hyperthyroidism events (and Grade 1-4 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. 
 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
9.6.6 Management of Hepatic toxicities 
 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  

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o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
9.7.7 Management of Renal Failure or Nephritis 
 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
9.7.8 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 9.7.8-1:  shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 9.7.8-1: Pembrolizumab 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 pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDS 
No subsequent dosing 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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 
 
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. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
 
9.7.9 Management of Nausea/vomiting 
Nausea and vomiting should be treated aggressively, and consideration should be given 
in subsequent cycles to the administration of prophylactic antiemetic therapy according to 
standard institutional practice.  Subjects should be strongly encouraged to maintain liberal 
oral fluid intake. 
 
9.7.10 Use of anti-infectives 
Subjects with a documented infectious complication should receive oral or IV antibiotics 
or other anti-infective agents as considered appropriate by the treating investigator for a 
given infectious condition, according to standard institutional practice. 
9.8 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea or vomiting. 
 
9.9 
Use in subjects with childbearing potential 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab has transient adverse effects on the composition of 
sperm. 
Non-pregnant, non-breast-feeding women may be enrolled if they avoid becoming 
pregnant while on treatment. Men must avoid fathering a child while on treatment. 
9.10 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed 
or terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., 
death, abortion, congenital anomaly, or other disabling or life-threatening complication to 
the mother or newborn).  The study investigator will make every effort to obtain permission 
to follow the outcome of the pregnancy and report the condition of the fetus or newborn to 
the Sponsor.   If a male subject impregnates his female partner the study personnel at the 

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site must be informed immediately and the pregnancy reported to the Sponsor and to 
Merck and followed as described above and in Section 11.1.2. 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment and should 
be removed from study immediately. 
9.11 Subject replacement strategy 
Subjects will be treated on protocol on a modified intention to treat analysis, whereby the 
following subjects will be excluded from efficacy analysis and replaced with a newly-
enrolled subject: 
 
subjects who fail to receive at least part of 1 dose of therapy; 
 
subjects who withdraw consent prior to week 13 and/or are lost to follow-up, 
precluding assessment of efficacy at week 13. 
Subjects who clinically progress prior to week 13 and discontinue therapy will be included 
as treatment failures in the determination of ORR. 
It may be possible that a subject is evaluable for safety/tolerability but not evaluable for 
efficacy. For example, a subject that withdraws consent and is lost to follow up at week 8 
would be eligible for safety/tolerability (since they received 6 weeks of therapy), but not 
efficacy (which is determined at week 13). Such subjects will be replaced with an additional 
subject, however they will be still included in the determination of safety/tolerability. 
Therefore, more than 14 subjects may be evaluable for safety/tolerability in each arm of 
the pilot phase. 
Conversely, subjects may be evaluable for efficacy but not safety/tolerability. For example, 
if a subject clinically progresses at week 4 and withdraws consent, this subject would not 
be included in the determination of safety/tolerability, but would be included in the 
determination of efficacy as a treatment failure. A strict cutoff of 60% of patients will be 
used as the threshold for determining safety/tolerability (i.e. at least, 8 of 13=61.5%, or 9 
of 14=64.3%, or 9 of 15=60%, etc.).  
9.12  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 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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10.0 EVALUATION DURING TREATMENT/INTERVENTION 
The following tables summarize the required evaluation and interventions for each of the therapeutic arms.   
Table 10-1: Schedule of Interventions/Assessments for Weekly Paclitaxel Arm 
 
Trial Period 
 
Treatment Cycles 
End
Of 
Treatment 
Post Treatment 
Treatment Cycle 
Screen 
Visit 1 
Cycles 1-4 
Cycle 5-6 
Cycles 7+ 
Repeating 
Discon 
Safety 
Follow-up 
Follow-up 
Survival 
Follow-up 
Treatment Week 
 
1, 4, 
7, 10 
2, 5, 
8, 11 
3, 
6, 
9, 
12 
13, 
16 
14, 
17 
15, 
18 
19 
2
0 
21 
 
 
 
 
Scheduling Window (Days) 
-28 to -1 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+
3 
 
At time of 
Discon 
30 Days post 
discon 
Every 12 weeks 
+/- 1 week 
Every 12 weeks 
+/- 1 week 
Treatment Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Paclitaxel 
 
X (10) 
 
 
 
 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inc / Exc Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Review 
X 
X 
X (1) 
 
X 
 
 
X 
 
 
X 
X 
 
 
Post-study therapy 
 
 
 
 
 
 
 
 
 
 
 
 
X (9) 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures / 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X (1) 
 
X 
 
 
X 
 
 
X 
 
 
 
Full Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Exam 
 
X 
X (1) 
 
X 
 
 
X 
 
 
X 
X 
X (9) 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs and Weight 
X 
X 
X (1) 
 
X 
 
 
X 
 
 
X 
X 
X (9) 
 
ECOG Performance status 
X 
X 
X (1) 
 
X 
 
 
X 
 
 
X 
X 
X (9) 
 
Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Trial Period 
 
Treatment Cycles 
End
Of 
Treatment 
Post Treatment 
Treatment Cycle 
Screen 
Visit 1 
Cycles 1-4 
Cycle 5-6 
Cycles 7+ 
Repeating 
Discon 
Safety 
Follow-up 
Follow-up 
Survival 
Follow-up 
Treatment Week 
 
1, 4, 
7, 10 
2, 5, 
8, 11 
3, 
6, 
9, 
12 
13, 
16 
14, 
17 
15, 
18 
19 
2
0 
21 
 
 
 
 
Scheduling Window (Days) 
-28 to -1 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+
3 
 
At time of 
Discon 
30 Days post 
discon 
Every 12 weeks 
+/- 1 week 
Every 12 weeks 
+/- 1 week 
Pregnancy Test – Urine or 
Serum B-HCG 
X (11) 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X (11) 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/ Diff 
X (11) 
X (12) 
X (1) 
 
X 
 
 
X 
 
 
 
 
 
 
HepBsAg, HepBcAB, Hep C 
antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
X (11) 
X (12) 
X (1) 
 
X 
 
 
X 
 
 
 
 
 
 
Urinalysis 
X (11) 
 
 
 
X(13)
 
 
X(13) 
 
 
 
 
 
 
T3, FT4, and TSH 
X (11) 
X (6) 
 
 
X (6) 
 
 
 
 
 
 
 
 
 
Tumor Markers (CEA, CA15-
3) 
 
X (7) 
 
 
X (7) 
 
 
X (7) 
 
 
 
 
 
 
Efficacy Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging – CT CAP or 
MRI 
X 
 
 
 
X (3) 
 
 
X (4,5) 
 
 
 
 
X (9) 
 
Correlative Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival or Fresh Tissue 
Collection 
X 
X (8) 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw 
X 
X 
X (1) 
 
X (2) 
 
 
 
 
 
 
 
 
 
 
1. 
Only during cycle 1 (week 2) 
2. 
Correlative Studies Blood collection terminates following week 13. One additional blood draw is allowed for characterization of interesting 
clinical/immunologic scenarios 
3. 
Imaging assessment to occur on week 13 +/- 1 week 
4. 
Every 12 week imaging to be conducted in patients with ongoing clinical benefit 
5. 
Additional imaging will be optional and will be conducted as per standard-of-care, for example to re-assess equivocal response or to assess new 
symptoms 
6. 
Thyroid function tests to be obtained on week 7 and week 13 
7. 
Tumor markers should be obtained on cycle 1, and every other cycle thereafter, in all subjects who have a history of elevated tumor markers. 
8. 
Post-treatment biopsy to occur on week 7 +/- 1 week 

