Neoadjuvant Her2-targeted Therapy and Immunotherapy With Pembrolizumab (neoHIP)
Phase: PHASE2
Conditions: HER2-positive Breast Cancer, Breast Cancer
Sponsor: University of Texas Southwestern Medical Center

 
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IIT2018-04-McArthur-neoHP 
 
Neoadjuvant HER2-targeted Therapy and Immunotherapy with Pembrolizumab 
(neoHIP) 
 
 
Principal Investigator: 
Heather McArthur, MD 
 
 
 
 
University of Texas Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd, Dallas, TX, 75390 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FDA Status:  
 
 
Exempt   
 
Funding Source:  
Merck, Breast Cancer Research Foundation 
 
ClincialTrials.gov Reg:  
Registered 
 
NCT Number:   
 
NCT03747120 
 
ClincialTrials.gov Reporting: Required 
 
Initial version:  
 
Protocol Version 1 dated 25SEP2018 
 
 
 
Protocol Version 2 dated 10JAN2019 
 
 
 
Protocol Version 3 dated 03MAR2020 
 
 
 
Protocol Version 4 dated 08DEC2020 
 
 
 
Protocol Version 5 dated 24MAR2021 
 
 
 
Protocol Version 5.1 dated 16JUN2021 
 
 
 
Protocol Version 6 dated 21JUN2022 
 
 
 
Protocol Version 7 dated 27FEB2023 
Current version: 
 
Protocol Version 8 dated 14DEC2023 
 

 
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Signature Page 
Protocol Version 8.0 Dated 14DEC2023 
 
 
The signature below constitutes the approval of this protocol and the attachments and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
 
 
 
 
 
 
 
 
 
______________________________________________ 
 
 
_________________ 
Principal Investigator (PI) Signature    
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS  
LIST OF ABBREVIATIONS .................................................................................. 1 
STUDY SCHEMA ................................................................................................. 4 
STUDY SUMMARY .............................................................................................. 5 
1.0 
BACKGROUND AND RATIONALE ........................................................... 6 
2.0 
STUDY OBJECTIVES .............................................................................. 12 
3.0 
STUDY DESIGN ....................................................................................... 15 
4.0 
PATIENT ELIGIBILITY ............................................................................. 17 
5.0 
TREATMENT PLAN ................................................................................. 21 
6.0 
STUDY PROCEDURES ............................................................................ 28 
7.0 
ADVERSE EVENTS (AE) ......................................................................... 33 
8.0 
CORRELATIVES/SPECIAL STUDIES ..................................................... 53 
9.0 
STATISTICAL CONSIDERATIONS ......................................................... 55 
 
10.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL …58 
SUPPLIES 
11.0 STUDY MANAGEMENT ........................................................................... 59 

 
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12.0 REFERENCES .......................................................................................... 64 
13.0 APPENDICES ........................................................................................... 68 
 

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LIST OF ABBREVIATIONS 
 
ADCC 
Antibody Dependent Cell-Mediated Cytotoxicity  
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
activated Partial Thromboplastin Time 
ASCO-CAP 
American Society of Clinical Oncology-College of American Pathologists 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BCG 
Bacillus Calmette–Guérin 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CBE 
Clinical Breast Exam 
CBR 
Clinical Benefit Rate 
CD 
Cluster of differentiation 
chemo 
chemotherapy 
CHF 
Congestive Heart Failure  
CISH 
Chromogenic in Situ Hybridization  
CMP 
Complete Metabolic Panel 
 
 
Conmed 
Concomitant medication 
CPT 
Cell Preparation tube 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CrCl 
Creatinine Clearance 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT CAP 
Computed Tomographic Chest Abdomen Pelvis 
CTFG 
Clinical Trial Facilitation Group 
CTL 
Cytotoxic T-lymphocyte 
CTLA-4 
Cytotoxic T-lymphocyte-associated protein 4 
DC 
Dendritic Cell  
ddAC 
Dose-dense Adriamycin + Cytoxan 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECI 
Event of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 

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EF 
Ejection Fraction 
EFS 
Event Free Survival 
ER 
Estrogen Receptor 
FDA 
Food and Drug Administration 
FFPE 
Fresh Frozen Paraffin Embedded  
FISH 
Fluorescence in-situ hybridization 
FOXP3 
Forkhead box P3 
FSH 
Follicle stimulating hormone  
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor  
GFR 
Glomerular Filtration Rate 
H&P 
History & Physical Exam 
Hr 
Hour 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HER2 
Human Epidermal Growth Receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
IB 
IDFS 
Investigator’s brochure 
Invasive Disease-Free Survival 
IFN 
Interferon 
IHC 
Immunohistochemistry 
IL-2 
Interleukin-2 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
irAE 
Immune-related adverse event 
ITT 
Intent-To-Treat 
IUD 
Intrauterine device 
IV 
Intravenously 
Kg 
Kilogram 
LH 
Luteinizing Hormone 
LVEF 
Left Ventricular Ejection Fraction  
Mg 
Milligram 
MHC 
Major Histocompatibility Complex  
mIHC 
Multispectral immunohistochemistry 
mRNA 
Messenger Ribonucleic acid 
MDSCs 
Myeloid Derived Suppressor Cell  
MK 
Merck 
Mg 
Milligram 
MHC 
Major Histocompatibility Complex 
mITT 
Modified Intent-To-Treat 
mL 
Milliliters  
MRI 
Magnetic Resonance Imaging 

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MTD 
Maximum Tolerated Dose 
MUGA scan 
Multigated Acquisition Scan  
N 
Nodal status 
NCI 
National Cancer Institute 
NSAIDs 
Non-Steroidal Anti Inflammatory Drugs  
NYHA 
New York Heart Association  
ORR 
Objective Response Rate 
OS 
Overall Survival  
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response  
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Cell Death Ligand 1 
PET/CT 
Positron Emission Tomography/Computed Tomography 
PFS 
Progression Free Survival 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PO 
Per oral 
PR 
Progesterone Receptor 
PRs 
Partial Response 
PT 
Prothrombin Time 
RCB 
Residual Cancer Burden 
Reg 
Regulatory 
RNA 
Ribonucleic acid 
RSD 
Reference Safety Dataset 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SOC 
Standard of care 
SGPT 
Serum Glutamic Pyruvic Transaminase 
T 
Tumor size 
T3/T4 
Triiodothyronine / Thyroxine  
TAA 
Tumor Associated Antigen  
TB 
Tuberculosis 
TCR 
T-Cell Receptor 
TIL 
Tumor infiltrating lymphocyte 
TNBC 
Triple-Negative Breast Cancer 
TNF-α 
Tumor necrosis factor-alpha 
Treg 
T regulatory cell 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper limit of normal 
WOCBP 
Women of child-bearing potential 

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STUDY SCHEMA: 
 
 
 
 
Randomization 
(n=174) 
Arm A: 
Paclitaxel weekly x12 + 
Trastuzumab + 
Pertuzumab (THP) 
 
 
N= 58 patients 
Arm B:  
Paclitaxel weekly x12 + 
Trastuzumab + 
Pertuzumab + 
Pembrolizumab (THP-K) 
 
N= 58 patients 
Arm C:  
Paclitaxel weekly x12 + 
Trastuzumab + 
Pembrolizumab (TH-K) 
ARM C is closed** 
 
N= 58 patients 
Neoadjuvant Chemo Candidates 
HER2-positive (by ASCO/CAP guidelines) unilateral invasive breast cancer, cT2-4N0 or cT1-4N1-3 
Surgical Resection Planned 
Primary endpoint: pathologic complete response (pCR) in the breast and axilla (ypT0/is ypN0). 
 
Patients will be stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive 
vs. negative). 
 
