Conditions: Estrogen Receptor Negative Estrogen Receptor Positive HER2/Neu Negative Progesterone Receptor Negative Progesterone Receptor Positive Stage IV Breast Cancer Triple-Negative Breast Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This phase II trial studies how well pembrolizumab and doxorubicin hydrochloride works compared to pembrolizumab with anti-estrogen therapy (anastrozole, letrozole, or exemestane) in treating patients with triple-negative or hormone-receptor positive breast cancer that has spread from the primary site (place where it started) to other places in the body. Pembrolizumab is an antibody drug that blocks a molecule called programmed death (PD)-1. PD-1 is a molecule that shuts down the body's immune responses and prevents the immune system from attacking the cancer. Doxorubicin hydrochloride is a drug used in chemotherapy that works to stop the growth of tumor cells by stopping them from dividing and by causing them to die. Anti-estrogen therapy, including anastrozole, letrozole, and exemestane, lowers estrogen levels in the body, which may help treat cancer that is hormone receptor-positive. Giving pembrolizumab together with standard treatment of either doxorubicin hydrochloride (triple-negative cancer) or anti-estrogen therapy (hormone receptor-positive cancer) may be an effective treatment for these types of breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate efficacy (overall response rate) of MK-3475 (pembrolizumab) and doxorubicin (doxorubicin hydrochloride) in patients with stage IV triple negative breast cancer.

II. To evaluate efficacy (overall response rate) of MK-3475 and an oral aromatase inhibitor in patients with stage IV hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

SECONDARY OBJECTIVES:

I. To assess clinical benefit rate (lack of progression for \> 24 weeks), duration of response, time-to-treatment failure, progression-free survival, and overall survival in triple negative (TN) stage IV breast cancer patients based primarily on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related (ir)RECIST.

II. To assess feasibility and toxicity.

III. To assess clinical benefit rate (lack of progression for \> 24 weeks), duration of response, time-to-treatment failure, progression-free survival, and overall survival in patients with stage IV HR+ breast cancer based primarily on RECIST 1.1, and irRECIST.

IV. To assess feasibility and toxicities.

TERTIARY OBJECTIVES:

I. To procure serial tumor (primary and metastatic) and blood (cellular and serum/plasma) samples and analyze them to better our understanding of cellular and humoral immune response correlates and predictors of clinical benefits, leading to optimized selection of target populations in future phase II and subsequent phase III randomized prospective trials.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

COHORT 1 (TRIPLE-NEGATIVE): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and doxorubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 6 courses, and then continues for up to 24 months with pembrolizumab alone in the absence of disease progression or unacceptable toxicity.

COHORT 2 (HORMONE/HER2+): Patients receive pembrolizumab IV over 30 minutes on day 1 and an aromatase inhibitor (exemestane, anastrozole, or letrozole) orally (PO) once daily (QD) on days 1-21. Treatment repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

In both arms, patients who stop pembrolizumab with stable disease or better may receive additional pembrolizumab therapy for up to 1 year if they progress after stopping study treatment.

After completion of study treatment, patients are followed up for 30 days after the end of treatment and then every 8-12 weeks thereafter.

Arms:
arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1 and doxorubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 6 courses, and then continues for up to 24 months with pembrolizumab alone in the absence of disease progression or unacceptable toxicity.

Patients who stop pembrolizumab with stable disease or better may receive additional pembrolizumab therapy for up to 1 year if they progress after stopping study treatment. arm 2: Patients receive pembrolizumab IV over 30 minutes on day 1 and an aromatase inhibitor (exemestane, anastrozole, or letrozole) PO QD on days 1-21. Treatment repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable toxicity.

In both arms, patients who stop pembrolizumab with stable disease or better may receive additional pembrolizumab therapy for up to 1 year if they progress after stopping study treatment.

Interventions: intervention 1: Anastrozole intervention 2: Doxorubicin Hydrochloride intervention 3: Exemestane intervention 4: Laboratory Biomarker Analysis intervention 5: Letrozole intervention 6: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Given PO intervention 4: Correlative studies intervention 5: Given PO intervention 6: Given IV

Protocol document:
Prot_SAP_000.pdf: 
  
IRB 15295 
 
      06/20/2017Packet: 18 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY                                                                 
 
TITLE:  
MK-3475 (pembrolizumab) in Combination with an Anthracycline or Anti-Estrogen Therapy in 
Patients with Triple Negative and Hormone Receptor Positive (HR+ HER2-) Metastatic Breast 
Cancer. 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 15295  
 
Protocol dated: 06/20/2017 
 
COH Initial Submission 
Protocol dated 12/23/2015 
Version: 00 
COH Amendment 01 
Protocol dated 11/29/2016 
Version: 01 
COH Amendment 02 
Title Page Dated 12/29/2016 
Version: 02 
COH Amendment 03 
Title Page Dated 01/10/2017 
Version: 03 
COH Amendment 04 
Protocol dated 01/31/2017 
Version: 04 
COH Amendment 05 
Title Page Dated 02/27/2017                                                Version: 05 
COH Amendment 06 
Protocol dated 03/03/2017                                                    Version: 06 
COH Amendment 07 
Title Page Dated 04/04/2017                                                 Version: 07 
COH Amendment 08 
Protocol Dated 06/02/2017                                                    Version: 08 
COH Amendment 09 
Protocol Dated 06/20/2017                                                    Version: 09 
COH Amendment 10 
Title Page Dated 12/11/2017                                                 Version: 10 
COH Amendment 11 
Title Page Dated 02/07/2018                                                 Version: 11 
COH Amendment 12 
Title Page Dated 10/27/2018                                                 Version: 12 
COH Amendment 13 
Title Page Dated 10/16/2018                                                 Version: 13 
COH Amendment 14 
Title Page Dated 11/16/2018                                                 Version: 14 
COH Amendment 15 
Title Page Dated 06/19/2019 
 
Version: 15 
COH Amendment 16 
Title Page Dated 10/22/2019 
 
Version: 16 
COH Amendment 17 
Title Page Dated 11/14/2019 
       Version: 17 
COH Amendment 18 at Cont 
Protocol dated 06/20/2017 (tp) 
Packet: 18 
 
 
SITE:  
 
 
 
 
Breast 
 
STAGE (If applicable): 
 
 
IV  
 
MODALITY:  
 
 
 
Immunotherapy: Monoclonal Antibody 
 
TYPE:  
 
 
 
 
 Phase 2 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
James Waisman, M.D. 
 
 
PARTICIPATING CLINICIANS: 
 
Joanne Mortimer, M.D., F.A.C.P. 
 
 
Yuan Yuan, M.D., Ph.D 
 
 
Daneng Li, M.D. 
 
 
Mina Sedrak, M.D. 
 
 
Niki Patel (Tank), M.D. 
Christina Yeon, M.D. 
Daphne Stewart, M.D. 
Samuel Chung, M.D. 
Stephen Koehler, M.D. 


  
IRB 15295 
 
      06/20/2017Packet: 18 
Carey Presant, M.D. 
Shanmuga Subbiah, M.D. 
Swapnil Rajurkar, M.D. 
Naveen Gupta, M.D. 
Misagh Karimi, M.D. 
Mohammadbagher Ziari, M.D. 
Stephen Forman, MD 
James Shen, M.D.  
Sayeh M. Lavasani M.D. 
Natasha Garg, M.D. 
 
Radiologists: 
Lusine Tumyan, MD 
Lalit Vora, M.D. 
 
Biostatistician:  
 
Paul Frankel, PhD 
 
PARTICIPATING SITES: 
 
 
City of Hope National Medical Center Duarte, CA 
 
 
 
 
 
 
City of Hope, South Pasadena, CA 
 
 
 
 
 
 
City of Hope, West Covina, CA  
 
 
 
 
 
 
City of Hope, Corona, CA  
 
 
 
 
 
 
City of Hope, Upland, CA  
 
 
 
 
 
 
City of Hope, Antelope Valley, CA  


1 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
 
 
SPONSOR: City of Hope Comprehensive Cancer Center 
 
 
TITLE: MK-3475 (pembrolizumab) in Combination with an Anthracycline or Anti-
Estrogen Therapy in Patients with Triple Negative and Hormone Receptor Positive 
(HR+ HER2-) Metastatic Breast Cancer. 
 
SPONSOR/IND NUMBER: 129257 
 
IND Supporter: Merck 
 
 
 
 
 
 
 
 
 
 


2 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 8 
2.0 
TRIAL DESIGN.......................................................................................................... 9 
2.1 
Trial Design ............................................................................................................. 9 
2.2 
Trial Diagram .......................................................................................................... 9 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................. 10 
3.1 
Primary Objective(s) & Hypothesis(es) .............................................................. 10 
3.2 
Secondary Objective(s) & Hypothesis(es)........................................................... 10 
3.3 
Exploratory Objective .......................................................................................... 11 
4.0 
BACKGROUND & RATIONALE .......................................................................... 11 
4.1 
Background ........................................................................................................... 11 
4.1.1 Pharmaceutical and Therapeutic Background .................................................... 11 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 12 
4.1.3 Rationale for the Trial and Selected Subject Population .................................... 13 
4.1.4 Rationale for Dose Selection/Regimen/Modification ......................................... 14 
4.1.5 Rationale for Endpoints ...................................................................................... 16 
5.0 
METHODOLOGY ................................................................................................... 19 
5.1 
Entry Criteria ........................................................................................................ 19 
5.1.1 Diagnosis/Condition for Entry into the Trial ...................................................... 19 
5.1.2 Subject Exclusion Criteria .................................................................................. 21 
5.2 
Participant Enrollment ......................................................................................... 23 
5.2.1 Pre-Enrollment Informed Consent and Screening Procedures ........................... 23 
5.2.2 COH DCC Availability and Contact Information ................................................. 23 


3 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
5.2.3 Slot verification and reservation ............................................................................ 23 
5.2.4 Registration procedure ........................................................................................... 23 
5.3 
Trial Treatments ................................................................................................... 24 
5.3.1 Dose Selection/Modification .............................................................................. 25 
5.3.2 Timing of Dose Administration .......................................................................... 27 
5.3.3 Doxorubicin ........................................................................................................ 27 
5.3.5Trial Blinding/Masking ........................................................................................... 28 
5.4 
Randomization or Treatment Allocation ............................................................ 28 
5.5 
Stratification .......................................................................................................... 28 
5.6 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 28 
5.6.1 Acceptable Concomitant Medications ................................................................ 28 
5.6.2 Prohibited Concomitant Medications.................................................................. 29 
5.7 
Rescue Medications & Supportive Care ............................................................. 29 
5.7.1 Supportive Care Guidelines ................................................................................ 29 
5.8 
Diet/Activity/Other Considerations ..................................................................... 33 
5.8.1 Diet ...................................................................................................................... 33 
5.8.2 Contraception ...................................................................................................... 33 
5.8.3 Use in Pregnancy ................................................................................................ 34 
5.8.4 Use in Nursing Women ....................................................................................... 34 
5.9 
Subject Withdrawal/Discontinuation Criteria ................................................... 34 
5.9.1 Discontinuation of Study Therapy after CR ....................................................... 35 
5.10 
Subject Replacement Strategy ............................................................................. 36 
5.11 
Clinical Criteria for Early Trial Termination ................................................... 36 
6.0 
TRIAL FLOW CHART ........................................................................................... 37 