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9. 
Patients who discontinue therapy without progression will be followed every 12 weeks, for consideration of re-treatment if eligible. If no longer eligible for 
re-treatment, patient will enter survival follow-up 
10. Ongoing treatment with paclitaxel following week 7 assessment is at the discretion of the treating investigator. Pembrolizumab can be given as 
monotherapy following week 7 
11. Pregnancy test must be within 72 hours of dose 1 of pembrolizumab; laboratory tests must be within 10 days of dose 1. Results of standard-of-care tests 
or examinations performed prior to informed consent and within 28 days prior to study entry are acceptable (except where otherwise specified) 
12. cycle 1 CBC and comprehensive serum chemistry (LDH, Uric Acid, Phos, Mg) do not need to be repeated at dose one if obtained within 7 days 
13. Urinalysis with microscopic if indicated weeks 13 and 19 and every 12 weeks thereafter while receiving active treatment 
 
 

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Table 10-2: Schedule of Interventions/Assessments for Capecitabine 
Trial Period 
 
Treatment Cycles 
End 
Of 
Treatment 
Post Treatment 
Treatment Cycle 
Screen 
Visit 1 
Cycles 1-4 
Cycle 5-6 
Cycles 7+ 
Repeating 
Discon 
Safety 
Follow-up 
Follow-up 
Survival 
Treatment Week 
 
1, 
4,  
7, 
10 
2, 
5,  
8, 
11 
3, 
6,  
9, 
12 
13, 
16 
14, 
17,  
15,18 
19 
20 
21 
 
 
 
 
Scheduling Window 
(Days) 
-28 to -
1 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
 
At time of 
Discon 
30 Days 
post discon 
Every 12 
weeks +/- 1 
week 
Every 12 weeks 
+/- 1 week 
Treatment Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Capecitabine 
 
X(10,11) 
 
 
 
 
 
 
 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inc / Exc Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics / Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Review 
X 
X 
X(1) 
 
X 
 
X 
 
 
X 
X 
 
 
Post-study therapy 
 
 
 
 
 
 
 
 
 
 
 
X(9) 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures / 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X(1) 
 
X 
 
X 
 
 
X 
 
 
 
Full Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Exam 
 
X 
X(1) 
 
X 
 
X 
 
 
X 
X 
X(9) 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs and Weight 
X 
X 
X(1) 
 
X 
 
X 
 
 
X 
X 
X(9) 
 
ECOG Performance status 
X 
X 
X(1) 
 
X 
 
X 
 
 
X 
X 
X(9) 
 
Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test – Urine or 
Serum B-HCG 
X(11) 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X(11) 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/ Diff 
X(11, 12) 
X 
X(1) 
 
X 
 
X 
 
 
 
 
 
 
HepBsAg, HepBcAB, Hep 
C antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
X(11, 12) 
X 
X(1) 
 
X 
 
X 
 
 
 
 
 
 
Urinalysis 
X(11) 
 
 
 
X(13)
 
X(13)
 
 
 
 
 
 
T3, FT4, and TSH 
X(11) 
X(6) 
 
 
X(6) 
 
 
 
 
 
 
 
 

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Trial Period 
 
Treatment Cycles 
End 
Of 
Treatment 
Post Treatment 
Treatment Cycle 
Screen 
Visit 1 
Cycles 1-4 
Cycle 5-6 
Cycles 7+ 
Repeating 
Discon 
Safety 
Follow-up 
Follow-up 
Survival 
Treatment Week 
 
1, 
4,  
7, 
10 
2, 
5,  
8, 
11 
3, 
6,  
9, 
12 
13, 
16 
14, 
17,  
15,18 
19 
20 
21 
 
 
 
 
Scheduling Window 
(Days) 
-28 to -
1 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
 
At time of 
Discon 
30 Days 
post discon 
Every 12 
weeks +/- 1 
week 
Every 12 weeks 
+/- 1 week 
Tumor Markers (CEA, 
CA15-3) 
 
X(7) 
 
 
X(7) 
 
X(7) 
 
 
 
 
 
 
Efficacy Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging – CT CAP 
or MRI 
X 
 
 
 
X(3) 
 
X(4,5) 
 
 
 
 
X(9) 
 
Correlative Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival or Fresh Tissue 
Collection 
X 
X(8) 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw 
X 
X 
X(1) 
 
X(2) 
 
 
 
 
 
 
 
 
1. 
Only during cycle 1 (week 2) 
2. 
Correlative Studies Blood collection terminates following week 13. One additional blood draw is allowed for characterization of interesting 
clinical/immunologic scenarios 
3. 
Imaging assessment to occur on week 13 +/- 1 week 
4. 
q12 week imaging to be conducted in patients with ongoing clinical benefit 
5. 
Additional imaging will be optional and will be conducted as per standard-of-care, for example to re-assess equivocal response or to assess new symptoms 
6. 
thyroid function tests to be obtained on week 7 and week 13 
7. 
tumor markers should be obtained on cycle 1, and every other cycle thereafter, in all subjects who have a history of elevated tumor markers. 
8. 
post-treatment biopsy to occur on week 7 +/- 1 week 
9. 
patients who discontinue therapy without progression will be followed every 12 weeks, for consideration of re-treatment if eligible. If no longer eligible for 
re-treatment, patient will enter survival follow-up 
10. ongoing treatment with capecitabine following week 7 assessment is at the discretion of the treating investigator. Pembrolizumab can be given as 
monotherapy following week 7 
11. pregnancy test must be within 72 hours of dose 1 of pembrolizumab; laboratory tests must be within 10 days of dose 1. Results of standard-of-care tests 
or examinations performed prior to informed consent and within 28 days prior to study entry are acceptable (except where otherwise specified) 
12. cycle 1 CBC and comprehensive serum chemistry (LDH, Uric Acid, Phos, Mg) do not need to be repeated at dose one if obtained within 7 days 
13. Urinalysis with microscopic if indicated weeks 13 and 19 and every 12 weeks thereafter while receiving active treatment 
 
 

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10.1 Detailed explanation of required evaluations and interventions 
Individual 
trial 
procedures 
are 
described 
in 
detail 
below. 
In 
addition 
to 
evaluations/interventions illustrated in tables 10-1 and 10-2, 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 
and/or Merck 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. 
 
10.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
Consent must be documented by the 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, or as 
determined by the IRB. 
 
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 requirements. 
 
10.1.2 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.  
 
10.1.3 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.  
  

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10.1.4 Prior and Concomitant Medications Review 
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.  
 
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. 
10.1.5 Disease Details and Treatments 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding 
disease status.  
 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
10.1.6 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, it is 
advised that the 30 day Safety Follow-up visit 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.  
10.1.7 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 schedule of assessments 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 
11.2).  Toxicities will be characterized in terms regarding seriousness, causality, toxicity 
grading, and action taken with regard to trial treatment.  
 
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab 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).   
 
Please refer to section 11.2 for detailed information regarding the assessment and 
recording of AEs.  
  
10.1.8 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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10.1.9 Directed Physical Exam 
For cycles that do not require a full physical exam per the schedule of assessments, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration. 
   
10.1.10 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of pembrolizumab treatment and at treatment discontinuation. 
Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure.  
Height will be measured at screening only. 
10.1.11 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at 
screening, prior to the administration of each dose of pembrolizumab and discontinuation 
of trial treatment.  
  
10.1.12 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this 
trial are provided below Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis) are specified in Table 10.1.12-1   
 

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Table 10.1.12-1:  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) 
Protein 
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 
results are noted 
Free thyroxine (FT4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
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.   
 