Trastuzumab loading dose of 8 mg/kg Cycle 1, and subsequent maintenance dose of 6 mg/kg Q3 weeks IV 
Pertuzumab loading dose of 840 mg and subsequent maintenance dose of 420 mg Q3 weeks IV 
Pembrolizumab is at fixed dose of 200mg Q3 weeks IV 
Paclitaxel will be administered weekly at a dose of 80mg/m2 for 12 weeks 
 
Physician’s Choice Adjuvant Therapy per Standard-of-Care 
(Additional chemotherapy permitted before surgery if biopsy proven residual disease) 
 
BREAST SURGERY 

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STUDY SUMMARY 
Title 
 
Neoadjuvant HER2-targeted Therapy and Immunotherapy with 
Pembrolizumab (neoHIP).   
Protocol Number 
IIT2018-04-MCARTHUR-NEOHP 
Phase 
2 
Methodology 
Prospective, open-label, multi-center therapeutic trial 
Study Duration 
36-month projected enrollment period and additional 84 months median 
follow-up 
Study Center(s) 
Cedars-Sinai Medical Center, Providence (Portland, OR), Massachusetts 
General Hospital (Boston, MA), University of Texas at Southwestern 
(Dallas, TX), New Mexico Cancer Center 
Objectives 
Primary Objectives: 
To explore rates of pathologic complete response (pCR) in the breast and 
axilla (ypT0/Tis ypN0) following 12 weeks of neoadjuvant HER2-directed 
systemic therapy with or without pembrolizumab 
 
Secondary Objective: 
To define the impact of the interventions on pathological invasive and in 
situ complete response in breast and axilla (ypT0 ypN0), pathologic 
invasive complete response in the breast only (ypT0/is), residual cancer 
burden (RCB), breast conserving surgery rate, event free survival (EFS), 
invasive disease free survival (IDFS), overall survival (OS), and safety. 
 
Exploratory Objective: 
1) To characterize the immunologic effect of pembrolizumab, 
pertuzumab and trastuzumab administration in peripheral blood, 
intratumorally, and within the microbiome. 
2) To correlate clinical outcomes with exploratory correlates wherever 
feasible, in order to explore potential predictive biomarkers of clinical 
efficacy or toxicity 
  
Number of Subjects 
174 patients 
Diagnosis and Main 
Inclusion Criteria 
-HER2-positive (by ASCO/CAP guidelines) invasive unilateral breast 
cancer 
-cT2-4N0 or cT1-4N1-3 
-Patients will be stratified by clinical nodal status (positive vs. negative) 
and hormone receptor status (positive vs. negative) 
Study Product(s), Dose, 
Route, Regimen 
-Paclitaxel 80mg/m2 weekly for 12 weeks  
-Trastuzumab 8mg/kg (loading dose) and then 6mg/kg IV every 3 weeks 
x 3 doses. Per local standard practice, an FDA-approved biosimilar 
administered intravenously may be substituted for trastuzumab at the 
same dose. Trastuzumab and hyaluronidase-oysk for subcutaneous 
administration may be substituted for trastuzumab, at 600 
mg/hyaluronidase 10,000 units once every 3 weeks for total of 4 doses. 
No loading dose is required for trastuzumab and hyaluronidase-oysk.   
-Pertuzumab 840mg (1 loading dose) and then 420mg/kg IV every 3 
weeks x 3 doses 
-Pembrolizumab 200mg IV every 3 weeks x 4 doses 
Duration of administration 
12 weeks 

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Reference therapy 
Trastuzumab, pertuzumab and paclitaxel 
Statistical Methodology 
The rate of pCR (ypT0/Tis ypN0) in the control group (SOC THP Arm A) 
is expected to be 50%. We assume the treatment group will achieve a 
pCR rate of 73%. With a trial design 1:1:1 of THP vs. 
THP+pembrolizumab (THP-K) vs. TH+pembrolizumab (TH-K), for 
alpha=0.05 and power=80%, 55 patients are required for each arm.  
To account for a 5% loss to follow up during the trial, 3 additional patients 
will be enrolled to each arm (58 patients/arm). Due to the binary nature of 
the primary endpoint, patients who discontinue study therapy without 
undergoing surgery will be considered as a non-responder (non-pCR). A 
total of 174 patients will be enrolled in this trial. 
A safety interim analysis will take place after every 15th patient receives at 
least one dose of study treatment in each of the experimental arms. An 
efficacy analysis will take place after 20 patients have enrolled to Arm C. 
1.0 
BACKGROUND AND RATIONALE 
1.1 Breast Cancer 
Breast cancer is the most frequent women cancer worldwide, with an incidence of more 
than 1.7 million new cases1. The American Cancer Society estimates for 2017 over 
255.000 new breast cancer cases within the United States2. Screening programs and 
effective local and systemic adjuvant therapies have been responsible for increasing 
survival rates, but still, more than 500.000 and 41000 breast cancer deaths are expected 
in 2017, globally and in the U.S.  respectively.  
 
One of the major advances in cancer research throughout the years was an in depth 
understanding of disease intrinsic biology, enabling a better clinical pathological and 
biological classification of breast cancer. There are three major clinically relevant 
subtypes that are managed differently: luminal (expressing the estrogen receptor (ER) 
and/or progesterone receptor (PR), human epidermal growth factor receptor-2+ (HER2+), 
and triple-negative, lacking expression of ER, PR, and HER2 (TNBC)3. The 8th edition of 
the American Joint Committee on Cancer (AJCC) Manual has incorporated biologic 
factors including tumor grade, ER, PR and HER2 status and the OncotypeDx Recurrence 
Score, helping clinicians with prognostic and predictive factors related to breast cancer4. 
Of these subtypes, HER2+ breast cancers and TNBCs are more likely than luminal breast 
cancers to harbor stromal tumor infiltrating lymphocytes (TILs) at diagnosis, with a linear 
relationship between stromal TIL content and clinical outcomes5. HER2+ breast cancers 
and TNBCs are also more likely to express the programmed cell death ligand 1 (PD-L1) 
in the tumor microenvironment than luminal breast cancers6,7.  
 
The classical approach to early stage breast cancer treatment is surgery, systemic 
adjuvant therapy and radiation therapy8. But some types of breast cancer are diagnosed 
at a locally advanced stage of disease, with increased rates of recurrence and metastasis 
after traditional treatment approaches9. The incorporation of neoadjuvant systemic 
therapy at this scenario has brought tremendous improvements, with some patients 
achieving a pathological complete response and consequently better survival10. Some 
subtypes of breast cancer derive better outcomes with this strategy (like HER2 positive 
and triple negative breast cancer)11. 
About 20% of breast cancer overexpresses HER2 protein12, conferring those patients 
with a worse prognosis. Since the discovery of trastuzumab and drug incorporation on 
the metastatic setting, increasing response and overall survival, a tremendous evolution 
of and understanding of this disease has taken place. In the adjuvant setting, several 
trials have demonstrated increased survival13. Since then, newer HER2 directed agents 

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have been developed14. The dual HER2 blockade therapeutic strategy demonstrated 
increased PFS and OS in the metastatic setting15, and increased pCR in the neoadjuvant 
setting16,17. Although, with greater pCR, comes more toxicity. In the NeoSphere adjuvant 
trial, one of the arms had a non-chemotherapy strategy using trastuzumab and 
pertuzumab for four cycles, achieving a 17% pCR and no chemotherapy related toxicity18. 
Definitely the therapeutic strategy needs to be challenged, with better treatment and less 
toxicity.  
 
Immunotherapy trials have focused mainly on triple negative breast cancer and at the 
metastatic scenario, with overall response rate of 18.5% in patients heavily pretreated 
that received pembrolizumab19. Even though responses are not of a great magnitude, 
some of those patients are long term survivors, suggesting a possible long term protective 
immune response. Also, some retrospective analysis suggests that higher levels of TILs 
at diagnosis predict benefit from adjuvant and neoadjuvant chemotherapy, with longer 
progression-free survival (PFS) and overall survival (OS)5. A higher CD8+ T cell/Treg 
ratio may also be associated with a greater likelihood of pCR to neoadjuvant 
chemotherapy20. 
 