4 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
6.1 
Study Flow Chart .................................................................................................. 37 
7.0 
TRIAL PROCEDURES ........................................................................................... 39 
7.1 
Trial Procedures ................................................................................................... 39 
7.1.1 Administrative Procedures .................................................................................. 39 
7.1.2 Clinical Procedures/Assessments ........................................................................ 41 
7.1.3 Other Procedures ................................................................................................. 44 
7.1.4 Visit Requirements .............................................................................................. 44 
7.2 
Assessing and Recording Adverse Events .......................................................... 47 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck ................................................................................... 48 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 48 
7.2.3 Data and Safety Monitoring Plan ........................................................................ 49 
7.2.4 Monitoring and Personnel Responsible for Monitoring ..................................... 49 
7.2.5 Adverse Event Name and Severity ..................................................................... 50 
7.2.6 Adverse Event Attribution .................................................................................. 50 
7.2.7 COH Held IND ................................................................................................... 51 
7.2.8 Deviations and Unanticipated Problems ............................................................. 51 
7.2.9 Single Subject Exception (SSE) .......................................................................... 51 
7.2.10 Unanticipated Problem (UP) – Any incident, experience, or outcome that 
meets all three of the following criteria: ............................................................. 52 
7.2.11 COH Held IND ................................................................................................... 52 
7.2.12 Adverse Events and Serious Adverse Events for Merck .................................... 52 
7.2.13 Immediate Reporting of Adverse Events to Merck ............................................ 52 
7.2.14 Evaluating Adverse Events ................................................................................. 54 
7.2.15 Sponsor Responsibility for Reporting Adverse Events ...................................... 57 


5 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 57 
8.1 
Statistical Analytical Plan Summary .................................................................. 57 
8.1.1 Statistical Analysis Plan Phase I ......................................................................... 57 
8.1.2 Definitions of DLTs ............................................................................................ 58 
8.1.3 3-at-risk—Rules of Level Assignment ............................................................... 59 
8.2 
Statistical Plan Phase II ........................................................................................ 60 
8.2.1 Cohort 1 .............................................................................................................. 60 
8.2.2 Cohort 2 .............................................................................................................. 61 
8.3 
Correlative Science ............................................................................................... 61 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 61 
9.1 
Investigational Product ........................................................................................ 61 
9.2 
Packaging and Labeling Information ................................................................. 62 
9.3 
Clinical Supplies Disclosure ................................................................................. 62 
9.4 
Storage and Handling Requirements .................................................................. 62 
9.5 
Returns and Reconciliation .................................................................................. 62 
10.0 
Other Study drugs: ................................................................................................... 62 
10.1 
Doxorubicin ........................................................................................................... 62 
10.1.1 Availability ......................................................................................................... 62 
10.1.2 Storage and Stability ........................................................................................... 63 
10.1.3 Preparation .......................................................................................................... 63 
10.1.4 Toxicities ............................................................................................................. 63 
10.2 
Exemestane ............................................................................................................ 63 
10.2.1 Availability: ........................................................................................................ 63 
10.2.2 Storage and Stability: .......................................................................................... 63 


6 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
10.2.3 Toxicity: .............................................................................................................. 63 
10.3 
Anastrozole ............................................................................................................ 64 
10.3.1 Availability: ........................................................................................................ 64 
10.3.2 Storage and Stability ........................................................................................... 64 
10.3.3 Toxicity: .............................................................................................................. 64 
10.4 
Letrozole: ............................................................................................................... 64 
10.4.1 Availability: ........................................................................................................ 64 
10.4.2 Storage and Stability ........................................................................................... 64 
10.4.3 Toxicities: ........................................................................................................... 64 
11.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 65 
11.1 
Confidentiality ....................................................................................................... 65 
11.2 
Compliance with Financial Disclosure Requirements ....................................... 65 
11.3 
Compliance with Law, Audit and Debarment ................................................... 65 
11.4 
Compliance with Trial Registration and Results Posting Requirements ........ 65 
11.5 
Quality Management System ............................................................................... 65 
11.6 
Data Management ................................................................................................. 65 
12.0 
APPENDICES ........................................................................................................... 66 
12.1 
ECOG Performance Status .................................................................................. 66 
12.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 66 
12.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 66 
12.4 
Events of Clinical Interest Guidance Documents .............................................. 67 
12.4.1 IB ......................................................................................................................... 67 
12.5 
Blood Sample Collection ...................................................................................... 68 
12.6 
Blood Sample Processing ...................................................................................... 68 


7 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
13.0 
REFERENCES .......................................................................................................... 69 
 


8 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
MK-3475 and doxorubicin or an aromatase inhibitor for breast cancer 
Trial Phase 
Phase II with 2 parallel cohorts; Cohort 1 MK-3475 with doxorubicin and 
Cohort 2 combines MK-3475 with an aromatase inhibitor; A safety lead-in 
for the combination of MK-3475 both with doxorubicin or the aromatase 
inhibitor will be tested.  
Clinical Indication 
Advanced breast cancer, stage IV  
Trial Type 
Interventional 
Type of control 
None 
Route of administration 
IV MK-3475, IV doxorubicin, oral anti-estrogen (aromatase inhibitor) 
therapy  
Open-label 
None 
Treatment Groups  
Cohort 1 : Triple negative breast cancer  
Pembrolizumab 200 mg IV every 3 weeks and doxorubicin 50-60 mg/m2 IV 
every 3 weeks (based on safety lead-in) x 6 cycles followed by a 
pembrolizumab alone for up to 35 cycles or a maximum of 24 months 
starting from the first cycle. Cohort 2: HR+ HER2- breast cancer 
Pembrolizumab 200 mg IV every 3 weeks and anastrozole 1 mg, letrozole 
2.5 mg, or exemestane 25 mg (preferred) daily (with a lead-in) 
Number of trial subjects 
Approximately 60 
Estimated enrollment period 
24 months 
Estimated duration of trial 
36 months 
Duration of Participation 
After signing the informed consent form (ICF), passing the screening phase 
and initiating therapy, patients will participate until death or discontinuation 
from trial treatment due to progression. Patients discontinuing treatment for 
reasons other than progression will be followed until progression and 
treatment-related toxicities have resolved or another treatment regimen is 
initiated.   Treatment with pembrolizumab for patients of the triple negative 
cohort (treated with 6 cycles of doxorubicin/pembrolizumab) will continue 
with 
pembrolizumab 
until 
disease 
progression, 
treatment-related 
unacceptable toxicities, intercurrent illness preventing further administration 
of study drug, subject or investigator’s decision to withdraw, pregnancy, or, 
if a patient receives a total of 24 months of pembrolizumab (including the 
cycles given with doxorubicin). Patients in the hormone-receptor positive 
cohort may also receive up to 24 months of pembrolizumab, as well. They 
can continue on their selected anti-estrogen therapy (whichever aromatase 
inhibitor was chosen with pembrolizumab) _until progression. Patients 
achieving a confirmed complete response may consider stopping 
pembrolizumab within a year of such response, and could be retreated within 
12 months from stoppage. Subjects who stop pembrolizumab with stable 
disease or better may be eligible for up to one year of additional 
pembrolizumab therapy if they progress no sooner than 8 weeks after 
stopping study treatment, for either cohort.   
After the end of treatment patients will be followed for 30 days for adverse 
event (AE) monitoring and serious adverse events (SAEs) and events of 
clinical interest will be collected for 90 days after the end of treatment, or 30 
days after the end of treatment if a patient initiates new anti-cancer therapy or 
until the treatment toxicities clearly stabilize or resolve (whichever is first).  
 


9 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is an open-label single institutional Phase II trial for patients with metastatic stage IV 
breast cancer. The study will include a cohort of  patients with stage IV metastatic triple 
negative (TN) breast cancer who are to receive a combination of pembrolizumab and 
doxorubicin (a lead-in dose escalation starting at doxorubicin at 50 mg/m2 and escalating to 
60 mg/m2 will be tested to establish safety using the a 3-at-risk dose escalation design) and a 
second cohort of patients with stage IV metastatic hormone receptor positive and HER2-
(HR+) breast cancer treated at standard dose for both the aromatase inhibitor and 
pembrolizumab with a lead-in at the standard dosing of both AI and pembrolizumab to help 
insure safety.  
One planned interim analysis to assess safety and futility/efficacy will be carried out in the 
TN cohort (beyond the initial period required to establish safe dose when combining 
pembrolizumab and doxorubicin  in the triple negative cohort) and the results will reviewed 
by the PI, sponsor and the City of Hope Data Safety Monitoring Committee. 
2.2 
Trial Diagram 
                                                Stratification 
Number of prior treatments in the metastatic setting   (none vs. unlimited) 
Cohort 1                                                                                      Cohort 2 
TN  Breast Cancer                                                            HR+ Breast Cancer 
Pembrolizumab 200 mg   IVQ3W      x 6 cycles   Pembrolizumab 200 mg  IVQ3W (24 mos)  
Doxorubicin    50-60 mg/m2 IVQ3W                          Anastrozole 1 mg, letrozole 2.5 mg, or  
 Pembrolizumab  200 mg IV q3 W up to 24 mos         Exemestane 25 mg po (preferred), QD 
                                                                                       until progression 
Progression/off study                                                     Progression/off study 
Safety and Survival                                                        Safety and Survival  
Follow-up                                                                       Follow-up  
 


10 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective:  
1.a To evaluate efficacy (overall response rate) of MK-3475 and doxorubicin in patients 
with stage IV triple negative breast cancer. 
Hypothesis: Interference with breast cancer-associated PD-1 receptor expression will 
lead to increased cellular (CD8+) immunity. This effect is likely to occur regardless of 
tumor subtype (i.e. hormone receptor positive, HER2+, or triple negative subtypes), but 
targeting the PD-1 receptor alone may not provide sufficient therapeutic benefit. 
Preclinical and clinical data suggest that the prevalence of PD-1 and PD-L1 expression is 
highest among patients with triple negative primary disease. We postulate that if such is 
also true in the metastatic setting, a combination of MK-3475 and a DNA-targeting 
chemotherapeutic agent with the potential to interfere with the interaction of PD-1 and 
PD-L1/L2 such as doxorubicin may be of additive or even synergistic therapeutic value 
through facilitating both cellular immune response and chemotherapy effects.  
(2) Objective:  
To evaluate efficacy (overall response rate) of MK-3475 and an oral aromatase inhibitor 
in patients with stage IV HR+ HER2- breast cancer. 
 