 

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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 3 days  prior to dosing.  Results must be 
reviewed by the investigator or qualified designee and found to be acceptable prior to each 
dose of pembrolizumab.  
 
10.1.14 RESEARCH BLOOD AND BIOPSY SPECIMENS 
10.1.14.1 Research blood 
For all patients, blood specimens will be obtained for research purposes during screening, 
on day 1, on day 8, then at weeks 4, 7, 10, and 13 (± 3 days).  An additional blood draw 
beyond week 13 is permitted based upon interesting clinical/immunological findings. 
 
Specimens should be collected prior to drug administration. One tube of blood (5cc) is to 
be collected in a cyto-chex BCT tube, and four 10cc tubes of blood are to be collected in 
sodium heparin tubes. Peripheral blood mononuclear cells and plasma/serum will then be 
isolated per institutional practice at immune monitoring facilities.  The cyto-chex BCT tube 
is shipped same day overnight Monday-Wednesday for processing at the Providence 
Immune monitoring unit. 
 
10.1.14.2 Research biopsy 
A pre-treatment tumor biopsy will be obtained during screening prior to initiation of 
pembrolizumab. Alternatively, archived tissue may be submitted for analysis if sufficient 
material is available (at least one tumor bearing FFPE core, or at least 18 5-micron FFPE 
slides) and if no intervening anti-neoplastic therapies were administered between the time 
of biopsy and initiation of study therapy. Fresh biopsy is preferred to archived biopsy if 
feasible. An on-treatment biopsy, from the same lesion biopsied during screening/prior to 
pembrolizumab if possible, will be obtained at week 7 (± 1 wk). 
 
Patients will be permitted to continue enrollment and treatment on protocol in the event 
that insufficient material was obtained from the biopsy. The on-treatment biopsy will not 
be required if this is no longer considered appropriate at the time of the planned procedure, 
for example, if tumor is no longer accessible or the procedure is deemed to be unsafe. 
Tumor lesions planned for on-treatment biopsy may be an index lesion if  2 cm in at least 
one diameter.  
If clinically practical, subjects will undergo up to 5 core biopsies.  Core biopsies will be 
placed in formalin and processed for FFPE. All tissue obtained during biopsy procedures 
will be batch shipped to the Providence Regional Laboratories Department of Pathology 
for analysis under this study as indicated in the lab/path manual. 
 
10.1.14.3 Tumor Imaging Assessments 
The preferred imaging modality is CT chest/abdomen/pelvis with intravenous contrast, 
which will be obtained as per the schedule of assessments. If patient is unable to receive 
CT contrast or the abdominal/ pelvic target lesion is indeterminate on CT, then MRI with 
contrast (abdomen and pelvis) plus CT without contrast (chest) may be performed. 
 
10.1.15 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 

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followed in accordance with the safety requirements outlined in the schedule of 
assessments.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they 
meet the criteria specified in Sections 9.4 and 9.5.  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. 
 
10.1.16 Visit Requirements 
Visit requirements are outlined in the schedule of assessments, and described below. 
10.1.16.1 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, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-
cancer treatment should also be followed and recorded.  Subjects who are eligible for 
retreatment with pembrolizumab may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
 
10.1.16.2 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (84 ± 7 days) by 
radiologic imaging to monitor disease status. 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 or if the subject begins retreatment with 
pembrolizumab as detailed in Sections 9.4 and 9.5.  Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated. 
 
Subjects who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Sections 9.4 and 9.5 will move from the follow-up phase to the Second Course 
Phase when they experience disease progression.  
 
10.1.16.3 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 assessed for 
survival every 12 weeks until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
  
11.0 
TOXICITIES/SIDE EFFECTS 
11.1 Summary of toxicities of investigational agents 
11.1.1 Weekly paclitaxel 
Paclitaxel is an FDA-approved agent on formulary for the treatment of metastatic TNBC. 
A comprehensive list of toxicities may be found in the Lexicomp chemotherapy guidelines. 
Principal side effects are listed in table 11.1.1-1. 
 
 
 

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Table 11.1.1-1: Principal side effects of paclitaxel 
Hematologic 
Neutropenia, leukopenia, thrombocytopenia, anemia 
Gastrointestinal 
Nausea/vomiting, diarrhea, mucositis 
Cardiac 
Heart block, bradycardia 
Neurologic 
Peripheral neuropathy, arthralgia/myalgia 
Dermatologic 
Alopecia, onycholysis 
Miscellaneous 
Moderate - severe  hypersensitivity reactions, flushing, rash, dyspnea, 
fatigue, radiation sensitizer 
 
11.1.2 Oral Capecitabine 
Oral capecitabine is an FDA-approved agent on formulary for the treatment of metastatic 
TNBC. A comprehensive list of toxicities may be found in the Lexicomp chemotherapy 
guidelines. Principal side effects of capecitabine are listed in table 11.1.2-1. 
 
Table 11.1.2-1: Principal side effects of capecitabine 
Hematological 
Neutropenia, anemia, and thrombocytopenia 
Gastrointestinal 
Diarrhea, mucositis, abdominal pain, nausea, vomiting, dyspepsia 
Hepatic 
Hyperbilirubinemia, elevated transaminases 
Neurologic 
Paresthesias  
Cardiovascular 
Increased risk of myocardial ischemia (in patients with history of ischemic heart 
disease) 
Dermatologic 
Hand-foot syndrome 
Miscellaneous 
Fatigue, myalgias, blepharitis 
 
11.1.3 Pembrolizumab 
Pembrolizumab is an FDA-approved agent on formulary for the treatment of metastatic 
melanoma. It is investigational for use in metastatic TNBC. A comprehensive list of 
toxicities may be found in Lexicomp and in the investigator’s brochure. Principal side 
effects of pembrolizumab are listed in table 11.1.5-1. 
 
Table 11.1.3-1: Principal side effects of pembrolizumab 
Cardiovascular 
Peripheral edema 
Central Nervous 
System 
Fatigue, headache, chills, insomnia, dizziness, optic neuritis (rare), uveitis (rare) 
Endocrine 
Hyperglycemia, hyponatremia, hypoalbuminemia, hypertriglyceridemia, 
hypocalcemia, adrenal insufficiency (rare), hypophysitis (rare) 
GI 
Nausea, decreased appetite, constipation, diarrhea, vomiting, abdominal pain, 
pancreatitis (rare), increased serum AST, hepatitis (rare) 
Heme 
Anemia, hemolytic anemia (rare) 
Neurological/Muscular Arthralgias, limb pain, myalgia, back pain, arthritis (rare), Lambert-Eaton syndrome 
(rare), myositis (rare), partial epilepsy (rare), rhabdomyolysis (rare),  
Respiratory 
Cough, dyspnea, upper respiratory tract infection 
Miscellaneous 
Fever 
Derm 
Exfoliative dermatitis (rare) 
Renal 
Interstitial nephritis (rare), nephritis (rare), 
11.2 Assessing and Recording Adverse Events 

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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 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 within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure. 
 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
 
All adverse events will be recorded from the time the consent form is signed through 30 
days following cessation of treatment and 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 11.5.1. 
 
11.3 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and 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 pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 

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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 Sponsor (via email at OREACRISAEreporting@providence.org)  and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-
1220) 
 
11.4 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
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), including the pregnancy of a male subject's 
female partner that occurs during the trial or within 120 days of completing the trial 
completing the trial, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier.  All subjects and female partners of male subjects 
who become pregnant 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. 
 