Since HER2 directed therapies, such as trastuzumab and pertuzumab, have an immune 
mediated mechanism of action21, and most of the toxicity on the neoadjuvant trials is 
related to the chemotherapy backbone, this trial intends to explore the synergistic role of 
neoadjuvant HER2 directed therapy (trastuzumab and pertuzumab) associated with an 
anti-PD1 therapy (pembrolizumab), on patients with HER2 positive non-metastatic breast 
cancer. Besides the classical clinical factors associated with response to treatment, our 
study design will allow for examination on immune correlatives.         
   
1.2 
Rationale for Immune Therapy in Breast Cancer 
The evolving understanding of breast cancer heterogeneity and biology and the 
tremendous efforts on advances in clinical trials through recent years has made possible 
for researchers to shift immune therapy from bench to bedside. Some pre-clinical studies 
have elucidated the relation between inflammation and innate immunity in mammary 
tumorigenesis. It all starts with acute inflammation, activation of innate immunity with 
tumor cell death and maturation of dendritic cells, priming tumor-specific T-cell response. 
If tumor cells are able to evade host immune response, there is a shift to chronic 
inflammation and a complex tumor microenvironment takes place, with lots of 
suppressive immune cells (Tregs, MDSCs and B-cells) and stromal cells (fibroblasts and 
endothelial cells), allowing immune escape and tumor progression22. At this point, 
immune checkpoint molecules are upregulated on tumor and immune cells23. This is the 
pre-clinical rationale for development of checkpoint blockade antibodies.  
The two most common target pathways are cytotoxic T lymphocyte-associated protein 4 
(CTLA-4) and the programmed cell death protein 1 / programmed cell death ligand 1 (PD-
1/PD-L1). Blocking these pathways would remove the inhibitory signals and allow the 
host immune system robust responses to tumor antigens24. Several phase 1 and 2 clinical 
trials have tested this hypothesis in metastatic breast cancer, with modest but 
encouraging initial results. Tremelimumab and ipilimumab, two anti-CTLA-4 antibodies, 
have been tested in Phase 1 or Pilot studies concurrent with other cancer therapies25 or 
cryoablation, with modest clinical results but very interesting correlative biological 
analysis that has been moved forward to the expansion phase26. Studies with the PD-
1/PD-L1 monoclonal antibodies avelumab27, atezolizumab28 and pembrolizumab29 alone 
in metastatic breast cancer have demonstrated overall response rates from 4.8% to 44%, 
depending on the tumor subtype (ER positive, PR positive, HER2 positive or triple 
negative breast cancer), expression of PD-L1 or line of treatment for metastatic breast 

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cancer. Phase 3 trials with pembrolizumab and atezolizumab in metastatic breast cancer 
are 
ongoing 
(NCT03199885, 
NCT02555657, 
NCT02954874, 
NCT02819518, 
NCT03125902, NCT02425891, NCT03371017). 
 
The utility of PD-1/PD-L1 blockade for TNBC in the adjuvant and neoadjuvant settings is 
under intensive investigation. Early data from the I-SPY trial revealed that adding 
pembrolizumab to neoadjuvant paclitaxel results in an estimated pCR rate of 46% versus 
16% in HER2 negative patients, 60% versus 20% in TNBC patients, and 34% versus 
13% in ER+/PR+/HER2- patients30. A trial investigating the combination of 
Pembrolizumab with chemotherapy in the neoadjuvant setting had preliminary results 
presented at ASCO 2017, suggesting that PD-L1 positive TNBC are more likely to 
respond to treatment31.  
 
Chemotherapy has a varied impact on immune responses, depending on the drug, dose 
and timing. By killing cancer cells and releasing tumor antigens, it would enhance immune 
priming and DC modulation. This is one rationale for combining chemotherapy to PD-
1/PD-L1 blockade32. A phase 1b trial that enrolled patients with metastatic TNBC 
regardless of the PD-L1 status tested atezolizumab with nab-paclitaxel33. Thirty-two 
patients were evaluable for safety and response. Grade 3-4 hematologic toxicity occurred 
in over half the patients, but was manageable. At a median follow up of >5 months, the 
ORR was 38%, with 1 CR, 11 PRs, and 2 additional patients demonstrating a non-
classical response. Responses occurred in patients with both PD-L1+ and PD-L1- 
disease, and there was a trend for higher response rate in patients treated first line 
relative to later line. A phase 3 registrational trial in first line is under way (NCT02425891). 
Pembrolizumab has been tested with eribulin in an ongoing trial designed to enroll 95 
patients with metastatic TNBC of any PD-L1 status treated with < 2 prior lines of 
chemotherapy34. An interim analysis of 39 patients demonstrated the safety of the 
combination, with the most common side effects of fatigue, alopecia, nausea, 
neutropenia, and peripheral neuropathy. The ORR for 17 patients treated first line was 
41.2%, and for those treated second or third line was 27.3%; this included 1 CR and 12 
PRs. The CBR was 41%. PD-L1 status did not appear to impact the likelihood of 
response; the ORR and CBR for PD-L1+ patients were 29.4% and 35.3%, and for PD-
L1- (negative) patients were 33.3% and 44.4%. The KEYNOTE-355 Phase 3 trial is 
evaluating pembrolizumab with chemotherapy relative to various chemotherapy 
regimens alone as first-line therapy for incurable TNBC (NCT02819518).   
 
1.3 Rationale for Immune Therapy and HER2 Directed Therapy in Breast Cancer 
 
Trastuzumab (H), a humanized monoclonal antibody that specifically binds to HER2 
homodimers, is the cornerstone of therapy for both early and late stage HER2-
overexpressing breast cancer. Trastuzumab itself has intrinsic immune modulating 
activity mediating ADCC35 and promoting a HER2-specific T-cell response36. A group 
from Johns Hopkins University, Baltimore, MD, has demonstrated that the pre-clinical 
equivalent of trastuzumab or trastuzumab itself can augment the activity of a cell based 
vaccine in preclinical models37 and in patients38. Also, pre-clinical models using HER2 
transgenic mice demonstrated enhanced Fc-mediated immune priming by DCs, 
augmented effector T-cell activity, and a durable memory T-cell response39. Stagg J. et 
al. have shown that combined therapy with a trastuzumab-like antibody plus a PD-1 
antibody markedly augments the clearance of HER2+ tumors in mice40.  
Multiple clinical trials are underway testing the addition of PD-1/PD-L1 blockade to HER2-
based therapies for both locally advanced and metastatic HER2+ breast cancer. A Phase 
2 global, randomized, double-blind, placebo controlled study is currently underway 
evaluating whether the addition of atezolizumab to TDM1 can further improve clinical 

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outcomes in patients with metastatic HER2+ breast cancer previously treated with 
trastuzumab and a taxane (NCT02924883). 
 
1.4  Rationale for Combining Trastuzumab, Pertuzumab, Paclitaxel 
Trastuzumab is a recombinant humanized anti-p185HER2 monoclonal antibody that 
binds with high affinity to the HER2 protein41. It was the first monoclonal antibody directed 
against the HER2 family receptors, showing clinical efficacy on HER2 overexpressing 
tumors42. Later trials on the metastatic43 and adjuvant scenario13 confirmed that when 
added to chemotherapy, trastuzumab based treatment provided better symptom control 
and prolonged survival on breast cancer patients whose tumors overexpressed HER2. 
Unfortunately, some patients develop disease recurrence after adjuvant treatment and, 
of those, near all of them develops metastatic disease44. The main toxicity signal related 
to trastuzumab is transient myocardial dysfunction, presented by decline on left 
ventricular ejection fraction on MUGA scans45. Strategies to overcome resistance to 
trastuzumab based therapy initially included: maintaining trastuzumab and changing the 
chemotherapy backbone46; changing trastuzumab for a HER2 directed tyrosine kinase 
inhibitor and Capecitabine47; dual HER2 directed therapy48 and the use of an antibody-
drug conjugate trastuzumab entamsine (TDM-1)49.    
 