Hypothesis:  The combination of MK-3475, and antiestrogen therapy will provide a 
novel treatment option for primarily endocrine therapy-resistant patients through 
enhancing cellular immune response while preserving the anti-estrogen effect. Current 
practice calls for initiating cytotoxic therapy once the first few lines of anti-estrogen 
treatment options have been exhausted. We postulate that MK-3475, when given together 
with whichever aromatase inhibitor has not been administered to a patient previously, 
may provide a less toxic and potentially better therapeutic option.  
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objectives:  
3.2.1 To assess clinical benefit rate (lack of progression for > 24 weeks), duration of 
response, time-to-treatment failure, progression-free survival, and overall survival in TN 
stage IV breast cancer patients based primarily on RECIST 1.1, and irRECIST.  
3.2.2 To assess feasibility and toxicity  
       Hypothesis:  A combination of pembrolizumab and doxorubicin in patients with TN 
breast cancer will provide favorable outcomes vs. the expected single agent response rate 
with either agent alone, and the combination will have a favorable toxicity profile/risk-
benefit ratio. 


11 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
(3) Objectives:  
3.2.3 To assess clinical benefit rate (lack of progression for > 24 weeks), duration of 
response, time-to-treatment failure, progression-free survival, and overall survival in 
patients with stage IV HR+ breast cancer based primarily on RECIST 1.1, and irRECIST. 
(4) 3.2.4 To assess feasibility and toxicities.  
       Hypothesis:  A combination of pembrolizumab and an aromatase inhibitor in patients   
with HR+ breast cancer will provide favorable outcomes vs. the expected single agent 
response rate with an aromatize inhibitor, or with pembrolizumab alone, and the combination 
will have a favorable toxicity profile/risk-benefit ratio. 
3.3 
Exploratory Objective 
(1) Objective: To procure serial tumor (primary and metastatic) and blood (cellular and 
serum/plasma) samples  and analyze them to better our understanding of cellular and 
humoral immune response correlates and predictors of clinical benefits, leading to 
optimized selection of target populations in future phase II and subsequent phase III 
randomized prospective trials.  
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer also to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475 (Appendix 12.4). 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 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 


12 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
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 
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 ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
Relevant to this proposal, data from the proof-of concept study KEYNOTE-012 showed that 
in (primarily) heavily pretreated PD-L1-positive triple negative breast cancer (n=27), 
pembrolizumab resulted in an overall response rate (ORR) of 18.2 % with durable responses 
(1).  
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.1.3.   Information on Other Trial-Related Therapy 
Anthracyclines  are active in stage IV breast cancer, and are prescribed both as single agents 
and in combination in the metastatic settings (2-3).  There are however, no specifics data 


13 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
available in triple negative stage IV breast cancer patients, whose median survival from first 
treatment is 9-12 months and their time to progression drops by approximately 50% with 
each line of therapy (4).  There is no “best” or optimal/targeted treatment option 
recommended currently for such patients except in the rare BRCA-mutated cases with data 
suggesting a benefit when treatment includes agents interfering with DNA repair.  
To complicate matters, there is significant heterogeneity and variable molecular subtypes in 
the TN phenotypic group of tumors, including the relatively small percentage of  
immunomodulatory subtype which is characterized by enriched gene expression for immune 
cell and cytokine signaling and related pathways.  Clinical observations point to a prognostic 
and possibly predictive role of the presence of tumor infiltrating lymphocytes in the tumors. 
Surface expression of the co-inhibitory programmed cell death receptor 1 (PD-1) on CD8+ 
cells together with its ligand PD-L1 on tumor cells are considered hallmarks of impaired 
cellular defense.  Consequently, the presence of both PD-1 and PD-L1 are implicated as 
adverse prognostic factors in patients with a variety of malignancies; PD-1 and PD-L1 
expression together with the presence of p53 mutations seems to be of higher prevalence in 
triple negative breast cancer compared to other breast cancer subtypes (5-11). The idea of 
combined PD-1 blockade and glucocorticoid-TNFR-related protein (GITR) stimulatory 
triggering with selected chemotherapeutic agents has also undergone evaluation suggesting 
that combining PD-1 blockade and DNA-targeting or microtubule-inhibiting agents is worth 
testing in the clinic (12).Sequential anti-estrogen therapy remains part of standard strategies 
when treating non-visceral stage IV HR+ breast cancer (13, 14).  Indeed, subsequent lines of 
aromatase inhibitors have been prescribed with variable success, regardless of the sequence, 
although non-steroidal anastrozole and letrozole) aromatase inhibitor treatment followed by 
steroidal aromatase inhibition (exemestane) may be preferred (15).  
 
4.1.3 Rationale for the Trial and Selected Subject Population 
Both in the adjuvant and neoadjuvant setting in patients treated with anthracycline-inclusive 
regimens immunomodulatory profiles have been implicated as predictors of outcome (16,17). 
There are preclinical data suggestive of doxorubicin as a downregulator of B7-H1 (PD-L1) 
expression (18). Since doxorubicin is an active agent in the treatment of metastatic –
including triple negative - breast cancers, and it has lost popularity in the adjuvant setting, 
combining this chemotherapeutic agent with the PD-1 inhibitor pembrolizumab is worth 
testing in the triple negative stage IV setting, particularly in patients who have not been 
previously exposed to anthracyclines. PD-L1 and PD-1 expression has recently been 
described in 59% and 70% of 53 triple negative breast cancer samples with concurrent 
expression seen in 45% of cases, hence the reason to target this subset of stage IV breast 
cancer (7).  Since the response rate and progression-free and overall survival are suboptimal 
even in the first line setting when patients are treated with standard agents including platinum 
and taxanes, new approaches are urgently needed. (19) 
As for HR+ disease: PD-L1 has been also observed in  33% of both Luminal B and A tumors 
and  PD-1 expression was seen in 44% and 25% of luminal B and A tumors (n:58), with 
concurrent expressions seen in 17% and 13%, respectively (7).  For patients with stage IV 
HR+ breast cancer, of Progression-free survival in two small trials describing either the effect 


14 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
of optimal dose fulvestrant (20), or a combination of letrozole and the moderately toxic agent 
CDK 4/6 inhibitor palbociclib (20), is approaching 2 years. However, in the second and third 
line setting, even with novel targeted therapies inclusive of the mTOR inhibitor everolimus 
and an aromatase inhibitor, response rates are low and progression-free survival is short (22). 
Response rates in patients with stage IV HR+ breast cancer progressing or relapsing on anti-
estrogen therapy are also suboptimal (~ 10%) with a combination of letrozole and 
palbociclib, although progression-free survival has improved vs. letrozole alone.(23).   Since 
most eligible patients are likely to have been exposed to non-steroidal aromatase inhibitors 
already either in the adjuvant or metastatic setting, and comparative efficacy data does not 
reveal a particular advantage using one AI over another in the metastatic first or second line 
setting, the steroidal aromatase inhibitor exemestane will be the preferred (but not the only) 
choice for AI in this trial. Clearly, there is an urgent and unmet need to improve response 
rates and progression-free and overall survival even in the “good-prognosis” HR+ stage IV 
group of breast cancer patients, and there is good rationale to assess the potential benefit of 
pembrolizumab and an aromatase inhibitor in HR+ patients who progressed on endocrine 
therapy, or failed first and beyond line therapies.   
Since PDL-1 expression has been observed across all subtypes (7) and stage IV MBC 
patients need significant improvements in therapeutic options with the goal of extending 
clinical benefit duration, time to progression, and overall survival, testing the feasibility and 
potential efficacy of pembrolizumab in both triple negative and HR+ sets of breast cancer 
may lead to improved therapeutic options in the future.  The future directions to take in case 
of a positive outcome with 6 cycles of combined therapy of pembrolizumab and doxorubicin 
and maintenance in the triple negative cohort will include testing doxorubicin and 
pembrolizumab in suitable patients in need of adjuvant therapy.  Similarly, adjuvant and 
neoadjuvant roles could be assessed in HR+ patients with the aromatase inhibitor and 
pembrolizumab combination. 
4.1.4 Rationale for Dose Selection/Regimen/Modification  
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 1 and 2 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 


15 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain 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. 
As for the dose selection of doxorubicin: it is estimated that standard dose of 50-60  mg/m2 
for up to 6 cycles with careful cardiac monitoring can be safely administered. Dosing of the 
chosen aromatase inhibitors will also be standard (anastrozole 1 mg po QD, or letrozole 2.5 
mg po QD, or exemestane 25 mg po QD).  
 


16 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
4.1.5 Rationale for Endpoints 
Primary: For Cohort 1 (TN stage IV breast cancer) the primary endpoint is to assess efficacy 
(overall response rate) in PD-L1 not enriched stage IV breast cancer when combining a 
previously untested combination of pembrolizumab and doxorubicin.  
For Cohort 2, (HR+ HER2- stage IV breast cancer) the primary endpoint is to assess efficacy 
(overall response rate) in PD-L1 not enriched cancer when combining a previously untested 
combination of pembrolizumab and an aromatase inhibitor (exemestane preferred).  
Safety analysis will be carried out based on toxicities assessed by CTCAE, version 4.0 
criteria. AEs will be analyzed including but not limited to all AEs, SAEs, fatal AEs, and 
laboratory changes. Immune-related adverse events (irAE) will be collected and designated 
as immune-related events of clinical interest (ECIs)  
Secondary: Clinical benefit rate (> 24 weeks of lack of progression, safety, tolerability, 
duration of response, progression-free survival, and overall survival and time to treatment 
failure are methods to assess efficacy of therapy of the two novel combinations. These 
endpoints will help provide information for future trial designs.  
4.1.5.1 Efficacy Endpoints 
RECIST 1.1 (24) will be used to assess response, duration of response (DOR) , and 
progression-free survival (PFS) ; Kaplan-Meier estimates will be generated for PFS, time-to-
treatment failure, and overall survival (OS). 
Exploratory analysis to assess survival endpoints, response and clinical benefit will be 
carried out also, using irRECIST, 
irRECIST 
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immuno-therapeutics. irRECIST will be used by site investigators and 
local radiology review to assess tumor response and progression, and make treatment 
decisions. This data will be collected in the clinical database. 
 
irRECIST will be used by the central imaging vendor, however, this evaluation will be done 
retrospectively. irRECIST takes into account the clinical condition/stability of subjects, as 
described in the Table below, in addition to response or progression via tumor imaging. 
 