Such events must be reported within 24 hours to the Sponsor (via email at 
OREACRISAEreporting@providence.org) and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
 
11.5 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
11.5.1 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 a new cancer (that is not a condition of the study); 
 
Is associated with an overdose; 
 
Is another important medical event  
Refer to Table 11.6.1 for additional details regarding each of the above criteria. 
 
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 that occurs to any subject 
from the time the consent is signed through 90 days following cessation of treatment, or 
the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to 
Merck product, must be reported within 24 hours to the Sponsor (via email at 
OREACRISAEreporting@providence.org)  and within 2 working days to Merck Global Safety.  
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 

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handled in the same manner as SAEs.  
 
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 outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number:  +1-215-993-1220 
 
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. 
 
11.5.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the Sponsor (via email at 
OREACRISAEreporting@providence.org) and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220).  Events of clinical interest for this 
trial include: 
1. an overdose of Merck product, as defined in Section 11.3 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, 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.   
 
11.5.3 Additional adverse events 
   
ECIs (both non-serious and serious adverse events) identified from the date of first dose 
through 90 days following cessation of treatment, or 30 days after the initiation of a new 
anticancer therapy, whichever is earlier, need to be reported within 24 hours to the 
Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220), regardless of attribution to study treatment, consistent with 
standard SAE reporting guidelines. 
 

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Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event.  Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or symptoms 
indicate a possible immune-related ECI, then additional testing should be performed to 
rule out other etiologic causes.  If no other cause is found, then it is assumed to be 
immune-related. 
 
 
11.6 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.

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Table 11.6-1:  Instructions of how an investigator should evaluate all adverse events 
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 
 
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 within 24 hours.
 
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 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(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.) 

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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 there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

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11.7 
Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 Pilot phase: determination of primary endpoint 
12.1.1 Definition of safety/tolerability 
The primary endpoint of the pilot phase is to establish tolerability of chemotherapy plus 
pembrolizumab. For each subject, the therapy will be deemed tolerable if the following 
criteria are met:  
 
Subjects receive at least 6 weeks of pembrolizumab (2 cycles) and remain free of 
serious adverse events and grade III/IV treatment-associated adverse events 
requiring discontinuation of pembrolizumab during that period; 
 
Subjects receive at least 7 weeks of chemotherapy within an acceptable 
therapeutic dosing/scheduling range   without chemotherapy discontinuation or 
chemotherapy dosing delay ≥21 days. Shorter chemotherapy delays (<21 days) 
and dose modifications are acceptable if they conform to guidelines specified in 
section 9.4.4.  
 
The first criterion is borrowed from similar phase Ib studies of combination 
immunotherapy, such as the phase 1b study of ipilimumab plus nivolumab in MTNBC 
(NCT01928394, MSKCC IRB #13-087, PI: Margaret Callahan). The rationale for 
stipulating only 2 cycles of pembrolizumab is that some patients may receive sustained 
clinical benefit from only one or two doses of immunotherapy.(Wolchok, Kluger et al. 2013) 
Furthermore, toxicities of pembrolizumab are generally reversible if intervened 
expeditiously with algorithm-based guidelines as summarized in section 9. 
  
The second criterion is based upon the overarching goal of the pilot phase of the study, 
which is to demonstrate that pembrolizumab can be added to chemotherapy without 
impairing the ability of a clinician to administer chemotherapy, at clinically active doses, 
for a sufficient period of time to allow priming of the immune response. Because 
chemotherapy alone often requires dose modifications/delays, dose modifications and 
delays will be allowed on protocol and will not automatically constitute intolerance. 
However, chemotherapy discontinuations or sustained chemotherapy delays for ≥21 days 
will constitute intolerance of the regimen. 
 
12.1.2 Threshold for declaring safety/tolerability 
In previously reported phase II/III studies, 71-91% of patients treated with chemotherapy 
(weekly taxol, oral capecitabine) tolerated therapy without requiring dose discontinuation 
(table 12.1.2-1). 
 
Table 12.1.2-1 Safety/tolerability for each chemotherapy regimen 
Therapeutic Arm 
Published toxicity-
associated chemotherapy 
discontinuation rate 
Anticipated 
tolerability of 
chemotherapy 
(1- discontinuation rate) 
Weekly 
paclitaxel 
9% (Fountzilas, Dafni et al. 
2009) 
91% 
Oral 
capecitabine 
22% (Gajria, Feigin et al. 
2011) 
78% 
 

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In this protocol, each therapeutic arm will be deemed tolerable if the percentage of patients 
tolerating therapy meets or exceeds 60%. Only subjects who are evaluable for at least 6 
weeks will be considered in determining tolerability/safety. For example, if a subject 
tolerates therapy but experiences clinical progression at week 4 requiring alternative 
systemic therapy, this subject will not be evaluable for safety/tolerability, but will count as 
treatment failures in determination of ORR.  
 
This threshold of 60% was selected because it acknowledges the limitations of statistical 
precision of the study, and because it acknowledges the possibility that pembrolizumab 
may potentially confer additive clinical benefit when combined with chemotherapy. This 
threshold applies to both the pilot phase as well as optional expansion phases. 
 
12.1.3 Descriptive reporting to toxicities and dose modifications/delays 
The rate of grade I/II toxicities, grade III/IV toxicities, and chemotherapy dose delays and 
modifications will be reported as additional, descriptive measures of tolerability. These 
data will not be used to determine the primary endpoint, but may be used to inform the 
decision of whether to advance a therapeutic arm to the phase II expansion phase. For 
instance, if virtually all patients of a given therapeutic arm require dose reductions for 
toxicity, then the committee may opt out of advancing that therapeutic arm to the phase II 
expansion cohort, or may consider amending the protocol to reduce the starting 
chemotherapy dose for the phase II expansion cohort. 
 
12.2 Phase II expansion cohort: determination of primary endpoint 
In addition to tolerability, clinical efficacy will also be assessed in the pilot cohort, as 
measured by RECIST v1.1 ORR. If the therapy is deemed tolerable and if an efficacy 
futility boundary is exceeded in the pilot cohort, clinical efficacy may be further evaluated 
via an expansion cohort(s) of one or more treatment arms. For a treatment arm to be 
eligible for expansion, overall response in the pilot stage must exceed ≥4/14 objective 
responses. This boundary is modeled after a Simon 2-stage design, whereby the first 
Simon stage is the pilot phase arm (n=14), and the second Simon stage is the expansion 
cohort (n=30). This design is powered, with a type I error rate of 10% and type II error rate 
of 10%, to discriminate between ORR of 25% (the estimated response rate for 
chemotherapy alone for each of the three regimens based on historical trials) versus 45%. 
Response will be adjudicated by the RECIST1.1 criteria. 
 
12.2.2 Objective response rate by RECIST v1.1 
For the purposes of this study, patients will be evaluated for response every 4 cycles 
(approximately 12 weeks), or as clinically indicated if interim toxicity occurs mandating 
cancer staging re-assessment. RECIST 1.1 criteria will be used. 
 
CT scan with contrast of the chest, abdomen, and pelvis  
 
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm. 
 
MRI scans 
 
MRI of the abdomen and pelvis is acceptable for measurement of lesions provided 
that the same anatomical plane is used for serial assessments. If possible, the same 
imaging device should be used for serial evaluations. In case of MRI, measurements 
will be preferably performed in the axial (transverse) plane on contrast-enhanced 
T1-weighted images. However, there are no specific sequence recommendations. 