Pertuzumab is a humanized monoclonal antibody and consists of two heavy chains 
(449 amino acid residues) and two light chains (214 residues). Like trastuzumab, 
pertuzumab is directed against the extracellular domain of HER2. However, it differs 
from trastuzumab in the epitope-binding regions of the light chain (12 amino acid 
differences) and heavy chain (29 amino acid differences). As a result, pertuzumab 
binds to the dimerization epitope of the HER2 receptor, thereby inhibiting dimerization of 
HER2 with other HER family receptors50. Trials that evaluated pertuzumab with 
chemotherapy for breast and other types of cancer showed modest clinical activity, with 
no extra cardiac signal toxicity, but with diarrhea, rash and mucosal inflammation51. Since 
trastuzumab and pertuzumab are HER2 directed monoclonal antibody with 
complementary modes of action, clinical trials were designed to confirm the possible 
synergism. Initial phase 2 trials confirmed this hypothesis52. The registrational phase 3 
CLEOPATRA Trial53 was a large randomized trial that tested the hypothesis of dual HER2 
blockade using trastuzumab, pertuzumab and docetaxel. The results were impressive, 
with more than 80% of the patients experiencing a clinical response, a 50% reduction in 
the risk of progression from breast cancer and an overall survival gain never observed 
on such a population, with median overall survival of almost 60 months. No extra cardiac 
toxicity signals were observed with rash, diarrhea and mucosal inflammation as the major 
toxicity signals with major improvements after chemotherapy cessation. Based on that, 
FDA approved the use of trastuzumab, pertuzumab and a taxane for the first line 
treatment of patients with HER2 positive metastatic breast cancer. Other trials have 
tested paclitaxel with this dual HER2 blockade, showing similar efficacy as the use of 
docetaxel54, with a better toxicity profile, regarding diarrhea and neutropenia.  
 
The synergistic effect of dual HER2 blockade with trastuzumab and pertuzumab have 
also been exemplified at the neoadjuvant setting: when systemic chemotherapy and/or 
biological therapy are administered before surgery. The initial goal of trials with 
neoadjuvant chemotherapy was to convert an inoperable breast tumor into an operable 
one, and to convert mastectomies into breast conserving surgery55. The CTNeoBC 
pooled analysis confirmed later on that patients with HER2 positive disease that achieve 
a pCR have significantly better event-free and overall survivor11, although there was not 
a direct correlation between the magnitude of the pCR and the survival benefit. Some 

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trials have tested the hypothesis that the addition of pertuzumab to a 
trastuzumab/chemotherapy neoadjuvant schema would increase the pCR rates. Trials 
like TRYPHAENA16 and NeoSphere18 have demonstrated levels of pCR never seen 
before, up to 66% in the hormone receptor negative population. Even though not 
technically powered to detect a survival difference, in the NeoSphere trial, patients that 
received trastuzumab, pertuzumab and docetaxel had a significantly better disease-free 
survival compared to those that received just trastuzumab and docetaxel. Based on that, 
the FDA granted approval for dual HER2 blockade with pertuzumab and trastuzumab in 
patients with HER2 positive breast cancer with tumors greater than 2 cm or with clinically 
axillary lymph node involvement56. Recently published, the APHINITY trial tested the 
hypothesis that adding pertuzumab to a trastuzumab based treatment for the adjuvant 
setting would increase invasive disease-free survival in breast cancer patients clinical 
stage I-III57. The trial demonstrated a statistically significant benefit on adding the dual 
HER2 direct therapy compared to trastuzumab based therapy, but with a modest 0.9% 
magnitude of a benefit. Thus, optimization of HER2 directed therapy in the neoadjuvant 
and adjuvant setting is needed.     
   
1.5 Rationale for Combining Trastuzumab, Pertuzumab, Paclitaxel and Pembrolizumab 
 
Some pre-clinical studies show that monoclonal antibodies against PD-1 or CTLA-4 could 
substantially boost the therapeutic activity of anti-HER2 in immunocompetent mice40. 
Their findings suggest that optimum activity of anti-HER2 treatment needs type I and type 
II interferons, and interferon γ can also enhance MHC class I and PD-L1 expression on 
tumor cells. Scientific evidence from translational data obtained from the neoadjuvant 
trials with dual HER2 blockade links tumor immune profile and pathological complete 
response. Using the NeoSphere trial tumor and blood samples, a group from Milan 
performed correlative analyses between immune gene mRNA expression (IFNγ, PD-1, 
PD-L1, PD-L2 and CTLA-4), lymphocyte infiltration and PD-L1 expression by 
immunohistochemistry and pCR in the breast58. What the authors found was an 
interesting contribution of the immune system with regards to HER2 direct therapy. In 
particular, expression of the immune check point PD-L1 was related to resistance to all 
regimens used in the trial (trastuzumab, pertuzumab, and docetaxel; trastuzumab and 
docetaxel; trastuzumab and pertuzumab; pertuzumab and docetaxel). Also, the 
expression of MHC I-related genes, which inhibit antibody-dependent cell cytotoxicity 
(ADCC), was also related to resistance.  
 
The only clinical data available to date testing the hypothesis of immune therapy reverting 
resistance to HER2 directed treatment comes from the Phase 1b/2 PANACEA Trial, 
presented at the 2017 San Antonio Breast Cancer Symposium59. In this trial, patients with 
HER2 positive metastatic breast cancer that had progressed previously on trastuzumab-
based treatment received a combination of trastuzumab and pembrolizumab. Tumors 
were assessed centrally for HER2 positivity and PD-L1 status, and for quantity of TILs. 
In the phase 1 portion, a dose escalation of pembrolizumab with trastuzumab showed no 
dose limiting toxicities. In the phase II part of the trial, 58 patients received the 
combination of trastuzumab at full dose and pembrolizumab 200mg IV every 3 weeks. In 
the PD-L1 positive patients (N=40), they observed a 15% objective response rate and a 
25% disease control rate. In patients with 5% or more TILs present in the metastatic 
lesion, the objective response rate was 39% and the disease control rate was 47%. These 
findings confirm the safety of pembrolizumab with HER2-directed therapy and confirms 
activity in HER2-positive subsets. This strategy could be further improved if co-
administered earlier in the course of disease in trastuzumab-naïve populations (i.e. in the 
curative intent setting) and may synergize when given with chemotherapy. The role of 
dual HER2-blockade when pembrolizumab and trastuzumab are co-administered is 

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uncertain. The goal is to improve responses with biologically rational strategies and 
ultimately improve cure rates, in part, by potentiating adaptive immunity, rendering long 
term cancer-specific immunity.60  
 
In terms of safety, pembrolizumab has been tested concomitantly with chemotherapy in 
the metastatic and neoadjuvant setting. The Keynote 173 trial had patients with triple 
negative breast cancer suited to neoadjuvant therapy used pembrolizumab at a dose of 
200mg every 3 weeks, together with nab-paclitaxel 125 mg/m2 for 4 cycles; then 
pembrolizumab 200mg every 3 weeks together with doxorubicin 60mg/2 and 
cyclophosphamide 600mg/m2 for another 4 cycles (Arm A).31 The Arm B was the same 
regimen, but added Carboplatin AUC 6 with the pembrolizumab and nab-paclitaxel part. 
In this small trial, all patients presented with treatment adverse events, but all were non-
fatal with 3 patients discontinuing due to adverse events. We hypothesize that checkpoint 
inhibitor therapy in combination with HER2-directed and cytotoxic chemotherapy in the 
preoperative setting has the potential to engage the immune system and lead to higher 
rates of pCR in women with HER2+ stage II-III breast cancer. 
 