Clinically stable is defined by the following criteria: 
Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values 
No decline in ECOG performance status 
Absence of rapid progression of disease 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention 


17 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
Table irRECIST: Tumor Imaging and Treatment after 1st Radiologic Evidence of PD or SD, 
CR or PR 
 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st 
radiologic 
evidence of PD 
Repeat imaging at > 4 
weeks 
at 
site 
to 
confirm PD 
May continue study 
treatment 
at 
the 
Investigator’s 
discretion 
while 
awaiting confirmatory 
scan by site 
Repeat imaging at > 4 
weeks to confirm PD 
per 
physician 
discretion only 
Discontinue treatment 
Repeat scan confirms 
PD 
No additional imaging 
required 
Discontinue treatment 
(exception is possible 
upon 
consultation 
with Sponsor). 
No additional imaging 
required 
N/A 
Repeat scan shows 
SD, PR or CR 
Continue 
regularly 
scheduled 
imaging 
assessments  
Continue 
study 
treatment 
at 
the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments  
May 
restart 
study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion.  Next scan 
should 
occur 
according to the every 
9 week (63 ± 7 days) 
imaging schedule. 
 
In determining whether or not the tumor burden has increased, decreased or stayed stable, 
site investigators should consider all target lesions as well as non-target lesions. 
 
Any subject deemed clinically unstable should be discontinued from trial treatment at first 
evidence of progressive disease by tumor imaging and is not required to have repeat tumor 
imaging for confirmation. 
 
For a clinically stable subject with first radiologic evidence of progressive disease (i.e., 
unconfirmed progression of disease), it is at the discretion of the site investigator to 
continue treating the subject with the assigned treatment per protocol until progression of 
disease is confirmed at least 28 days from the date of the tumor imaging first suggesting PD. 
If progression is not confirmed on the subsequent tumor imaging, the subject should continue 
to receive study therapy and have tumor imaging performed every 9 weeks (± 7 days) in the 
first year or every 12 weeks after the first year, or sooner if clinically indicated, to monitor 
disease status. If radiologic progression is confirmed by subsequent tumor imaging, then the 
subject will be discontinued from trial treatment. 
 


18 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
NOTE: If a subject with confirmed progression by tumor imaging (i.e. 2 scans at least 28 
days apart demonstrating progressive disease) is clinically stable or clinically improved, and 
there is no further increase in the tumor burden at the confirmatory scan, an exception may 
be considered to continue treatment upon consultation with the Sponsor. 
 
4.1.5.2 Biomarker Research 
Preliminary studies suggest that CD8 T cell infiltration and PD-L1 expression within tumors 
may predict efficacy for pembrolizumab, but definitive biomarkers are not yet available. To 
identify biomarkers to predict and/or follow efficacy for pembrolizumab in combination with 
other agents in metastatic breast cancer, we propose the following correlative studies to 
analyze the immune and stromal cells within metastatic tumors, as well as immune cells in 
peripheral blood, before and after therapy:  
 
 
We will obtain archived biopsies or fresh biopsies as feasible of one or more metastatic 
lesion(s) before and one month post treatment. In addition, blood samples will be obtained at 
weeks 0, 2, 4, 6, 8, 10, 20, and 30 to track the temporal dynamics of the host immune 
response. Key questions we will address include: 
1. Immune and stromal cells characteristics before treatment that correlate with clinical 
response. 
2. Changes in immune and stromal cells after therapy that correlate with clinical response. 
 
Approaches: 
1. 12-color FACS analysis to enumerate/phenotype immune cell subsets and functional 
readouts, including cytokine production and signaling (phosflow)  
2. TCR repertoire analysis via deep sequencing. Expansion of the T cell repertoire after 
therapy will be evidence for an immunological response and may indicate epitope spread. 
3. Immunohistology using a novel quantitative, spatial image analysis system (Vectra, Perkin 
Elmer) that will enable us to analyze immune, stromal, and cancer cells in metastatic tumors 
via 8-color histology. 
4. Gene expression analysis of stromal cells via RNA-Seq or microarrays. 
5. Morphological / IHC TIL analysis of tumor biopsies. 
 
Serial Cytokine Measurements 
We will procure and analyze blood samples prior to initiating cycle one, and prior to cycle 2. 
The Human Cytokine Thirty-Plex Antibody Bead Kit (Invitrogen, Camarillo, CA) will be 
used according to manufacturer’s instructions. The 30 cytokine panel includes: epidermal 
growth factor (EGF), eotaxin, basic fibroblast growth factor (FGF-basic), granulocyte 
colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-
CSF), hepatocyte growth factor (HGF), interferon alpha (IFN-α); IFN-gamma (γ), 
interleukin-1 beta (IL-1β), interleukin-1 receptor antagonist (IL-1RA), IL-2; interleukin-2 
receptor (IL-2R), IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40/p70, IL-13, IL-15, IL-17, 
IFN-γ-inducible protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), monokine 
induced by IFN-γ (MIG), monocyte inflammatory protein-1 alpha (MIP-1α), monocyte 
inflammatory protein-1 beta (MIP-1β), regulated upon activation, normal T cell expressed 


19 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
and secreted cytokine (RANTES), tumor necrosis factor (TNF)-α, and VEGF. Cytokine 
concentrations will be measured using the Bio-plex HTF Luminex instrument and results 
calculated using Bio-plex Manager 3.0 Software. The inter-assay precision for all cytokines 
is <10 % and the lower limit of quantitation is between 1 and 15 pg/ml, depending on the 
target. (25-29) 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Patients who are 18 years or older with 1) stage IV metastatic triple negative breast cancer  
(triple negative is defined as ER and PgR status is <1% of tumor cell nuclei are 
immunoreactive for ER or PgR, and HER2 status is FISH negative or IHC 0 or 1+)  or 2) 
Stage IV HR+ HER2- (HR+) breast cancer (defined as ER or PgR >1% of tumor cell nuclei 
are immunoreactive for ER or PgR and HER2 status is FISH negative or ICH 0 or 1+). 
 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1.   
4. 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 up to 6 weeks (42 
days) prior to initiation of treatment on Day 1.  Subjects for whom newly-obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may submit 
an archived specimen only upon agreement from the Sponsor. 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
6. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 7 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 
≤1.5 X upper limit of normal (ULN) OR 


20 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Cardiac 
 
Left ventricular ejection fraction by 
MUGA or Echocardiogram# 
#  ≥55%; ^≥ upper limit of institutional normal 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤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 
Reproductive status for cohort 2: HR+ 
stage IV post-menopausal breast cancer 
Post-menopausal is defined by at least one of the following 
criteria:  
Prior bilateral oophorectomy OR Amenorrheic for ≥ 12 months 
(if ≤ 55 years of age and prior chemotherapy or on medical 
ovarian ablative therapy or received ovarian radiation for 
ablation in the past 5 years and/or tamoxifen or an AI within the 
past year, then FSH and estradiol must be in the post-
menopausal range and obtained within 28 days prior to 
registration) OR  
Previous hysterectomy with one or both ovaries left in place (or 
previous hysterectomy in which documentation of bilateral 
oophorectomy is unavailable AND FSH values consistent with 
the institutional normal values for the post-menopausal state. 
FSH levels must be obtained within 28 days prior to registration. 
aCreatinine clearance should be calculated per institutional standard. # For patients with triple negative 
breast cancer ^ For patient with HR+ breast cancer 
 
7. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
8. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
9. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 


21 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
10. 
Subjects currently on a bisphosphonate or denosumab are eligible for study 
therapy. 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Cohort 1: Has triple negative breast cancer, is considered for cohort 1 participation, 
and received prior anthracycline therapy. 
Cohort 2: Has received prior aromatase inhibitor therapy and is deemed to be resistant 
to all three (anastrozole, letrozole, exemestane) approved AIs. Resistance is defined 
as progression within 12 months or while on an AI. 
2. Patient is premenopausal (see Table 1, medical ovarian suppression is allowed)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. 
3. 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. 
 
4. Has a known history of active TB   (Bacillus Tuberculosis) 
 
5. Hypersensitivity to pembrolizumab or any of its excipients. 
 
6. Suboptimal cardiac function as defined by decreased left ventricular ejection fraction 
< 55% for cohort 1, and < 50% for cohort 2. 
 
7. Prior pembrolizumab. 
 
8. 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. 
9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 


22 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
10. Has a known additional malignancy that has progressed or required active treatment 
in the past 5 years.  Exceptions include basal cell carcinoma of the skin or squamous 
cell carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer. 
11. 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.   
12. 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.  
13. Has a history of, active, pneumonitis requiring treatment with steroids or history 
of/active interstitial lung disease.  
14. Has an active infection requiring systemic therapy. 
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the 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.   
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
17. 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. 
18. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 


23 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
21. Has a history of (non-infectious) pneumonitis that required steroids or currently has 
pneumonitis. 
22. 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. 
5.2 
Participant Enrollment 
5.2.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done 
only after obtaining written informed consent.  Studies or procedures that are performed for 
clinical indications (not exclusively to determine study eligibility) may be used for baseline 
values and/or to determine pre-eligibility, even if the studies were done before informed 
consent was obtained. The informed consent process is to be fully documented, and the 
prospective participant must receive a copy of the signed informed consent document.   
5.2.2 COH DCC Availability and Contact Information 
Eligible subjects will be registered on the study centrally by the Data Coordinating Center 
(DCC) at City of Hope.  DCC staff are available between the hours of 8:00 a.m. and 
5:00p.m. PST, Monday through Friday (except holidays).   DCC contact information is as 
follows: 
 phone: (626) 256-4673 ext. 83968 
 e-mail: DCC@coh.org 
5.2.3 Slot verification and reservation 
The study team personnel (including physicians, protocol nurses and/or CRCs) may wish to 
contact the DCC to verify slot availability and to reserve an open slot or be placed in queue 
for slot opening.  Slots may only be held for a limited time which will be determined by the 
PMT. The Data Coordinating Center should be notified of cancellations of prospective 
participants holding slots as soon as possible. 
5.2.4 Registration procedure 
To register a participant, the subsequent procedure is to be followed. 
1. The coordinator/research nurse should contact the DCC via telephone or email to provide 
notification regarding the pending registration and communicate desired timeline of the 
registration, especially if it must be completed promptly. 