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Measurability of Tumor Lesions  
Tumor lesions will be categorized as follows: 
 
Measurable Lesions -  Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
of:  
 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double 
the slice thickness and a minimum of 10 mm)  
 
10 mm caliper measurement by clinical exam (when superficial) 
 
Malignant lymph nodes are 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). 
 
 
Nonmeasurable Lesions - Nonmeasurable lesions are defined as 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). Lesions considered truly 
nonmeasurable 
include 
the 
following: 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 
 
 
Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 2 
lesions per organ) representative of all involved organs should be identified as target 
lesions. 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 which can be 
measured reproducibly should be selected. 
 
 
Non-target Lesions - It is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g., “multiple enlarged pelvic 
lymph nodes” or “multiple liver metastases”) 
 
Response Criteria 
Evaluation of Target Lesions 
 
Complete Response - Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm (the 
sum may not be “0” if there are target nodes).  
 
 
Partial Response - At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
 
Progressive Disease - At least a 20% increase in the sum of 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 progression.) 
 
 
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 

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Evaluation of Non-target Lesions 
 
Complete Response - 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).  
 
 
Non-complete response/Non-progressive disease - Persistence of 1 or more non-
target lesion(s) and/or maintenance of tumor marker level above the normal limits. 
 
 
Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, 
even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. In the absence of measurable 
disease, change in non-measurable disease comparable in magnitude to the increase 
that would be required to declare PD for measurable disease. Examples include an 
increase in a pleural effusion from ‘trace’ to ‘large,’ an increase in lymphangitic disease 
from localized to widespread. 
 
Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. 
Considering the unique response kinetics that have been observed with immunotherapy, 
new lesions may not represent true disease progression. In the absence of rapid clinical 
deterioration, subjects may continue to receive treatment with pembrolizumab. 
 
Evaluation of Overall Response 
Table 12.1-1 provides overall responses for all possible combinations of tumor responses 
in target and non-target lesions with or without the appearance of new lesions. 
 
Table 12.1-1 
Evaluation of Overall Response 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
No 
Complete response 
Complete response 
Not evaluable 
No 
Partial response 
Complete response 
Non-complete response / 
non-progressive disease 
No 
Partial response 
Partial response 
Non-progressive disease and 
not evaluable a 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluable a 
No 
Stable disease 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
Progressive disease 
Any 
Yes/No 
Progressive disease 
Any 
Progressive disease 
Yes/No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
a Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
 
 
 

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12.3 Objective response rate by immune related RECIST v1.1 
With immunomodulatory therapy, clinical benefit may be observed in the setting of new 
lesions (Wolchok, Hoos et al. 2009) or following initial progression. The immune-related 
RECIST v1.1 criteria account for these unique considerations by incorporating the 
following modifications: (Nishino, Gargano et al. 2014) 
 
The presence of new lesions does not define progression, however the measures 
of the new lesion(s) should be included in the sum of the measurements; 
 
A lymph node has to be ≥15mm in short axis to be a measurable new lesion, and 
its short axis measurement is included in the sum; 
 
Up to 2 new lesions per organ, and up to 5 new lesions in total can be added to 
the measurements. 
 
As a secondary endpoint, response rate by irRECIST will be determined. 
 
12.4 Correlative Studies 
Pharmacodynamic changes may be evaluated for associations with clinical activity, and 
safety (adverse event) data. Core biopsies may be used for correlative studies such as 
IHC/immunofluorescence, 
tumor 
mutation 
analysis, 
proteomic 
analysis, 
and 
immunodiversity.  Assessments will be performed at Providence Health & Services and 
Cedars-Sinai, or with third party collaborators under a Material Transfer Agreement. 
 
12.4.1 Whole Blood 
Flow cytometry will be performed at baseline and during treatment to assess baseline and 
changes in composition/activation status of lymphocyte subsets present in peripheral 
blood mononuclear cell preparations (PBMCs).  Lymphocyte subsets to be assayed may 
include, but are not limited to CD8+ and CD4+ T-cell subsets (activated; effector/memory; 
regulatory) and populations of those cells as defined by the expression of activation, 
exhaustion, or signaling markers such as ICOS, HLA-DR, PD-1, CTLA-4, and/or 
intracellular IFNγ. Additional flow cytometry-based assays will focus on defining and 
monitoring the abundance of myeloid-derived suppressor cells (MDSCs), a cell type which 
appears to negatively impact  anti-tumor activity and which has been shown to promote 
immune escape by limiting activated CD8 T-cell infiltration into the tumor 
microenvironment (Postow, Callahan et al. 2012). NK and other cell populations may be 
monitored in a similar fashion with a focus on characterizing subsets defined by the 
expression of activation markers. Immune cells may be evaluated using HLA-A2-restricted 
tetramer assays to detect and quantify the presence of T cells directed against specific 
antigens which are anticipated to be presented to the immune system due to study 
treatment. Detecting on-treatment increases in these T cell populations may be 
considered evidence of adaptive immune responses in TNBC.  
 
12.4.2 Plasma 
To understand the prevalence of circulating proteins and the impact they may have on the 
clinical activity and/or safety of pembrolizumab treatment, the protein concentrations of a 
panel of cytokines, chemokines, and other relevant immunomodulatory, soluble factors 
may be investigated by ELISA and/or other relevant multiplex-based protein assay 
methods. Examples of analytes to be assessed may include but are not limited to factors 
induced by IFNγ signaling (e.g., T cell chemoattractants CXCL9; CXCL10) and other 
factors generally involved in inflammatory processes. Plasma may be used also to assess 
the presence and/or concentration of anti-tumor antibodies using a mulitplex platform such 
as Invitrogen’s Protoarray platform(c). Levels of sPD-L1 in peripheral blood may also be 
assessed. 

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12.4.3 Tumor Tissue 
The presence of TILs within tumors in response to pembrolizumab treatment will be 
evaluated baseline and on-treatment biopsies. Archived tissue and biopsy tissue will be 
analyzed using immunohistochemistry/immunofluorescence for PD-L1 expression and 
other immune-related proteins. In samples where tissue quantity permits, gene expression 
(Nanostring and/or RT- QPCR) research platforms will be conducted to further 
characterize immune phenotype and correlate with response.  Laser Capture 
Microdissection may be utilized to enrich specific regions of tumor material for use in 
similar or additional downstream applications, which may include in-situ hybridization, flow 
cytometry, ELISA, and/or assessment of miRNA. DNA may be sequenced to quantify the 
presence of T-cells and T-cell clonal subpopulations. In all cases, the goal may be to 
determine the abundance of a battery of immunoregulatory genes or proteins associated 
with cancer cells and/or cancer-interacting lymphocytes derived from biopsied material. 
Other biomarkers may be evaluated as determined by additional data. Remaining 
specimens may be stored for future studies related to TNBC immunity. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  
 
A subject must be discontinued from the trial for any of the following reasons: 
 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 
Confirmed radiographic disease progression 
 
Note: A subject may continue on treatment with confirmed radiographic progression if 
clinically stable or clinically improved. 
 
 
Unacceptable adverse experiences 
 
Intercurrent illness that prevents further administration of treatment 
 
Investigator’s decision to withdraw the subject 
 
Noncompliance with trial treatment or procedure requirements 
 
The subject is lost to follow-up 
 
Completed 24 months of treatment with pembrolizumab 
 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of additional 
study treatment at the discretion of the PI if they responded during the initial 24 months 
and then progressed after stopping study treatment. 
 
 
Administrative reasons 
 
After the end of treatment, each subject will be followed for 30 days for adverse event monitoring 
(serious adverse events will be collected for 90 days after the end of treatment). 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, for up to 2 years. After documented disease progression 

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each subject will be followed by telephone for overall survival until death, withdrawal of consent, 
the end of the study, or 2 years, whichever occurs first. 
 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation.  
 