1.6 Rationale for Correlative Studies 
 
Tumor Tissue: 
Infiltration of immune cells has predicted improved prognosis and response to therapy in 
many different tumor types including breast cancer61,62. The greatest clinical benefit is 
seen when TILs comprise at least 50-60% of the tumor60. While a baseline TIL score 
indicates the immunogenicity of a tumor, the influx of TILs with therapy indicates the 
engagement of the immune system as a result of therapy. 
In addition to the amount of lymphocytic infiltrate, the phenotype of that infiltrate has also 
been shown to be prognostic. Type 1 T-cells are associated with favorable prognosis. 
Type 1 CD4+ T-helper cells facilitate antigen presentation and activation of CD8+ cytotoxic 
T-cells (CTL), which are essential for tumor destruction63. On the other hand, type 2 CD4+ 
T-helper cells, including Forkhead box P3 (FOXP3) CD4+ regulatory T-cells, contribute to 
a tumor environment that inhibits CTL function and promotes tumor growth64.  
Multiplex IHC (mIHC) allows for multiple fluorescently tagged antibodies to be applied to 
paraffin-embedded tissue quantification of cell types including macrophages (CD163+), 
effector T-cells (CD3+CD8+), and regulatory T-cells (CD3+CD4+FOXP3+). Assays can 
also be used to assess the activation and proliferation of TILs using markers such as Ki-
67, PD-1, CTLA-4. Flow cytometry can similarly be used on fresh or frozen tissue to 
quantify cell types including effector T-cells (CD3+CD8+), and regulatory T-cells 
(CD3+CD4+FOXP3+). 
Activation of the immune system can be further assessed using sequencing technology. 
Using TCR sequencing analysis on extracted DNA from paraffin-embedded tissue, 
increase in shared clones suggests that therapy is enhancing proliferation of antigen 
experienced cells within the tumor. 
Single cell gene expression profiling can be used to assess the transcriptome of individual 
cells. Innovative technology allows for the evaluation of the transcriptome in single cells 
within the tumor and the tumor microenvironment65. Serial assessment of the 
transcriptome through the course of therapy can identify genes that are indicators and/or 
effectors of safety and response.  
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An increase in circulating cytokines is an indicator of systemic immune activation. Further, 
flow cytometry can also be performed on fresh or frozen blood to assess the composition 
of systemic immune cells. Similarly, TCR sequencing can be conducted on blood to 
assess the clonality of systemic immune cells. 
 
Optional Fecal Samples for Analysis 
 
Many factors have been shown to regulate the anti-tumor immune response. The 
interaction of the immune system and the individual gastrointestinal microbiome can 
impact responses to immune therapy 66. The microbiome can also influence the toxicity 
from immune therapy67. Thus, we will collect optional fecal samples for microbiome 
analysis as a potential biological correlate for efficacy and/or toxicity.  
 
Optional Breast Tumor Biopsies for Analysis 
 
We hypothesize that given the high expression of Fc receptors on macrophages (Shiao 
Cancer Immunol Res 2015) and the importance of PD-1 in regulating macrophage 
phagocytosis 
and 
antigen-presentation 
(Gordon 
Nature 
2017) 
that 
adding 
pembrolizumab to HER2-directed therapy and chemotherapy will lead to increased 
numbers of phagocytic and antigen-presenting macrophages that promote the formation 
and activation of cytotoxic T cells. 
 
 

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2.0 
STUDY OBJECTIVES 
2.1 Primary Objective 
 
To explore the impact of checkpoint blockade administration with (mono- vs. dual) HER2-
directed therapy on post-surgery pathologic complete response (pCR) rate in the breast 
and axilla (ypT0/Tis ypN0) following 4 cycles (12 weeks) of treatment and surgery. A pCR 
is defined at the time of surgery and the rate will be reported as the proportion of the 
intent-to-treat population that achieve a pCR. 
 
The purpose of this phase II study is to identify whether Arm B (THP-K) or Arm C (TH-K) 
or both demonstrate a clinically significant pCR rate improvement over Arm A (THP). 
 
2.2 Secondary Objectives  
 
To define the impact of the interventions on pathological invasive and in situ complete 
response in breast and axilla (ypT0 ypN0), pathologic invasive complete response in the 
breast only (ypT0/is), breast conserving surgery rate, event free survival (EFS), invasive 
disease free survival (IDFS) overall survival, and safety. 
 
2.3 Exploratory Objectives 
 
2.3.1  To characterize the immunologic effect of pembrolizumab, pertuzumab  
            and trastuzumab administration, both in peripheral blood,  
            intratumorally and on the microbiome, for example, by:  
• 
Describing changes in peripheral blood CD3+, CD4+, CD8+, or 
regulatory (CD4+FOXP3+) T-cells by flow cytometry over time;  
• 
Characterizing the effect of the intervention on peripheral levels of Th1 
and Th2-type cytokines over time; 
• 
Characterizing tumor infiltrating lymphocytes (TILs) isolated from tumor 
biopsies and resection specimens using flow cytometry; 
• 
Assessing changes in the microbiome during the study period. 
 
2.3.2 
 To correlate clinical outcomes with exploratory correlates wherever feasible,  
in order to explore potential predictive biomarkers of clinical efficacy or toxicity 
 
2.4 Endpoints 
 
2.4.1 Primary Efficacy Endpoint 
 
The primary endpoint is pathological complete response rate (pCR) in the breast and 
axilla (ypT0/Tis ypN0). It is defined as the proportion of subjects without residual invasive 
cancer on hematoxylin and eosin evaluation of the complete resected breast specimen 
and all sampled regional lymph nodes following completion of neoadjuvant systemic 
therapy by AJCC staging criteria (8th edition) assessed by the local pathologist at the time 
of definitive surgery. 
 
Subjects who are discontinued from the study treatment and continue with another 
neoadjuvant treatment not specified by the study prior to definitive surgery will be 

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classified as not having a pCR (non-responders). Subjects who are discontinued from 
study treatment due to the reasons that preclude surgery are considered non-responders.  
 
 
2.4.2 Secondary Efficacy Endpoints  
 
The secondary efficacy variables are pathological invasive and in situ complete 
response in breast and axilla (ypT0 ypN0), pathologic invasive complete response in the 
breast only (ypT0/is), residual cancer burden (RCB), the proportion of patients 
achieving breast conserving surgery, invasive disease-free survival, event-free 
survival, overall survival, and safety . 
 
Pathological complete invasive and in situ response rate (pCR) in breast and axilla 
(ypT0 ypN0):  It is defined as the proportion of subjects without residual invasive cancer 
and in situ disease on hematoxylin and eosin evaluation of the complete resected breast 
specimen and all sampled regional lymph nodes following completion of neoadjuvant 
systemic therapy by AJCC staging criteria (8th edition) assessed by the local pathologist 
at the time of definitive surgery. 
 
Pathological complete response rate (pCR) in the breast only (ypT0/is): It is defined 
as the proportion of subjects without residual invasive cancer on hematoxylin and eosin 
evaluation of the complete resected breast specimen following completion of neoadjuvant 
systemic therapy by AJCC staging criteria (8th edition) assessed by the local pathologist 
at the time of definitive surgery. 
 
Residual cancer burden (RCB) index: it is defined as a component of four distinct 
pathological parameters: bi-dimensional diameter of primary tumor bed, percent of 
cellularity in the tumor bed, number of involved lymph nodes and size of the largest 
nodal metastasis. This information is inputted in a web based mathematical model and 
four different classes are possible depending on the scores: RCB 0 (pCR), RCB I, RCB 
II, RCB III 
(http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3). 
The method has been described and validated before68, pathologists involved in this 
protocol have been trained to use the RCB index.      
 
Breast conserving surgery rate: This is defined as the proportion of patients who 
achieved breast conserving surgery out of the intent-to-treat population without 
inflammatory breast cancer, as these patients will receive mastectomy irrespective 
of their response to neoadjuvant treatment. 
 
Event Free Survival: this is defined as time from randomization to any of the following 
events: progression of disease that precludes surgery, local or distant recurrence, or 
death due to any cause.  
 
Invasive Disease-free survival (IDFS): This is defined as the time from the first date 
of no disease (i.e. date of surgery) to the first documentation of invasive progressive 
disease or death. All in situ cancer events (ipsilateral or contralateral DCIS, ipsilateral 
or contralateral LCIS and all in situ cancers of non-breast sites) are excluded as an event 
in the endpoint. IDFS will be described separately in patients who achieve a pCR from 
those who do not and overall for all patients that had surgery. Patients who are 
withdrawn from the study without documented progression and for whom there exists 

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eCRF evidence that evaluations have been made, will be censored at the date of the 
last assessment when the patient was known to be disease-free. 
 
Overall survival (OS): This is defined as the time from the date of randomization to the 
first documentation of death from any cause, measured in the intent-to-treat population.  
 