24 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
2. The coordinator/research nurse should then e-mail copies to DCC@coh.org  of the 
following documents to the DCC:  
o Completed Eligibility Criteria List (printed from Section 5.1.1 
and 5.1.2 of the protocol) 
o Source documentation to support eligibility criteria**  
o Signed informed consent document 
o Signed HIPAA authorization form (if separate from the 
informed consent document) 
o Signed subject’s Bill of Rights (COH only)  
**For COH participants, provide copies of source documentation only if not 
readily available as a finalized record in the COH EMR. 
3. After having received all documentation, the DCC will complete the review the documents 
to verify eligibility, working with the staff as needed to resolve any missing required source 
elements. A subject failing to meet all protocol eligibility requirements will not be registered.  
4. Once eligibility has been confirmed, DCC staff will register the participant by assigning a 
participant study number and will enter the subject into the eCRF system, Medidata RAVE 
(once dosing is confirmed).  The COH CRC will directly accession into MIDAS as per 
current policy and procedure. 
5.  Once registration has been completed, DCC staff will send a Confirmation of Registration 
Form, including the participant study number and cohort assignment to:   
 the site study team: site PI, treating physician, biostatistician, protocol nurse, CRC 
and IDS pharmacy. 
 
5.3 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2Table 2 
Table 2  Trial Treatment   
Cohort 1 Triple negative breast cancer 
Drug 
Dose 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg  
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Doxorubicin*     50-60 
mg/m2 
Q3W 
X 6 cycles 
IV infusion 
Day 1 of each 3 week cycle, standard 
*starting dose 50 mg/m2 for cohort 1, escalating to 60mg/m2 based on acceptable 
toxicity during safety-lead in. see Statistical Section. No intrapatient dose escalation 


25 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
is allowed. After 6 cycles of doxorubicin and pembrolizumab, patients will continue 
on pembrolizumab alone up to a total of 24 cycles. 
Subjects who stop pembrolizumab with stable disease or better may be eligible for up 
to one year of additional pembrolizumab therapy if they progress after stopping study 
treatment.   
Cohort 2 HR+ breast cancer 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg  
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Aromatase 
inhibitor (AI)*    
Exemestane 
25 mg daily 
po preferred, 
Anastrozole 
1 mg daily 
po, 
or 
letrozole 2.5 
mg daily po 
are options 
QD 
Po 
QD cycle, standard 
*pending prior exposure: patients could not have failed all three commercially 
available AIs.  
Trial treatment should begin as close as possible to the date on which treatment is 
allocated/assigned. 
Subjects who stop pembrolizumab with stable disease or better may be eligible for up to one 
year of additional pembrolizumab therapy if they progress after stopping study treatment.   
 
5.3.1 Dose Selection/Modification 
5.3.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual (Appendix 12.4.)   


26 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
5.3.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 
5.6.1 and Events of Clinical Interest Guidance Document for supportive care guidelines, 
including use of corticosteroids.Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure.  
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for [pneumonitis) drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 


27 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
5.3.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps 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). 
Follow the package insert for the preparation of the pembrolizumab infusion fluid and 
administration of infusion solution. 
5.3.3 Doxorubicin  
For patients accrued on cohort 1: For dose adjustment see package insert for subjects 
receiving this agent, once the trial dose is selected. We will have a safety lead-in employing a 
3-at-risk rolling design. For each treatment, we will permit only 3 patients to be a risk for 
first cycle toxicities at any one time during the safety-lead in.  Dose escalation from 
50mg/m2 to 60mg/m2 will be permitted according the 3-at-risk dose escalation rules (below).  
Once the safety lead-in is complete, accrual will proceed. Any dose de-escalation from 
50mg/m2 will require discussion with the sponsor and an amendment.  DLTs are defined in 
section 8.1. below. 
.5.3.4 Aromatase inhibitors  
Exemestane 25 mg daily po, anastrozole 1 mg po daily, or letrozole2.5 mg po daily will be 
administered as per package insert. There will be no dose-adjustment for these agents. 


28 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
5.3.5Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.4 
Randomization or Treatment Allocation 
Patients with triple negative stage 4 breast cancer will receive pembrolizumab and 
doxorubicin in cohort 1; patients with HR+ stage IV breast cancer will receive 
pembrolizumab and an aromatase inhibitor. 
5.5 
Stratification 
Accrual will not depend on stratification, but for Cohort 1 we will consider stratified analysis 
based on first-line (for metastatic or newly diagnosed), versus lines 2 or beyond for 
metastatic disease. 
 
5.6 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.6.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. Subjects who are taking a 
bisphosphonate or denosumab when they enter the study may continue to take the drug while 
on the study treatment. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 


29 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
5.6.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
Antineoplastic systemic chemotherapy or biological therapy  
Immunotherapy not specified in this protocol 
Chemotherapy not specified in this protocol 
Investigational agents other than pembrolizumab 
Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at 
the investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiological doses of 
corticosteroids (≤ 10 mg prednisone or equivalent po daily) is allowed.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.7 
Rescue Medications & Supportive Care 
5.7.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below 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 


30 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
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 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
 
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 Diarrhea/Colitis:  
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.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 


31 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
 Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 Hyperthyroidism or Hypothyroidism:  
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 3-4 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. 
 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 


32 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
 
 Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
Table  
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 4 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 symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
No subsequent dosing 


33 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
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. 
 
 
 
5.8 
Diet/Activity/Other Considerations 
5.8.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.8.2 Contraception 
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 are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has 
not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be 
either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Subjects should start using birth control from study Visit 1 throughout the study period up to 
120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor and to Merck.  If there is any question that a subject 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 


34 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
5.8.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the 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 to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 
5.8.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.9 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.3 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 
4.1.5.1 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 4.1.5.1 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 


35 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
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 if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.4.5 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.4 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.1.5.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.9.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression no sooner than 8 weeks after 
completion of pembrolizumab may be eligible for up to one year of additional treatment with 
pembrolizumab via the Second Course Phase at the discretion of the investigator if no cancer 
treatment was administered since the last dose of pembrolizumab, the subject meets the 
safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects 
will resume therapy at the same dose and schedule at the time of initial discontinuation.  
Additional details are provided in Section 7.1.4.5. 
5.9.2. Discontinuation of doxorubicin for patients treated in cohort 1 should be considered 
after either a cumulative dose of 360 mg/m2, a drop in left ventricular ejection fraction below 
50%, or 2 cycles after complete remission is confirmed, whichever occurs sooner. 


36 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
5.10 
Subject Replacement Strategy 
A subject discontinuing therapy will not be replaced.  Patients who are screen-failed but were 
never treated will be replaced. 
5.11 
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. 
 


Product:   Pembrolizumab 
37 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discont. 
Safety 
Follow-up 
Follow Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discont. 
30 days 
post 
Discont. 
Every 8 
weeks post 
Discont. 
Every 
12 
weeks  
Administrative Procedures 
Pre-screening Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Trial Treatment Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Full Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


Product:   Pembrolizumab 
38 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discont. 
Safety 
Follow-up 
Follow Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discont. 
30 days 
post 
Discont. 
Every 8 
weeks post 
Discont. 
Every 
12 
weeks  
Comprehensive Serum Chemistry Panel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
T3, FT4 and TSH 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Efficacy Measurements 
Tumor Imaging with CT (chest, abdomen, 
pelvis, bone scan, other modalities as 
deemed appropriate clinically) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Cardiac evaluation:Echo,or MUGA and 
ECG for triple negative and MUGA or 
ECHO for the HR+ cohort 
 
X 
 
 
 
 
 
 
X@ 
 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
 
X 
 
X# 
 
 
 
 
 
 
X 
 
 
 
Correlative Studies Blood Collection## 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
#optional ## if pts agree ask for weeks 4,6,8,10, 20,30 
@For triple negative patients, Echo or MUGA evaluations will be repeated after cycle 6, at least a week prior to cycle 7. Subsequent cardiac testing will be 
carried out as clinically indicated. For hormone receptor positive patients, only a baseline Echo or MUGA scan is required, any subsequent cardiac testing 
will be as clinically indicated 


Product:   Pembrolizumab 
39 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor 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. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 


Product:   Pembrolizumab 
40 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before 


Product:   Pembrolizumab 
41 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up.  
7.1.1.6 Assignment of Screening Number 
All consented subjects will be given a unique screening number according to their 
designated cohorts (Cohort 1: triple negative; Cohort 2 HR+).  
7.1.1.7 Assignment of Cohort Number will  be based as above. 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from protocol-specified treatment for greater than 12 weeks require 
consultations between the investigator/PI and sponsors. 
Instructions on how to prepare pembrolizumab will be per Pharmacy manual.  Doxorubicin 
and AIs will be prepared or prescribed as per approved product label and standard practice 
guidelines. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 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); see the separate ECI guidance document in Appendix 4 
regarding the identification, evaluation and management of potential irAEs.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  


Product:   Pembrolizumab 
42 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) 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 trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
 Tumor imaging may be performed by CT, MRI, FDG/PET/CT but the same technique needs 
to be performed throughout the trial.  Cardiac assessment (Cohort 1 patients) can be 
performed by MUGA or Echocardiogram.  
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 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) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.  


Product:   Pembrolizumab 
43 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Table 5  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 triiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
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  
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 


Product:   Pembrolizumab 
44 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 7 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.2.8 Pharmacokinetic/Pharmacodynamic Evaluations 
Not applicable. 
7.1.2.8.1 Blood Collection for Serum Pembrolizumab 
N/A 
7.1.2.8.2 Blood Collection for Anti-Pembrolizumab Antibodies NA 
7.1.3 Other Procedures 
7.1.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.4.5.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
7.1.3.2 Blinding/Unblinding   
Not applicable.  
7.1.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.4.1 Screening 
Patients will be identified by the breast cancer team at their  regular weekly treatment 
planning conference, or as they are being seen by team members. 
 


Product:   Pembrolizumab 
45 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
7.1.4.1.1 Screening Period 
Laboratory information should be within 7 days of initiating treatment, radiographic and 
other images should be within 28 days prior to starting treatment.   
7.1.4.2 Treatment Period 
See 6.1. 
7.1.4.3 Post-Treatment Visits 
See section 6.1 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, 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 (as described in Section 7.1.4.5) may have up to two safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase. 
7.1.4.4 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 6 weeks (42 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 9 weeks (± 7 days). 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 Section 
7.1.4.5.  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 Section 7.1.4.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart for 
Retreatment.    
7.1.4.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  


Product:   Pembrolizumab 
46 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
7.1.4.5 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 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy and has not progressed within 8 weeks of completion of such 
therapy, but not beyond 12 months of being off therapy. 
 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 
 Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
 Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
 Has a performance status of 0 or 1 on the ECOG Performance Scale 
 Demonstrates adequate organ function as detailed in Section 5.1.2 
 Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
 Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
 Male subject should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.   