14.0 
BIOSTATISTICS 
14.1 Sample Size Determination  
The primary objective of the pilot phase is to establish safety/tolerability, whereas the 
primary endpoint of the expansion phase is to estimate efficacy of one or more of the 
treatment arms.  
 
Sample size of the pilot arms and expansion cohorts are determined by a Simon two-stage 
optimal design which will discriminate whether pembrolizumab plus chemotherapy yields 
a week 13 ORR that is at least 20% greater than the anticipated ORR of chemotherapy 
alone. This design limits the expected number of subjects who receive pembrolizumab 
plus chemotherapy when the true week 13 ORR is not appreciably higher than with 
chemotherapy alone. 
   
The Simon design will test the null hypothesis that the true ORR is ≤25% versus the 
alternative hypothesis that the true ORR is >45%. The 2-stage testing will target a Type I 
error rate of 10% and will have 90% power to reject the null hypothesis if the true ORR is 
≤ 25%.  Given that the therapy is deemed tolerable, the probability of terminating the study 
early .52 under the null. 
  
The Simon design requires 14 treated subjects assigned to treatment for the first stage 
(the pilot phase) and prohibits expansion of that treatment arm if there are <4 subjects 
with OR amongst the 14 subjects treated in the pilot phase. Otherwise, if ≥4/14 subjects 
from the pilot phase achieve OR, then a phase II expansion cohort will be considered for 
that arm. 
 
As delineated in 9.11, subjects who are not evaluable for OR at week 13 will be replaced.  
 
Assessment of safety/tolerability 
This pilot/phase II design enables 14 subjects to be treated across each of three 
chemotherapy arms, allowing for an adequate assessment of tolerability before an 
expansion cohort is considered. In previously reported phase II/III studies, 78-91% of 
patients treated with chemotherapy (weekly taxol or oral capecitabine) tolerated therapy 
without requiring dose discontinuation. Accordingly, we will deem the therapy 
safe/tolerable if at least 60% of the patients are able to tolerate therapy. Assuming that all 
14 patients are evaluable for safety/tolerability, there is a 0.49 probability that the therapy 
will be deemed safe if we assume a 0.6 true safety/tolerability probability.  If the true 
probability is assumed to be 0.7 and 0.8, the probability of deeming the therapy tolerable 
is 0.78 and 0.96 respectively. Safety will continue to be assessed in the expansion cohorts, 
using the same safety/tolerability threshold of at least 60% of all evaluable patients. 
 
14.1.1.1 Rationale of Alternative Hypothesis 
The addition of pembrolizumab to chemotherapy could potentially enhance the clinical 
benefit of either therapy alone. We will evaluate for an improvement in OR by at least 20% 

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compared to historical controls, which is clinically meaningful improvement and can be 
readily identified with a sample size that is small enough to permit expeditious accrual.  
14.1.1.2 Rationale of Null Hypothesis 
As per section 3.1.1, the reported response rates of the chemotherapy arms across large 
phase II/III trials are as follows: 
 
Weekly paclitaxel (Mauri, Kamposioras et al. 2010): 18%-49% (Miller, Wang et al. 
2007, Seidman, Berry et al. 2008, Fountzilas, Dafni et al. 2009, Brufsky, Valero et al. 
2012, Miles, Dieras et al. 2013). The contemporary response rate is estimated to be 
closer to 20-30% owing to increased use of paclitaxel in the (neo)adjuvant setting.  
 
Oral capecitabine: 18-30% (Oshaughnessy, Blum et al. 2001, Fumoleau, Largillier et 
al. 2004, Brufsky, Valero et al. 2012, Miles, Dieras et al. 2013) 
From the above trials, the median historical ORRs is adopted as the null hypothesis for 
this pilot study (ORR 25%). In practice, response rates of chemotherapy decline with line 
of therapy, however we anticipate that we will accrue a mix of 1st-line subjects and 2nd-line 
subjects, thus emulating the patient populations treated in the above randomized trials. 
Therefore, we have selected a null hypothesis of 25% across each treatment arm. 
14.3 Secondary clinical endpoints  
The ORR by immune-related response criteria will be reported as secondary endpoints. 
The exact 80% and 95% CI of ORR will be estimated using the binomial distribution. 
 
14.4 Exploratory biomarker analyses 
This design also allows for indirect comparison of the immunologic effects of 
pembrolizumab when combined with each of two chemotherapy regimens. These data 
may be informative in generating hypotheses regarding the relative immune-stimulating 
properties of each of the three combination regimens. While a randomized design would 
be preferred to enable a direct comparative assessment, a randomized design would pose 
a significant barrier to patient accrual, which is the limiting factor in the design of a small, 
investigator-initiated trial.  
 
Exploratory research studies will be done to evaluate the effect of this therapy using 
research blood draws and tumor biopsies at baseline and at week 7. 
  
The pharmacodynamic effect of pembrolizumab and chemotherapy on Tumor Infiltrating 
Lymphocytes (TILs), such as CD4+ and CD8+ T-cells, and expression of tumor markers, 
will be assessed by summary statistics, and investigated graphically to explore patterns 
of change from pre-treatment to post-treatment specimens.  
 
The pharmacodynamic effect of pembrolizumab chemotherapy on markers in peripheral 
blood, such as ICOS, HLA-DR, PD-1, CTLA-4; and, serum proteins, such as CXCL9; 
CXCL10, will be assessed by summary statistics, and investigated graphically to explore 
patterns of change over time.    
 
In addition, the relationship of TIL changes and tumor marker expression with measures 
of peripheral blood markers will be summarized descriptively.  
 

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Associations between the markers and response by RECIST will be explored.  
 
Fisher’s exact test will be employed to assess associations between categorical variables 
while Spearman's rank correlation will be used for continuous variables. Wilcoxon signed 
rank test will be used to test for differences in continuous expression tumor markers 
between pre- and post-treatment specimens while McNemar’s test will be used to assess 
these relationships for binary markers. Fisher’s exact test will be employed to assess 
associations between categorical variables. 
 
15.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
To register a patient, email the Data Management Office of the Robert W. Franz Cancer 
Research Center at OREACRIRandomization@providence.org with the following 
information: 
 
Investigator's name 
 
Patient's initials and date of birth 
 
Eligibility Verification 
 
Treatment Decision and date of first dose. 
 
Patients must meet all of the eligibility requirements and undergo all pre-study procedures. 
If a patient enrolls in the study, but does not receive study therapy, the patient’s enrollment 
may be canceled. Reasons for cancellation will be documented in writing. Any patient 
whose enrollment was canceled before receiving study therapy will be replaced.  
 
Assignment of Study Numbers 
Study Numbers will be assigned at enrollment based on order of enrollment. For example: 
• 
MFH is the 4th patient enrolled to study. Study Number PPC - 04  
• 
B-A is 9th patient enrolled to study. Study Number PPC - 09 
 
All case report forms, study reports, and laboratory samples for research tests, including 
immune parameters or pharmacokinetics, will be labeled with the full patient Study 
Number. 
 
15.2 
Randomization 
Randomization is not applicable in this protocol. 
16.0 
DATA MANAGEMENT 
16.1 
Data collection 
Clinical data will be recorded on study-specific electronic case report forms (eCRFs) in 
the Velos eResearch clinical data management system (CTMS). The investigator will 
ensure the accuracy, completeness, and timeliness of data recorded on the eCRFs  
  
16.1 
Quality Assurance 
All case report forms will undergo quality assurance review.  All quality assurance reviews 
will include verification of the accuracy and integrity of data entered to case report forms. 
Incorrect data will be identified and corrected.  The existence of adequate source 
documents for all data will be verified. 
 