Safety: Safety of the pre-operative (neoadjuvant) treatment regimen will be evaluated 
as follows: 
1. Incidence of symptomatic cardiac events and asymptomatic LVEF events (LVEF < 
50% or a decrease ≥ 10 ejection fraction points from baseline); 
 
2. LVEF measures over the course of the study; 
 
3. Incidence and severity of adverse events and serious adverse events; 
 
4. Laboratory test abnormalities.  
 
All patients who received at least one dose of treatment and received at least one post-
baseline safety assessment will be included in the safety evaluation. 
 
2.4.3 
 
Exploratory Endpoints: 
Exploratory correlative studies will be performed to characterize the immunologic 
response of the intervention, and to correlate immunologic laboratory parameters with 
clinical efficacy and toxicity. Breast cancer tissue specimens, axillary lymph node 
specimens when available, peripheral blood samples and optional fecal samples will 
be studied. The correlatives will be conducted by the Cedars Sinai collaborating 
scientists. 
 
The exploratory aims of this study are: 
1. 
To characterize the immunologic effect of pre-operative pembrolizumab and 
HER2-directed therapy administration, both in peripheral blood, intratumorally and 
on the microbiome; 
2. 
To evaluate for the induction of an antigen-specific immune response; 
3. 
To evaluate the effect of subsequent systemic cytotoxic therapy on the immune 
response; 
4. 
To evaluate molecular tumor characteristics, such as mutational burden, RNA 
expression and protein expression, and correlate with markers of immune 
response; 
5. 
To evaluate these laboratory correlates as potential predictive biomarkers of 
clinical efficacy or toxicity.  
 
To this end, specimens to be collected for evaluation include: 
1. 
Core needle biopsy of primary tumor with 2 cores (1 cm each) obtained for 
immune response studies and confirmation of diagnosis. If the diagnostic core 
needle biopsy specimen has enough material, another procedure will not be 
mandated;  
2. 
Lumpectomy/mastectomy specimens for all study participants; 
3. 
Sentinel or non-sentinel lymph node specimens where available (collected on the 
core biopsy and/or surgical date); 
4. 
Serial peripheral blood samples – collected from all study participants, as per the 
schedule in Table 3; 
5. 
Optional fecal samples collected as per the schedule in Table 3;  

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6. 
Optional breast biopsies collected as per the schedule in Table 3. 
 
 

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3.0 
STUDY DESIGN 
3.1 Overview of Study Design: 
 
This is a Phase 2 open-label, randomized, multi-center trial to evaluate the efficacy and safety of 
trastuzumab, pertuzumab and weekly paclitaxel as compared to trastuzumab, pertuzumab, 
pembrolizumab and weekly paclitaxel, or trastuzumab, pembrolizumab and weekly paclitaxel in chemo 
naive patients with invasive HER2 positive (by ASCO/CAP guidelines) unilateral breast cancer whose 
primary tumors are > 2 cm or clinically lymph node positive (cT2-4N0 or cT1-4N1-3). 
To participate in the trial, a patient must fulfill all inclusion/exclusion criteria and will need to consent 
to allow the storage of blood and tumor tissue samples for biomarker research as specified in Section 
4.1.  
Patients will be randomized (see Figure 1) to either Arm A (trastuzumab, pertuzumab and weekly 
paclitaxel), Arm B (trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel) or Arm C 
(trastuzumab, pembrolizumab and weekly paclitaxel). Patients will be stratified according to hormone 
receptor status (positive versus negative) and lymph node status (clinically positive versus negative). All 
patients will be treated every three weeks for four cycles (only paclitaxel will be administered weekly) 
and then undergo breast surgery. Arm A patients will be regarded as the reference group. 
After surgery, patients in all arms will be treated at their physician’s discretion, with standard of care HER2 
positive breast cancer adjuvant therapy after receiving neoadjuvant taxane and dual HER2 blockade. 
After completion of post-operative chemotherapy, patients will receive radiotherapy as per local clinical 
standard and those patients whose tumors were estrogen-receptor positive will receive hormone 
manipulation as per local clinical standard. Further details of the study treatment and administration can 
be found in Section 5.1. 
Patients whose neoadjuvant study treatment is discontinued prior to surgery will be managed as per 
local practice. Patients, whose adjuvant (post-operative) chemotherapy is discontinued due to 
standard chemotherapy related intolerable toxicity, will continue with trastuzumab until they have 
received a total of 17 cycles of treatment. Patients with biopsy-proven residual disease after 
completing the study treatment may receive additional chemotherapy (i.e. four cycles of adriamycin + –
cyclophosphamide administered every two weeks) prior to surgery at the treating physician discretion 
and should be seen in follow-up at each additional treatment prior to surgery.  
Subjects will be followed on protocol after surgery every 3 months until 36 (+/-1) months from the date 
of surgical resection and every 6 months during year 4 and 5, then annually until year 10. Thereafter, 
every effort will be made to continue monitoring these subjects via standard-of-care visits, so that late 
recurrences can be identified and overall survival can be estimated. 
 
 

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Figure 1: Study treatment plan 
 
 
3.1.1 Rationale of Dosage Selection of Paclitaxel 
 
For further information see Sections 1.4 and 5.0. 
3.1.2 Rationale of Dosage Selection of Trastuzumab and Pertuzumab 
 
For further information see Sections 1.4 and 5.0. 
 
3.1.3 Rationale of Dosage Selection of Pembrolizumab 
 
For further information see Sections 1.5 and 5.0.

 
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4.0 
PATIENT ELIGIBILITY  
4.1 Participant Inclusion Criteria 
 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Male/female patients with histologically confirmed invasive HER2-positive (by ASCO/CAP 
guidelines) unilateral breast cancer. 
2. Patient has untreated non-metastatic (M0), cT2-4N0 or cT1-4N1-3 (biopsies of clinically suspicious 
lymph nodes to confirm nodal status is encouraged).  
 
3. Multifocal/centric disease is permitted if all suspicious foci have been biopsied and are consistent 
with HER2-positive (by ASCO/CAP guidelines) invasive breast cancer. 
4. Be a male or female subject ≥18 years of age on day of signing informed consent. 
5. Male participants: 
A male participant must agree to use a contraception as detailed in Appendix C of this protocol 
during the treatment period and for at least 6 months after the last dose of study treatment and 
refrain from donating sperm during this period. 
6. Female participants:  
A female participant is eligible to participate if she is not pregnant (see Appendix C), not 
breastfeeding, and at least one of the following conditions applies:  
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix C OR  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix C during the treatment 
period and for at least 6 months after the last dose of study treatment. 
7. The participant (or legally acceptable representative if applicable) provides written informed consent 
for the trial.   
8. Provides adequate archival tumor tissue sample or newly obtained core or excisional biopsy of a 
tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded (FFPE) tissue blocks are 
preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting 
unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days 
from the date slides are cut (see section 8.1).  
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.  
10. Have adequate organ function as defined in the following table (Table 1).  

 
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Table 1:  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total 
bilirubin levels >1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with liver metastases) 
Coagulation 
 
International 
normalized 
ratio 
(INR) 
OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants 
Cardiac 
 
Echocardiogram or MUGA 
Baseline LVEF ≥ 55% 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of 
normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies. 

 
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4.2 Participant Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. 
A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization (see 
Appendix C).  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. 
Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first 
dose of study treatment, another pregnancy test (urine or serum) must be performed and must be 
negative in order for subject to start receiving study medication. 
2. 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). 
3. 
Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior 
to randomization. 
Note: If participant received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting study treatment. 
4. 
Has received prior radiotherapy within 2 weeks of start of study treatment.  Participants must have 
recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation 
pneumonitis.   
5.  
Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study 
drug.  Administration of killed vaccines is allowed.  
6. 
Is currently participating in or has participated in a study of an investigational agent or has used an 
investigational device within 4 weeks prior to the first dose of study treatment. 
Note:  Participants who have entered the follow-up phase of an investigational study may participate 
as long as it has been 4 weeks after the last dose of the previous investigational agent. 
7. 
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of study drug. 
8. 
Has a known additional malignancy (other than their current breast cancer diagnosis) that is 
progressing or has required active systemic treatment within the past 3 years.   
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or 
carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially 
curative therapy are not excluded. 
9.  
Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
10.  Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has 
current pneumonitis/interstitial lung disease. 
11. 
Has an active infection requiring systemic therapy. 
12. 
Has a known history of Human Immunodeficiency Virus (HIV).   
13. 
Has known active Hepatitis B or Hepatitis C virus infection. 