Product:   Pembrolizumab 
47 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 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. 
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 Section 6.0 – Trial Flow Chart. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Merck’s 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 


Product:   Pembrolizumab 
48 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
7.2.1 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. 
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 and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 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 and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 


Product:   Pembrolizumab 
49 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
7.2.3 Data and Safety Monitoring Plan 
7.2.3.1 Definition of Risk Level 
This is a Risk Level 4 study as defined in the City of Hope Institutional Data and Safety 
Monitoring Plan.  This determination was made because the study involves a COH IND. 
7.2.4 Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) is responsible for monitoring the data and safety of 
this study.  The PMT consists of the Principal Investigator (PI), Biostatistician, Research 
Protocol Nurse, and Clinical Research Coordinator.   
 
The PMT is required to submit periodic status reports (i.e., the PMT Report) according to the 
frequency prescribed in the City of Hope Institutional Data and Safety Monitoring Plan.  
Important decisions made during PMT meetings (i.e., dose escalation, de-escalation, etc.) 
only need to be noted in the PMT Report submitted to the Data and Safety Monitoring 
Committee (DSMC). 
Adverse Event (AE) - An adverse event is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
Reporting Non-serious Adverse Events – Adverse events will be collected after the patient 
is given the study treatment or any study related procedures.  Adverse events will be 
monitored by the PMT.  Adverse events that do not meet the criteria of serious OR are not 
unanticipated problems will be reported only in the PMT Report. 
Serious Adverse Event (SAE) [Modified from the definition of unexpected adverse drug 
experience in 21 CFR 312.32] - defined as any expected or unexpected adverse events that 
result in any of the following outcomes: 
 Death 
 Is life-threatening experience (places the subject at immediate risk of death from the 
event as it occurred) 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the outcomes listed above (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, blood 
dyscrasias of convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse). 
 


Product:   Pembrolizumab 
50 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Reporting Serious Adverse Events - begins after study treatment or any study related 
procedures.  All SAEs occurring during this study, whether observed by the physician, nurse, 
or reported by the patient, will be reported according to the approved COH policy.  Serious 
Adverse Events that require expedited reporting will be submitted electronically using iRIS. 
 
7.2.5 Adverse Event Name and Severity 
The PI will determine the adverse event name and severity (grade) by using the CTCAE 
version 4.  
Expected Adverse Event - Any event that does not meet the criteria for an unexpected 
event, OR is an expected natural progression of any underlying disease, disorder, condition, 
or predisposed risk factor of the research participant experiencing the adverse event. 
Unexpected Adverse Event [21 CFR 312.32 (a)] – An adverse event is unexpected if it is 
not listed in the investigator’s brochure and/or package insert; is not listed at the specificity 
or severity that has been observed; is not consistent with the risk information described in the 
protocol and/or consent; is not an expected natural progression of any underlying disease, 
disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
7.2.6 Adverse Event Attribution 
The following definitions will be used to determine the causality (attribution) of the event to 
the study agent or study procedure. 
Definite - The AE is clearly related to the investigational agent or study procedure and 
unrelated to any other cause. 
Probable - The AE is likely related to the investigational agent or study procedure and 
unlikely related to other cause(s). 
Possible -The AE may be related to the investigational agent or study procedure and may 
be related to another cause(s). 
Unlikely -The AE is doubtfully related to the investigational agent or study procedure 
and likely related to another cause(s). 
Unrelated -The AE is clearly not related to the investigational agent or study procedure 
and is attributable to another cause(s). 


Product:   Pembrolizumab 
51 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
7.2.7 COH Held IND  
Serious Adverse Events meeting the requirements for expedited reporting to the Food and 
Drug Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety 
report using the MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the Medwatch 3500A are: 
 Any unexpected fatal or life threatening adverse experience associated with use of the 
drug must be reported to the FDA no later than 7 calendar days after initial receipt of 
the information [21 CFR 312.32(c)(2)] 
 Any adverse experience associated with use of the drug that is both serious and 
unexpected must be submitted no later than 15 calendar days after initial receipt of 
the information [21 CFR 312.32(c)(1)] 
 Any follow-up information to a study report shall be reported as soon as the relevant 
information becomes available. [21 CFR 312.32(d)(3)] 
 
The PI or designee will be responsible for contacting the Office of IND Development and 
Regulatory Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the 
FDA.  OIDRA will assist the PI with the preparation of the report and submit the report to 
the FDA in accordance with the approved COH policy. 
 
7.2.8 Deviations and Unanticipated Problems 
Deviation - A deviation is a divergence from a specific element of a protocol that occurred 
without prior IRB approval.  Investigators may deviate from the protocol to eliminate 
immediate hazard(s) for the protection, safety, and well-being of the study subjects without 
prior IRB approval.  For any such deviation, the PI will notify the COH DSMC and IRB 
within 5 calendar days of its occurrence via iRIS in accordance with the Clinical Research 
Protocol Deviation policy. 
 
7.2.9 Single Subject Exception (SSE) 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific 
procedures called for in a protocol are not in the best interests of a specific patient.  It is a 
deviation that is anticipated and receives prior approval by the PI and the IRB.  The SSE 
must be submitted as a “Single Subject Exception Amendment Request” via iRIS in 
accordance with IRB guidelines and the Clinical Research Protocol Deviation policy.  An 
IRB approved SSE does not need to be submitted as a deviation to the DSMC. 
 


Product:   Pembrolizumab 
52 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
7.2.10 Unanticipated Problem (UP) – Any incident, experience, or outcome that meets 
all three of the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure (IB); 
and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcomes may have been 
caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or 
recognized. 
Any UP that occurs during study conduct will be reported to the DSMC and IRB in 
accordance with the City of Hope’s Institutional policy using iRIS.   
7.2.11 COH Held IND  
The Office of IND Development and Regulatory Affairs (OIDRA) will assist the PI in 
reporting the event to the Food and Drug Administration (FDA). 
7.2.12 Adverse Events and Serious Adverse Events for Merck 
The PI will be responsible for determining the event name, assessing the severity (i.e., 
grade), expectedness, and attribution of all adverse events. 
7.2.13 Immediate Reporting of Adverse Events to Merck 
7.2.13.1 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 an other important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 


Product:   Pembrolizumab 
53 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
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 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 
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. 
7.2.13.2 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 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 7.2.1 - 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 


Product:   Pembrolizumab 
54 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
1. Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-
Related Adverse Event Guidance Document”).  This document can be found in Appendix 
4 and provides guidance regarding identification, evaluation and management of ECIs 
and irAEs.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
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. 
 
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. 
7.2.14 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. 


Product:  MK-3475 
55 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of 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 
 


Product:  MK-3475 
56 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
 
 
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.) 
 
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.) 


Product:  MK-3475 
57 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
7.2.15 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.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analytical Plan Summary 
8.1.1 Statistical Analysis Plan Phase I 
Phase I lead-in considerations: 
Cohort 1: doxorubicin + pembrolizumab 
Drug 
Doxorubicin Pembrolizumab 
Level 1 
50 mg/m2 
200 mg  
Level 2     
60 mg/m2 
200 mg  
 
Cohort 2: AI + pembrolizumab (AIs are combined for the safety/activity primary endpoints) 
 
* Exemestane 25 mg daily po preferred, Anastrozole 1 mg daily po, or letrozole 2.5 mg daily 
po are options. 
8.1.1.1 Safety Lead-in and Dose Escalation and De-escalation 
For both cohorts we will have a safety lead-in employing a 3-at-risk rolling design. For each 
treatment, we will permit only 3 patients to be a risk for first cycle toxicities at any one time 
during the safety-lead in.   
8.1.1.1.1 Cohort 1 (Pembrolizumab and Doxorubicin)   
For cohort 1, a dose escalation from 50mg/m2 to 60mg/m2 will be permitted according the 3-
at-risk dose escalation rules (below).  There will not be intra-patient dose-escalation. Once 
the safety lead-in is complete, accrual will proceed based on the phase II considerations for 
cohort 1 below. Any dose de-escalation from 50mg/m2 will require discussion with the 
sponsor and an amendment. 
Drug 
Anti-
estrogen 
Pembrolizumab 
Level 1 
Standard* 
200 mg 


Product:  MK-3475 
58 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
8.1.1.1.2. Cohort 2 (pembrolizumab and Aromatase Inhibitor) 
For cohort 2, when the first 6 patients have been completed cycle 1 with at most 1 dose 
limiting toxicities (DLT), the safety-lead in for that doublet will be considered successful, 
and accrual will proceed based on the Phase II considerations below.  For cohort 2, if 2 DLTs 
are observed on dose level 1 in the first 6 patients the study will hold accrual pending 
discussion with sponsor, PI, and COH DSMB for the selection of a dose level -1 or terminate 
consideration of that treatment doublet.   
8.1.2 Definitions of DLTs 
DLTs for both cohorts are defined as: 
Hematologic Toxicities: 
• Any Grade 4 thrombocytopenia or neutropenia lasting >7 days 
Nonhematologic Toxicities: 
• Episcleritis, uveitis, or iritis of Grade 2 or higher  
• Any Grade 4 toxicity 
• Any Grade 3 toxicity EXCLUDING: 
o Nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours 
o Grade 3 rash in the absence of desquamation, no mucosal involvement, does not 
require steroids, and resolves to Grade 1 by the next scheduled dose of 
pembrolizumab. 
o Rapidly reversible electrolyte abnormalities (within 72 hrs.). 
o Transient Grade 3 AST or ALT elevation, defined as no more than 3 days with or 
without steroid use 
• Discontinuation or delay of more than 2 weeks of any study drug due to treatment-related 
AE will be considered as a DLT 
Toxicity will be graded according to the NCI CTCAE version 4.0.  To be evaluable for 
toxicity, a patient must receive at least one complete course of treatment and be observed for 
at least 21 days after the start of the first course or have experienced a DLT.  All patients who 
receive any amount of drug will be considered evaluable for toxicity.   
 
 


Product:  MK-3475 
59 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
8.1.3 3-at-risk—Rules of Level Assignment 
     3-at-risk -- Rules for Dose Level Assignment  
# Patients on Current Level 
Action 
DLT 
EVAL EVAL+At 
Risk 
 
0 
0 
1-2 
Accrue next patient at this level* 
0 
0 
3 
Hold accrual 
0 
1 
1-3 
Accrue next patient at this level 
0 
1 
4 
Hold accrual 
0 
2 
2-4 
Accrue next patient at this level 
0 
2 
5 
Hold accrual 
0 
3 
3-5 
Accrue next patient at the next higher level* 
1 
1 
1-2 
Accrue next patient at this level 
1 
1 
3 
Hold Accrual 
1 
2 
2 
Accrue next patient at this level 
1  
2 
3-4 
Hold accrual 
1 
3-5 
3-5 
Accrue next patient at this level 
1 
3-5  
6 
Hold accrual 
1 
6 
6 
Accrue next patient at the next higher level* 
2** 
any 
Any 
Accrue next patient at the next lower level to a 
maximum of 6 
*If in dose-escalation portion. If higher dose level already closed, the next lower dose will 
accrue to a total of 6 patients, with 2 or higher DLTs requiring further dose de-escalation.  If 
there is no next higher dose, the next patient will be accrued to the current level. 
**Patients treated on a higher dose during cycle 1 will have their treatment modified to the 
dose below the dose level with 2 DLTs. 