16.2 
Monitoring 

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Monitoring will occur at intervals stipulated in the monitoring plan for the study.  Monitoring 
may  be  performed  on‐site  or  remotely.    Monitoring  will  include:  review  regulatory 
documentation,  CRFs,  source  documentation,  and  investigational  product  storage, 
preparation, and accountability. The CRFs will be reviewed for completeness and accuracy 
compared to the source documents.  
  
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved 
consent form indicating their consent to participate. This consent form meets the 
requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following:  
 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time.  
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information.   
 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
 

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19.0 
REFERENCES 
1. Antonia, S. J., J. R. Brahmer, S. N. Gettinger, L. Q. M. Chow, R. A. Juergens, F. A. 
Shepherd, S. A. Laurie, D. E. Gerber, J. W. Goldman, Y. Shen, C. Harbison, S. Alaparthy, 
A. C. Chen, H. Borghaei and N. A. Rizvi (2014). "Nivolumab (anti-PD-1; BMS-936558, 
ONO-4538) in combination with platinum-based doublet chemotherapy (PT-DC) in 
advanced non-small cell lung cancer (NSCLC)." ASCO Meeting Abstracts 32(15_suppl): 
8113. 
 
2. Brufsky, A., V. Valero, B. Tiangco, S. Dakhil, A. Brize, H. S. Rugo, R. Rivera, A. Duenne, 
N. Bousfoul and D. A. Yardley (2012). "Second-line bevacizumab-containing therapy in 
patients with triple-negative breast cancer: subgroup analysis of the RIBBON-2 trial." 
Breast Cancer Res Treat 133(3): 1067-1075. 
 
3. Emens, L. A., F. S. Braiteh, P. A. Cassier, J. Delord, J. P. Eder, X. Shen, Y. Xiao, Y. Wang, 
P. S. Hegde, D. S. Chen and I. E. Krop (2014). Inhibition of PD-L1 by MPDL3280A leads 
to clinical activity in patients with metastastic triple-negative breast cancer. 2014 San 
Antonio Breast Cancer Symposium, San Antonio, TX. 
 
4. Fountzilas, G., U. Dafni, M. A. Dimopoulos, A. Koutras, D. Skarlos, P. Papakostas, H. 
Gogas, D. Bafaloukos, A. Kalogera-Fountzila, E. Samantas, E. Briasoulis, D. Pectasides, 
N. Maniadakis, F. Matsiakou, G. Aravantinos, C. Papadimitriou, M. Karina, C. 
Christodoulou, P. Kosmidis and H. P. Kalofonos (2009). "A randomized phase III study 
comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in 
metastatic breast cancer: a Hellenic Cooperative Oncology Group study." Breast Cancer 
Res Treat 115(1): 87-99. 
 
5. Fumoleau, P., R. Largillier, C. Clippe, V. Dieras, H. Orfeuvre, T. Lesimple, S. Culine, B. 
Audhuy, D. Serin, H. Cure, E. Vuillemin, J. F. Morere, F. Montestruc, Z. Mouri and M. 
Namer (2004). "Multicentre, phase II study evaluating capecitabine monotherapy in 
patients with anthracycline- and taxane-pretreated metastatic breast cancer." Eur J 
Cancer 40(4): 536-542. 
 
6. Gajria, D., K. Feigin, L. K. Tan, S. Patil, S. Geneus, M. Theodoulou, L. Norton, C. A. Hudis 
and T. A. Traina (2011). "Phase 2 trial of a novel capecitabine dosing schedule in 
combination with bevacizumab for patients with metastatic breast cancer." Cancer 
117(18): 4125-4131. 
 
7. Gajria, D., J. Gonzalez, K. Feigin, S. Patil, C. Chen, M. Theodoulou, P. Drullinsky, G. 
D'Andrea, D. Lake, L. Norton, C. A. Hudis and T. A. Traina (2012). "Phase II trial of a novel 
capecitabine dosing schedule in combination with lapatinib for the treatment of patients 
with HER2-positive metastatic breast cancer." Breast Cancer Res Treat 131(1): 111-116. 
 
8. Kuo, W. H., Y. Y. Chang, L. C. Lai, M. H. Tsai, C. K. Hsiao, K. J. Chang and E. Y. Chuang 
(2012). "Molecular characteristics and metastasis predictor genes of triple-negative breast 
cancer: a clinical study of triple-negative breast carcinomas." PLoS One 7(9): e45831. 
 
9. Lesterhuis, W. J., J. Salmons, A. K. Nowak, E. N. Rozali, A. Khong, I. M. Dick, J. A. 
Harken, B. W. Robinson and R. A. Lake (2013). "Synergistic effect of CTLA-4 blockade 

IRB#: 16-001 
Page 68 of 70 
 
and cancer chemotherapy in the induction of anti-tumor immunity." PLoS One 8(4): 
e61895. 
 
10. Lynch, T. J., I. Bondarenko, A. Luft, P. Serwatowski, F. Barlesi, R. Chacko, M. Sebastian, 
J. Neal, H. Lu, J. M. Cuillerot and M. Reck (2012). "Ipilimumab in combination with 
paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: 
results from a randomized, double-blind, multicenter phase II study." J Clin Oncol 30(17): 
2046-2054. 
 
11. Mauri, D., K. Kamposioras, L. Tsali, M. Bristianou, A. Valachis, I. Karathanasi, C. Georgiou 
and N. P. Polyzos (2010). "Overall survival benefit for weekly vs. three-weekly taxanes 
regimens in advanced breast cancer: A meta-analysis." Cancer Treat Rev 36(1): 69-74. 
 
12. Miles, D. W., V. Dieras, J. Cortes, A. A. Duenne, J. Yi and J. O'Shaughnessy (2013). "First-
line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast 
cancer: pooled and subgroup analyses of data from 2447 patients." Ann Oncol 24(11): 
2773-2780. 
 
13. Miller, K., M. Wang, J. Gralow, M. Dickler, M. Cobleigh, E. A. Perez, T. Shenkier, D. Cella 
and N. E. Davidson (2007). "Paclitaxel plus bevacizumab versus paclitaxel alone for 
metastatic breast cancer." N Engl J Med 357(26): 2666-2676. 
 
14. Miyashita, M., H. Sasano, K. Tamaki, M. Chan, H. Hirakawa, A. Suzuki, H. Tada, G. 
Watanabe, N. Nemoto, S. Nakagawa, T. Ishida and N. Ohuchi (2014). "Tumor-infiltrating 
CD8+ and FOXP3+ lymphocytes in triple-negative breast cancer: its correlation with 
pathological complete response to neoadjuvant chemotherapy." Breast Cancer Res Treat 
148(3): 525-534. 
 
15. Nishino, M., M. Gargano, M. Suda, N. H. Ramaiya and F. S. Hodi (2014). "Optimizing 
immune-related tumor response assessment: does reducing the number of lesions impact 
response assessment in melanoma patients treated with ipilimumab?" J Immunother 
Cancer 2: 17. 
 
16. Oshaughnessy, J. A., J. Blum, V. Moiseyenko, S. E. Jones, D. Miles, D. Bell, R. Rosso, L. 
Mauriac, B. Osterwalder, H. U. Burger and S. Laws (2001). "Randomized, open-label, 
phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF 
(cyclophosphamide, 
methotrexate 
and 
5-fluorouracil) 
as 
first-line 
therapy 
for 
advanced/metastatic breast cancer." Ann Oncol 12(9): 1247-1254. 
 