 
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14. 
Has a known history of active TB (Bacillus Tuberculosis). 
15. 
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the subject’s participation for the full duration of the 
study, 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 study, starting with the screening visit through 120 days after the last dose of trial treatment. 
18. Has significant cardiovascular disease, such as: 
• 
History of myocardial infarction, acute coronary syndrome or coronary 
angioplasty/stenting/bypass grafting within the last 6 months 
• 
Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of 
CHF NYHA class III or IV 
• 
Angina pectoris requiring anti-anginal medication, uncontrolled arrhythmias, or uncontrolled 
hypertension (systolic blood pressure > 180mmHg and/or diastolic blood pressure > 
100mmHg).   
 
 

 
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5.0 
TREATMENT PLAN 
 
5.1 
Treatment Dosage and Administration 
 
Arm A 
Trastuzumab I.V. followed by pertuzumab I.V. every three weeks for four cycles. A loading 
dose of 8 mg/kg of trastuzumab and 840 mg of pertuzumab is required on Day 1 Cycle 1, 
thereafter a maintenance dose of 6 mg/kg and 420 mg is required from Cycle 2 onwards, 
respectively. Paclitaxel will be administered weekly at a dose of 80mg/m2 for 12 weeks. 
Arm B 
Trastuzumab I.V. followed by pertuzumab I.V. followed by pembrolizumab I.V.  every three 
weeks for four cycles. A loading dose of 8 mg/kg of trastuzumab and 840 mg of pertuzumab 
is required on Day 1 Cycle 1, thereafter a maintenance dose of 6 mg/kg and 420 mg is 
required from Cycle 2 onwards, respectively. Pembrolizumab is administered at fixed dose of 
200mg. Paclitaxel will be administered weekly at a dose of 80mg/ m2 for 12 weeks.  
 
Arm C 
Trastuzumab I.V. followed by pembrolizumab I.V. every three weeks for four cycles. 
A loading dose of 8 mg/kg of trastuzumab is required on Day 1 Cycle 1, thereafter a 
maintenance dose of 6 mg/kg is required from Cycle 2 onwards. Pembrolizumab is at fixed 
dose of 200mg. Paclitaxel will be administered weekly at a dose of 80mg/ m2 for 12 weeks. 
Study treatment will be administered every three weeks for four cycles then the patient will 
undergo breast surgery. 
 
Trastuzumab 
 
Trastuzumab will be administered on Day 1 of Cycle 1 at the required loading dose of 8 mg/kg, 
as an I.V. infusion. On Day 22 (three weeks after the first dose) and every three weeks 
thereafter, trastuzumab will be administered at a dose of 6 mg/kg as an I.V. infusion. The 
initial dose of trastuzumab will be administered over 90 (± 10) minutes. Interruption or slowing of 
the infusion may help control infusion-related symptoms and infusion may be resumed when 
symptoms. abate. If the infusion is well tolerated, subsequent infusions may be administered 
over 30 (± 10) minutes.  All infusion-related symptoms must have resolved before study 
treatment is given or the patient is discharged (see Section 7.5.1). Patients who experience 
infusion-related symptoms may be pre-medicated with paracetamol and antihistamines for 
subsequent infusions. Dose reductions for toxicity are not permitted. Trastuzumab will be 
administered every three weeks for four cycles. 
Per local standard practice or institutional guidelines, an FDA-approve biosimilar is an appropriate 
substitute for trastuzumab per the US FDA labeling information (e.g. trastuzumab-anns, 
trastuzumab-dkst, trastuzumab-pkrb or trastuzumab-qyyp). Dose is similar to trastuzumab 
administered as an IV infusion.  
Trastuzumab and hyaluronidase administered subcutaneously may be substituted for trastuzumab 
at 600 mg of trastuzumab/10,000 units of hyaluronidase every 3 weeks. No loading dose is required 
for trastuzumab/hyaluronidase.   

 
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Pertuzumab 
Pertuzumab will be administered on Day 1 of cycle 1 at the required loading dose of 840 
mg as an I.V. infusion. On Day 22 (three weeks after the first dose), and every three weeks 
thereafter, pertuzumab will be administered at a dose of 420 mg as an I.V. infusion. The initial dose 
of pertuzumab will be administered over 60 (± 10) minutes. Following infusion, it is recommended, 
but not required that patients be observed for a further 30-60 minutes or per institutional standards 
of practice on Day 1 of Cycle 1 for symptoms like fever, chills and other infusion-related symptoms. 
The infusion should be slowed or interrupted if the patient experiencing fever, chills and other 
infusion-related symptoms. If the infusion   is   well   tolerated, subsequent   doses   may   be   
administered   over 30 (± 10) minutes. All infusion-related symptoms must have resolved before 
chemotherapy (Arm B only) is given or the patient is discharged. Patients who experience 
infusion-related symptoms may be pre-medicated with paracetamol and antihistamines for 
subsequent infusions. Dose reductions for toxicity are not permitted. Pertuzumab will be 
administered every three weeks for four cycles. 
  
Pembrolizumab 
 
Pembrolizumab is a highly selective humanized monoclonal antibody designed to block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. Subjects will receive pembrolizumab 
200 mg as an IV infusion. Pembrolizumab will be administered as a 30-minute IV infusion (every 
effort should be made to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).  
Pembrolizumab is manufactured by Merck. Please refer to investigator brochure69 and MK-3475 
Drug Preparation Instructions’ manual. 
 
Table 2 Product Descriptions  
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/4 mL 
Solution for Injection 
 
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 
products in accordance with the protocol and any applicable laws and regulations. Clinical supplies 
will be affixed with a clinical label in accordance with regulatory requirements. 
 
Paclitaxel  
 
Paclitaxel will be administered weekly for 12 weeks at 80 mg/m2 as an I.V. infusion over a 
minimum of 1 hour per institutional standards. Paclitaxel will be administered after the 
trastuzumab and pertuzumab infusion observation period in Arm A, after the trastuzumab, 
pertuzumab and pembrolizumab infusion observation period in Arm B, and after trastuzumab and 
pembrolizumab infusion observation period in Arm C. Additional premedication should be 
administered as per standard practice. 

 
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Nab-paclitaxel may be substituted for paclitaxel due to medical necessity (e.g. hypersensitivity 
reaction) per local standard practice. If substituted, administer nab-paclitaxel at 125 mg/m2 IV over 
30 minutes (±10 minutes) weekly for total of 12 weeks including paclitaxel doses that were 
previously administered before substitution). Premedication is not generally necessary prior to nab-
paclitaxel, although may be administered per standard practice or in patients with prior mild to 
moderate hypersensitivity reactions.  
 
5.2 
Dose Modification and Delays 
 
5.2.1 Modification of the Amount of Study Drug Administered due to Changes in   
Patient’s Weight 
The amount of trastuzumab administered is calculated according to the patient’s 
actual body weight, with no upper limit. Weight should be recorded at baseline 
and at every scheduled visit for all patients. The amount to be administered must be 
recalculated if the patient’s body weight has changed by > 10% (increased or 
decreased) from baseline. 
 