Product:  MK-3475 
60 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Note:  “DLT” – a patient with a documented first-cycle DLT; “PASS” – a patient without a 
first-cycle DLT fully evaluable for toxicity for the purpose of dose escalations; “EVAL” – a 
patient who is either DLT or PASS; “Inevaluable” – a patient who is off treatment without 
being DLT or PASS; “At Risk” – a patient who is on study in the first cycle and not yet DLT, 
PASS, or Inevaluable 
8.2 
Statistical Plan Phase II 
Phase II considerations: 
8.2.1 Cohort 1 
Cohort 1 (doxorubicin plus pembrolizumab):  
Cohort 1: All patients treated in cohort 1 (regardless of dose level) will be included in the 
efficacy assessments as it is unclear, based on historical data, if there is a significant clinical 
advantage to higher dose intensity once beyond 50mg/m2. Patients with triple negative 
metastatic breast cancer are eligible.  All patients must be doxorubicin and pembrolizumab 
naïve. Patients will be treated with doxorubicin and pembrolizumab. For each treatment, 
following the safety lead-in, we will accrue to a total of 36 patients over 18-24months.   
Recent (19) data on single agent platinum treatment in first and second line metastatic 
patients are 25.6% (95% CI 16.8-36.1%), with second line cisplatin at 22.2% and first-line 
carboplatin at 22.9%.   First-line patients who will be likely candidates for this study will 
either have peripheral neuropathy preventing taxanes and platinum, or will have recurred 
rapidly after taxane-platinum containing adjuvant therapy, or progressed, suggesting low 
efficacy of standard approach. Patients would need to be doxorubicin naïve. As a result of 
this patient selection, we have set a discouraging response rate at 15% and an encouraging 
rate at 34%.  The null hypothesis H0: is ORR<=15%, and the alternative H1: ORR>=34%.  
Specifically, for we follow Simon’s MinMax two-stage design with a type I error of 10% and 
a power of 90%: If 3 or fewer responses are noted in the first 22 patients in this cohort, the 
study will hold accrual for futility.  In the case of early stopping, evaluation of patient subsets 
(e.g. immune phenotype), in consultation with the PI, statistician, sponsor and DSMB, may 
permit the study to continue for specific subsets following an amendment if it is deemed to 
be inadequately evaluated and there appears to be sufficient promise for that subset. If early 
stopping does not occur, accrual will continue to a total of 36 patients are treated in this 
cohort.  With 36 patients, 9 patients with an ORR (25%) are required to deem this 
combination worthy of further evaluation. This maintains the type I error at 10% to reject the 
null hypothesis and the power at 90% to declare a positive finding if the alternative 
hypothesis holds.  Secondary analysis endpoints, including progression-free survival, time-
to-treatment failure, and toxicity may influence the overall recommendation for future 
evaluation.  With 36 patients on this cohort, we expect at least 10 patients on this cohort to 
have pre- and post-treatment biopsy material for correlative analysis and approximately 36 
patients with pre-treatment biopsy. 


Product:  MK-3475 
61 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
8.2.2 Cohort 2 
Cohort 2 (AI+pembrolizumab): Patients with ER+ HR2- metastatic breast cancer who have 
recurred on or after, or progressed on prior endocrine therapy.  Objective response in this 
setting is rare for AI (~10%), which has suggested the following design:  
We will accrue 20 patients over 12-24 months.  With 20 patients, if 3 or more patients 
experience a response, this would be considered worthy of further evaluation.  This rule has a 
power of over 80% to detect a true response rate of 20% (encouraging, alternative 
hypothesis) and a type I error of less than 8% for falsely declaring a 5% response rate 
(discouraging, null hypothesis) as promising.   This rule establishes the minimum response 
rate for declaring the combination promising, however, it does not preclude the combination 
could be promising based on secondary endpoints such as progression-free survival. Analysis 
by prior treatment may also influence the overall recommendation.   
In addition, with 20 patients in this cohort, we expect to obtain at least 10 patients with pre 
and post-treatment biopsy for correlative analysis, although all patients will have tissue for 
baseline evaluation. 
8.3 
Correlative Science 
The correlative studies will be used to potentially refine patient selection for future studies, 
and understand the role of immune changes and baseline status on the activity of the 
combination of pembrolizumab with AIs, or doxorubicin.  These correlative studies are 
considered exploratory in the context of this limited Phase II study.  
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 


Product:  MK-3475 
62 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
10.0 OTHER STUDY DRUGS: 
10.1 
Doxorubicin 
10.1.1 Availability 
Doxorubicin is commercially available as lyophilized powder for reconstitution in 10, 20, 50, 
100 and 150 mg vials.  Also available as 2 mg/ml solution for injection in 10, 20, 50, 75, and 
200 mg vials. Please refer to the FDA-approved package insert for complete product 
information 


Product:  MK-3475 
63 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
10.1.2 Storage and Stability 
Intact vials of doxorubicin solution should be stored in the refrigerator.  Intact vials of 
powder for reconstitution should be stored at room temperature.  Reconstituted solutions are 
stable for 7 days at room temperature and 15 days under refrigeration when protected from 
light.  Commercially available solutions labeled as such are intended to be multidose vials. 
10.1.3 Preparation 
Reconstitute the vials of doxorubicin powder with 5, 10, 25, 50 or 75 ml, respectively, of  
Sodium Chloride for Injection, USP, resulting in a concentration of 2 mg/ml. 
10.1.4 Toxicities 
Common: Hair loss, vomiting, red colored urine, saliva and/or sweat 
Less Common: Nausea, damage to the heart, heart failure, heart attack, swelling of the heart, 
swelling and redness of the area of radiation (if radiation is part of treatment) or at the site of 
the medication injection, belly pain, sores in the mouth, throat, or stomach, infection, 
especially when white blood cell count is low, bruising, bleeding, hepatitis or damage to the 
liver, tiredness, allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat, swelling of the lungs which may cause 
shortness of breath, cancer of bone marrow (leukemia) caused by chemotherapy, damage to 
the bone marrow (irreversible) which may cause infection, bleeding, may require 
transfusions, darkening of the nail beds or skin or hands and feet, loss of nails 
 
Rare: Severe blood infection 
 
10.2 
Exemestane 
10.2.1 Availability: 
Exemestane is commercially available as a 25 mg tablet 
10.2.2 Storage and Stability: 
Exemestane should be stored at room temperature 
10.2.3 Toxicity: 
Common: Hot flashes, osteopenia, vaginal discharge and/or dryness, joint/muscle pain, 
fatigue, headache, insomnia, nausea, hair thinning 
Less Likely: Bone fractures from osteoporosis, shortness of breath, diarrhea, constipation, 
loss of appetite, dry skin/skin rash, diarrhea, stomach ache, indigestion, vision changes, 
dizziness, nervousness, reduced libido. 


Product:  MK-3475 
64 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Rare: drowsiness, muscle weakness, inflammation of the liver 
10.3 
Anastrozole 
10.3.1 Availability: 
Anastrozole is commercially available as a 1 mg film coated tablet. 
10.3.2 Storage and Stability 
Anastrozole should be stored at room temperature. 
10.3.3 Toxicity: 
Common: headaches, hot flushes and sweats, nausea, rashes, painful or stiff joints, arthritis, 
feeling weak, loss of bone density caused by a lack of estrogen over a long period of time, 
mood changes, tiredness or fatigue, reduced libido  
Less Common: Bone pain, carpal tunnel syndrome, hair thinning, loss of appetite, raised 
cholesterol levels, feeling sleepy, vomiting, liver changes, diarrhea, dryness of the vagina, 
vaginal bleeding 
Rare: Inflammation of the liver (hepatitis), trigger finger 
10.4 
Letrozole: 
10.4.1 Availability:   
Letrozole (Femara) 2.5 mg tablets are dark yellow, film-coated, round, slightly biconvex, 
with beveled edges imprinted with the letters FV on one side and CG on the other side.  
Letrozole is for oral administration.  Letrozole is commercially available. Refer to the 
Product Information Sheet for information regarding the physical and chemical properties of 
letrozole. 
10.4.2 Storage and Stability 
Letrozole should be stored at room temperature and away from excess heat and moisture. 
10.4.3 Toxicities: 
Common: Hot flushes and sweats, pain in joints or bones, tiredness and weakness (fatigue), 
increased levels of cholesterol in the blood  
Less Common: Skin rashes, headaches , dizziness, malaise, nausea and vomiting, fluid 
retention, loss of appetite or indigestion, hair thinning, diarrhea, constipation, vaginal 
dryness, reduced libido, sadness or depression,  cough and breathlessness, osteoporosis, 
vaginal bleeding, muscle pain, weight gain, hypertension, pain in the abdomen  


Product:  MK-3475 
65 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
Rare: Nervous disorders such as anxiety, nervousness, feeling irritable, drowsiness, memory 
problems, difficulty sleeping, changes in sensation, especially touch, eyesight changes such 
as blurred vision, red, sore eyes, heart palpitations, joint stiffness (arthritis), trigger finger, 
carpal tunnel syndrome, breast pain, fever, taste changes,  dry mouth and feeling thirsty, 
weight loss, urine infections 
11.0 ADMINISTRATIVE AND REGULATORY DETAILS 
11.1 
Confidentiality 
As per City of Hope Standard Operating Procedures. 
11.2 
Compliance with Financial Disclosure Requirements 
As per City of Hope Standard Operating Procedures 
11.3 
Compliance with Law, Audit and Debarment 
11.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
11.5 
Quality Management System 
As per City of Hope Data Safety Monitoring and Clinical Trials Office Standard Operating 
Procedures. 
11.6 
Data Management 
As per City of Hope Standard Bioinformatics Standard Operating Procedures. 
 