17. Postow, M. A., M. K. Callahan, C. A. Barker, Y. Yamada, J. Yuan, S. Kitano, Z. Mu, T. 
Rasalan, M. Adamow, E. Ritter, C. Sedrak, A. A. Jungbluth, R. Chua, A. S. Yang, R. A. 
Roman, S. Rosner, B. Benson, J. P. Allison, A. M. Lesokhin, S. Gnjatic and J. D. Wolchok 
(2012). "Immunologic correlates of the abscopal effect in a patient with melanoma." N Engl 
J Med 366(10): 925-931. 
 
18. Reck, M., I. Bondarenko, A. Luft, P. Serwatowski, F. Barlesi, R. Chacko, M. Sebastian, H. 
Lu, J. M. Cuillerot and T. J. Lynch (2013). "Ipilimumab in combination with paclitaxel and 
carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a 
randomized, double-blind, multicenter phase 2 trial." Ann Oncol 24(1): 75-83. 
 

IRB#: 16-001 
Page 69 of 70 
 
19. Robert, C., L. Thomas, I. Bondarenko, S. O'Day, D. J. M, C. Garbe, C. Lebbe, J. F. 
Baurain, A. Testori, J. J. Grob, N. Davidson, J. Richards, M. Maio, A. Hauschild, W. H. 
Miller, Jr., P. Gascon, M. Lotem, K. Harmankaya, R. Ibrahim, S. Francis, T. T. Chen, R. 
Humphrey, A. Hoos and J. D. Wolchok (2011). "Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma." N Engl J Med 364(26): 2517-2526. 
 
20. Salgado, R., C. Denkert, S. Demaria, N. Sirtaine, F. Klauschen, G. Pruneri, S. Wienert, G. 
Van den Eynden, F. L. Baehne, F. Penault-Llorca, E. A. Perez, E. A. Thompson, W. F. 
Symmans, A. L. Richardson, J. Brock, C. Criscitiello, H. Bailey, M. Ignatiadis, G. Floris, J. 
Sparano, Z. Kos, T. Nielsen, D. L. Rimm, K. H. Allison, J. S. Reis-Filho, S. Loibl, C. 
Sotiriou, G. Viale, S. Badve, S. Adams, K. Willard-Gallo and S. Loi (2014). "Harmonization 
of the evaluation of tumor infiltrating lymphocytes (TILs) in breast cancer: 
recommendations by an international TILs-working group 2014." Ann Oncol. 
 
21. Seidman, A. D., D. Berry, C. Cirrincione, L. Harris, H. Muss, P. K. Marcom, G. Gipson, H. 
Burstein, D. Lake, C. L. Shapiro, P. Ungaro, L. Norton, E. Winer and C. Hudis (2008). 
"Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for 
metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random 
assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer 
and Leukemia Group B protocol 9840." J Clin Oncol 26(10): 1642-1649. 
 
22. Sistigu, A., T. Yamazaki, E. Vacchelli, K. Chaba, D. P. Enot, J. Adam, I. Vitale, A. Goubar, 
E. E. Baracco, C. Remedios, L. Fend, D. Hannani, L. Aymeric, Y. Ma, M. Niso-Santano, 
O. Kepp, J. L. Schultze, T. Tuting, F. Belardelli, L. Bracci, V. La Sorsa, G. Ziccheddu, P. 
Sestili, F. Urbani, M. Delorenzi, M. Lacroix-Triki, V. Quidville, R. Conforti, J. P. Spano, L. 
Pusztai, V. Poirier-Colame, S. Delaloge, F. Penault-Llorca, S. Ladoire, L. Arnould, J. 
Cyrta, M. C. Dessoliers, A. Eggermont, M. E. Bianchi, M. Pittet, C. Engblom, C. Pfirschke, 
X. Preville, G. Uze, R. D. Schreiber, M. T. Chow, M. J. Smyth, E. Proietti, F. Andre, G. 
Kroemer and L. Zitvogel (2014). "Cancer cell-autonomous contribution of type I interferon 
signaling to the efficacy of chemotherapy." Nat Med. 
 
23. Society, A. B. C. (2012). "Breast Cancer Facts & Figures 2011-2012."   Retrieved May 9, 
2013, 
from 
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/docum
ent/acspc-030975.pdf. 
 
24. Topalian, S. L., C. G. Drake and D. M. Pardoll (2012). "Targeting the PD-1/B7-H1(PD-L1) 
pathway to activate anti-tumor immunity." Curr Opin Immunol 24(2): 207-212. 
 
25. Traina, T. A., U. Dugan, B. Higgins, K. Kolinsky, M. Theodoulou, C. A. Hudis and L. Norton 
(2010). "Optimizing chemotherapy dose and schedule by Norton-Simon mathematical 
modeling." Breast Dis 31(1): 7-18. 
 
26. Tumeh, P. C., C. L. Harview, J. H. Yearley, I. P. Shintaku, E. J. Taylor, L. Robert, B. 
Chmielowski, M. Spasic, G. Henry, V. Ciobanu, A. N. West, M. Carmona, C. Kivork, E. 
Seja, G. Cherry, A. J. Gutierrez, T. R. Grogan, C. Mateus, G. Tomasic, J. A. Glaspy, R. 
O. Emerson, H. Robins, R. H. Pierce, D. A. Elashoff, C. Robert and A. Ribas (2014). "PD-
1 blockade induces responses by inhibiting adaptive immune resistance." Nature 
515(7528): 568-571. 
 

IRB#: 16-001 
Page 70 of 70 
 
27. Weber, J., O. Hamid, A. Amin, S. O'Day, E. Masson, S. M. Goldberg, D. Williams, S. M. 
Parker, S. D. Chasalow, S. Alaparthy and J. D. Wolchok (2013). "Randomized phase I 
pharmacokinetic study of ipilimumab with or without one of two different chemotherapy 
regimens in patients with untreated advanced melanoma." Cancer Immun 13: 7. 
 
28. Weber, J., J. A. Thompson, O. Hamid, D. Minor, A. Amin, I. Ron, R. Ridolfi, H. Assi, A. 
Maraveyas, D. Berman, J. Siegel and S. J. O'Day (2009). "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(17): 5591-5598. 
 
29. Wolchok, J. D., A. Hoos, S. O'Day, J. S. Weber, O. Hamid, C. Lebbe, M. Maio, M. Binder, 
O. Bohnsack, G. Nichol, R. Humphrey and F. S. Hodi (2009). "Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria." 
Clin Cancer Res 15(23): 7412-7420. 
 
30. Wolchok, J. D., H. Kluger, M. K. Callahan, M. A. Postow, N. A. Rizvi, A. M. Lesokhin, N. 
H. Segal, C. E. Ariyan, R. A. Gordon, K. Reed, M. M. Burke, A. Caldwell, S. A. Kronenberg, 
B. U. Agunwamba, X. Zhang, I. Lowy, H. D. Inzunza, W. Feely, C. E. Horak, Q. Hong, A. 
J. Korman, J. M. Wigginton, A. Gupta and M. Sznol (2013). "Nivolumab plus Ipilimumab 
in Advanced Melanoma." N Engl J Med. 
 
31. Zitvogel, L., L. Apetoh, F. Ghiringhelli and G. Kroemer (2008). "Immunological aspects of 
cancer chemotherapy." Nat Rev Immunol 8(1): 59-73.