Product:  MK-3475 
66 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
12.0 APPENDICES 
12.1 
ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* 
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
12.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
12.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study. 
* As published in the European Journal of Cancer: 


Product:  MK-3475 
67 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
12.4 
Events of Clinical Interest Guidance Documents 
12.4.1 IB 
 


Product:  MK-3475 
68 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
 
12.5 
Blood Sample Collection 
Blood samples will be collected from an indwelling venous catheter or by venipuncture. At 
each time point indicated in the study calendar, peripheral blood will be collected into three 7 
mL green-top tubes (sodium or lithium heparin) to prevent blood clotting. Tubes will be 
inverted several times and then immediately placed on ice for transportation to the COH 
Analytical Pharmacology Core or local research specimen processing laboratory. The whole 
blood should be processed within 4 hours of collection. While awaiting processing, the blood 
should be kept on a rocker set at low speed to mimic circulation and avoid clot formation.   
12.6 
Blood Sample Processing 
Plasma 
 For plasma preparation, anti-coagulated whole blood (two 7 mL green-top tubes) will 
be processed by centrifugation for 10 minutes at 1000 x g at 4⁰ C. The resulting 
upper plasma layer from each tube will be drawn up sequentially into a sterile 5 mL 
syringe and pushed through a sterile 0.2/0.8 micron disposable filter (PALL Acrodisc 
PF, Cat. 4658). The filtered plasma will then be transferred in 500 µL aliquots into 
multiple appropriately-labeled Starstedt microfuge tubes (Starstedt Cat 72.692.005). 
To one aliquot, add 0.5 mL glycerol/0.02% sodium azide solution to dilute the plasma 
50/50 v/v. Keep the diluted plasma sample at -20˚C and do not freeze. All the 
remaining plasma aliquots will be stored frozen at -80˚C until ready for testing. 
 
 
PBMCs 
 Any blood remaining in the two 7 mL green-top tubes used to prepare plasma above 
will be diluted 1:1 with Hank’s Balanced Salt Solution (“HBSS”, Irvine Scientific, 
Cat. 9228 or equivalent)  and combined with the whole blood from the unused green-
top tube in a sterile 50 ml  conical centrifuge tube. Peripheral blood mononuclear 
cells (PBMC) will then be isolated from the combined whole blood sample by Ficoll-
gradient separation as described below; 
o Allow Accuspin-Histopaque tubes (“Accuspin”, Sigma Cat. A6929 or A0561, 
for 12 or 100 tubes, respectively) and HBSS to warm to room temperature. 
Place a Mr. Frosty container in the refrigerator and prepare the freezing media 
by adding 10% DMSO to fetal calf serum and chill at 4˚C or on ice.  
o Prepare Accuspin tubes by centrifuging at 1000 x g for 1 minute at room 
temperature (RT) with brakes on. Each tube can process up to 20 mLs of 
whole blood; prepare the appropriate amount of tubes necessary. After 
centrifugation, the Histopaque reagent should be below the barrier of the tube. 
Add 5 mLs of HBSS to the Accuspin tube. Add up to 20 mls of whole blood 
to each Accuspin tube until all the blood has been distributed.  
o Centrifuge the blood sample at 800 x g for 15 minutes at RT with brakes on 
LOW. After centrifugation, three layers should be visible above the barrier of 
the tube: the plasma layer at the top, a cloudy layer in the middle where the 


Product:  MK-3475 
69 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
PBMC are, and a clear Histopaque reagent layer right below. Using a pipette, 
remove the upper plasma layer to within 2 cm of the cloudy interphase. 
Carefully pipette the cloudy PBMC interphase and transfer to a sterile 50 mL 
centrifuge tube.  
o Add HBSS up to the 45 mL mark in the centrifuge tube with the PBMC and 
spin at 400 x g for 10 minutes at RT with brakes on. Decant the supernatant 
and loosen the cell pellet before adding HBSS to the 45-mL mark again for a 
second wash. Centrifuge at 300 x g for 10 minutes at RT with brakes on. 
Decant the supernatant, loosen the cell pellet and then add a known volume of 
HBSS to resuspend the cells for counting. Mix the cell suspension up and 
down with a pipette several times before removing a small aliquot for cell 
count. 
o Centrifuge the cell suspension one final time at 300 x g for 10 minutes at RT 
with brakes on. PBMC should be frozen down at 0.5 – 1 x 107 cells/vial. 
Determine the volume of freezing media (fetal calf serum with 10% DMSO) 
needed to give a 1 x 107 cell/mL suspension. After the last centrifugation is 
complete, discard supernatant and loosen the cell pellet before adding freezing 
media slowly, a small volume at a time with mixing in between (vortex at low 
speed). Aliquot 0.5 - 1 mL of the final cell suspension into individually 
labeled cryovials. Transfer the cryovials into Mr. Frosty and store at -80˚C. 
Twenty four hours later, cryovials will be transferred to liquid nitrogen tanks 
for long-term storage.   
 
13.0      REFERENCES 
1. 
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. A phase Ib study of 
pembrolizumab in patients with triple negative breast cancer. SABCS 2014; S1-09 
2. 
Chen WW, Chang DY, Huang SM, Lin CH, Hsu C, Lin MH et al, The first two lines 
of chemotherapy for anthracycyline-naïve metastatic breast cancer: A comparative 
study of the efficacy of anthracyclines and non-anthracyclines. The Breast 2013; 
22:1148-53 
3. 
Partridge AH et al. Chemotherapy and targeted therapy for women with human 
epidermal growth factor receptor 2-negative (or unknown) advanced breast 
cancer:ASCO Clinical Practice Guideline. J Clin Oncol. 2014;32(29):3307-29 
 
4. 
Dent R et al. Triple-negative breast cancer. Clinical features and patterns of 
recurrence. Clin Cancer Res. 2007;13:4429-4434 
5. 
Muenst S et al. Expression of programmed death ligand 1(PDL-1) is associated with 
poor prognosis in human breast cancer. Breast Cancer Res Treat 2014; 146(1): 15-24 
 


Product:  MK-3475 
70 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
6. 
Adams S et al. Prognostic value of tumor –infiltrating lymphocytes in triple-negative 
breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 
2197 and ECOG 1199. J Clin Oncol 2014;Jul 28 Epub 
 
7. 
Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, et al. 
Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their 
correlation with molecular cancer type  Cancer Epid Biomarkers Prev; 
2014;23(12):2965-70 
8. 
Chawla A et al. Immune checkpoints: a therapeutic target in triple - breast cancer. 
Oncoimmunology 2014; 3(3):e28325 
 
9. 
Schalper KA et al. In situ tumor PD-L1 mRNA expression is associated with 
increased TILs and better outcome in breast carcinomas. Clin Cancer Res 2014; 
20(10):2773-82 
 
10. 
Sun S et al.  PD-1 (+) immune cell infiltration inversely correlates with survival of 
operable breast cancer. Cancer Immunol Immunother 2014; 63(4):395-406. 
 
11. 
Soliman H et al. PD-L1 expression is increased in a subset of basal type breast cancer 
cells. Plos One 2014; 92:e88557 
 
12. 
Lu  L et al. Combined PD-1 blockade and GITR triggering induce a potent antitumor 
immunity in murine cancer models and synergizes with chemotherapy drugs.  J 
Transl Med 2014; 12:3 
13. 
Chia S et al.  Double-blind, randomized placebo controlled trial of fulvestrant 
compared with exemestane after prior non-steroidal aromatase inhibitor therapy in 
postmenopausal 
women 
with 
hormone 
receptor-positive,advanced 
breast 
cancer:results from EFECT. J Clin Oncol 26(10):1664-70, 2008.  
14. 
Mehta RS et al. Combination anastrozole and fulvestrant in metastatic breast cancer. 
N EJM 2012;367(5):435-44, 2012.  
 
15. 
Gennatas C, Michalaki V, Carvounis E, Psychogios J, Poulakaki N, Kasiamis G, et al, 
Third line treatment with exemestane in postmenopausal patients with advanced 
breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by 
the Hellenic Group Oncology (HELGO). Tumori, 2006;92(1):13-17. 
 
16. 
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F et al. Prognostic and 
predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant 
breast cancer trial in node-positive breast cancer comparing the addition of docetaxel 
to doxorubicin with doxorubicin-based chemotherapy:BIG 0298. J Clin Oncol 2013; 
31(7):860-7 
17. 
Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R et al. 
Tumor-infiltrating lymphocytes and response to neoadjuvant therapy with or without 


Product:  MK-3475 
71 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9 
 
carboplatin in human epidermal growth factor receptor 2-positive and triple negative 
primary breast cancers. J Clin Oncol. 2015. 33(9):983-91.  
18. 
Ghebeh H, Lehe C, Barhoush E, Al-Romaih K, Tulbah A, Al-Alwan M, et al. 
Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear 
expression in breast cancer cells: role of B7-H1 as an antiapoptotic molecule.  Breast 
Cancer Res 2010; 12(4):R48 
19. 
Robertson JF, et al. Fulvestrant 500 mg versus anastrozole 1 mg for first-line 
treatment of advanced breast cancer:follow-up analysis from the randomized “FIRST’ 
study. Breast Cancer Treat Res 2012 136:503-11 
20. 
Isakoff SJ et al. TBCRC009: A multicenter phase II clinical trial of platinum 
monotherapy with biomarker assessment in metastatic triple negative breast cancer. J 
Clin Oncol/ 2015 33:1902-1909 
21. 
Turner NC et al. Palbociclib in hormone-receptor-positive advanced breast cancer.  N 
Engl J Med  2015;373:209-19 
22. 
Baselga J et al.  Everolimus in postmenopausal hormone-receptor–positive advanced 
breast cancer.  N Engl J Med 2012;366(6):520-9, 2012 
23. 
E.A. Eisenhauer, et al. New response evaluation criteria in solid tumors: Revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
24. 
Chang AY, Bhattacharya N, Mu J, et al. Spatial organization of dendritic cells within 
tumor draining lymph nodes impacts clinical outcome in breast cancer patients. J 
Transl Med 2013;11:242 
25. 
Critchley-Thorne RJ, Simons DL, Yan N et al. Impaired interferon signaling is a 
common immune defect in human cancer. Proc Natl Acad Sci USA 
2009;106(22):9010-5 
26. 
Critchley-Thorne RJ, Yan N, Nacu N, et al. Down-regulation of interferon-signaling 
pathway in T lymphocytes from patients with metastatic melanoma. PLoS Med 2007; 
4(5):3176 
27. 
Setiadi AF, Ray NC, Kohrt HE et al. Quantitative architectural analysis of immune 
cell subsets in tumor-draining lymph nodes from breast cancer patients and healthy 
lymph nodes. PLos One 2010;5(8):e12420 
28. 
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G et al. The 
evaluation 
of 
tumor-infiltrating 
lymphocytes 
(TILs) 
in 
breast 
cancer: 
recommendations by an international TILs Working Group 2014. Ann Oncol 
2015;26(2):259-71 


Product:  MK-3475 
72 
Protocol/Amendment No.:   
 
 
IRB# 15295 
 
06/20/17 
Version: 9