The amount of paclitaxel or nab-paclitaxel is calculated according to the patient’s 
body surface area (BSA). Weight and height should be recorded at baseline and 
the BSA calculated; thereafter, at every scheduled visit all patients should be re-
weighed. The amount to be administered must be recalculated if the patient’s body 
weight has changed by > 10% (increased or decreased) from baseline. 
5.2.2 Dose Modifications for Pertuzumab, Trastuzumab, and Paclitaxel 
 
Administration may be delayed to assess or treat adverse events, such as cardiac 
adverse events, myelosuppression and immune mediated events. Since 
trastuzumab, pertuzumab and paclitaxel are widely available drugs on daily practice 
and FDA approved for neoadjuvant breast cancer treatment, dose delays or 
adjustments according to toxicity should follow the current standard of care 
guidelines.   
Please refer to Section 7.4 for drug specific Supportive Care Guidelines.  
In the neo-adjuvant setting (Cycles 1-4), a dose delay of up to two weeks will be 
permitted to allow recovery to baseline. Thereafter, one further dose delay of up to 
two weeks will be permitted before the patient is discontinued from the study. 
Following a dose delay of two weeks or less, trastuzumab does not need to be re-
loaded (the maintenance dose only needs to be given). 
 
5.2.3 
Dose Modifications and delays for pembrolizumab 
 
AEs associated with pembrolizumab exposure, including coadministration with 
additional compounds, may represent an immunologic aetiology. These immune-
related AEs (irAEs) may occur shortly after the first dose or several months after the 

 
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last dose of pembrolizumab/combination treatment and may affect more than one 
body system simultaneously. Therefore, early recognition and initiation of treatment 
is critical to reduce complications.  Based on existing clinical study data, most irAEs 
were 
reversible 
and 
could 
be 
managed 
with 
interruptions 
of 
pembrolizumab/combination treatment, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Dose modification 
and 
toxicity 
management 
guidelines 
for 
irAEs 
associated 
with 
pembrolizumab/combination treatment are provided in Table 6. 
 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse 
event to a single component is likely to be difficult.  Therefore, while the investigator 
may attribute a toxicity event to the combination, or to pembrolizumab alone, for 
adverse events listed in Table 6, both interventions must be held according to the 
criteria in Table 6 Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events Associated with Pembrolizumab. 
 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered 
immune-related, both interventions should be held according to recommended dose 
modifications. 
 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 6. 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions. 
If the toxicities do resolve and conditions are aligned with what is defined in Table 3, 
the combination and pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination, re-
initiation of pembrolizumab as a monotherapy may be considered at the principal 
investigator’s discretion. 
 
Dosing Interruptions: 
Table 6 shows treatment guidelines for dose modification and toxicity management 
guidelines for immune-related AEs associated with administration of 
pembrolizumab. Pembrolizumab may be interrupted for situations other than 
treatment-related AEs such as medical/surgical events or logistical reasons not 
related to study therapy. Participants should be placed back on study therapy within 

 
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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 Method of Assigning Subjects to Treatment Groups  
 
Randomization will be conducted using a web-based randomization system within the EDC 
database Clinical Studio. Randomization will be accomplished by the method of random 
permuted block. Eligible patients will be randomized in a 1:1:1 ratio between the experimental 
arm and control arm. 
Patients will be randomized and assigned unique randomization numbers. As confirmation, the 
investigator will be provided a written verification of each patient’s registration. Treatment 
should occur within 5 business days of the patient being randomized into the study. 
No patient may begin treatment prior to randomization and assignment of a medication 
number. 
The patient randomization numbers are to be allocated dynamically in the order in which the 
patients are enrolled. The dynamic allocation will be stratified by hormone receptor status 
(positive or negative) and lymph node status (positive or negative). 
 
 
5.4 Concomitant Medication and Treatment 
 
Allowed Therapies 
 
In general, all medications taken by the patient for concomitant diseases should continue 
during the study treatment period and should be recorded on the eCRF. The following list 
of allowed medications is provided as a guidance, treatment prescribed to the patients 
should be adapted according to local standard practice. 
 
• H1 and H2 antagonist (e.g. diphenhydramine, cimetidine); 
 
• Analgesics (e.g. paracetamol, meperidine, opioids); 
 
• Corticosteroids to treat or prevent allergic or infusion reactions; 
 
• Corticosteroids to treat immune related adverse events 
 
• Thyroid medications  
 
• Anti-emetic (approved prophylactic serotonin-antagonists, benzodiazepines, 
ondansetron, etc.); 
 
• Medication to treat diarrhea (e.g. loperamide); 
 
• Colony stimulating factors (e.g. G-CSF); 
 

 
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• Estrogen receptor antagonist (e.g. tamoxifen) or aromatase inhibitors(e.g. anastrozole, 
exemestane) in the adjuvant setting per local practice; 
 
• Gonadotropin-Releasing Hormone Analog/Agonists for fertility preservation during 
chemotherapy 
 
• Acceptable methods of contraception must be used when the female patient or male 
partner are not surgically sterilized or do not meet the study definition of post-
menopausal (≥12 months of amenorrhea). 
 
Excluded Therapies 
 
The following therapies are excluded during the study: 
 
• Anti-cancer therapies other than those administered in this study, including cytotoxic 
chemotherapy (except for ddAC in patients with biopsy proven residual disease before surgery), 
radiotherapy (except for adjuvant radiotherapy for breast cancer after completion of 
chemotherapy), immunotherapy, and biological/targeted anti-cancer therapy; 
 
• Any investigational agent, except for those used for this study; 
 
• Initiation of herbal remedies. Herbal remedies initiated prior to study entry and continuing 
during the study are permitted and must be reported on the appropriate eCRF; 
 
• Any oral, injected or implanted hormonal methods of contraception; 
 
• Proton pump inhibitors, while not excluded are discouraged while on protocol treatment. It 
is strongly encouraged that proton pump inhibitors (i.e. pantoprazole, etc.) be discontinued 
from the time of consent until the Post-Treatment Follow-up phase; 
 
• Live vaccines or live-attenuated vaccines within 30 days prior to the first dose of study treatment 
and while participating in the study. Administration of killed vaccines is allowed.  
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician decision. However, the decision to 
continue the participant on study treatment requires the mutual agreement of the investigator, 
the Sponsor and the participant. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
Rescue Medications and Supportive Care 

 
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Participants should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. Suggested supportive care measures for the management of AEs 
with potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 7.4.2 [Table 6]. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  
For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the Investigator determines the events 
to be related to pembrolizumab. 
 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance. Refer to Table 6 in Section 
7.4.2 for guidelines regarding dose modification and supportive care.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
5.5 
Other Modalities or Procedures/ Research vs. Standard of Care Procedures 
 
After the completed neoadjuvant treatment, patients will continue to standard of care breast 
surgery per local SOC guidelines approximately 3-6 weeks following discontinuation or completion 
of study treatment in the neoadjuvant treatment phase. After surgery, patients will receive adjuvant 
chemotherapy and HER2-directed therapy, by their physician’s choice. Standard of care is the use 
of adjuvant anthracycline-based chemotherapy followed by trastuzumab for a total of 12 months 
(considering the neoadjuvant treatment).  
 
 
5.6 
Duration of Study Participation  
 
The study duration per subject will be up to 37 months, with up to 28 days of screening, up to 90 
days on treatment, and 84 months of follow-up. The total enrollment period is 36 months.  
 
5.7 Criteria for Premature Withdrawal 
 
Subjects have the right to withdraw from the study at any time for any reason. The 
investigator also has the right to withdraw subjects from the study in the event of intercurrent 
illness, adverse events, treatment failure after a prescribed procedure, protocol violation, 
cure, administrative reasons or for other reasons. An excessive rate of withdrawals can render 
the study uninterpretable; therefore, unnecessary withdrawal of subjects should be avoided. 
 
Should a subject decide to withdraw, all efforts will be made to complete and report the 
observations as thoroughly as possible. 
 

 
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The investigator should contact the subject or a responsible relative by telephone or through 
a personal visit to establish as completely as possible the reason for the withdrawal. A complete 
final evaluation at the time of the subject’s withdrawal should be made with an explanation of why 
the subject is withdrawing from the study. If the reason for removal of a subject from the study 
is an adverse event, the principal specific event will be recorded on the Electronic Case Report 
Form. 
 
In the case that the subject decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further information. 
The outcome of that discussion should be documented in both the medical records and in the 
eCRF. 
 
5.8 
Removal of Patients from Protocol  
 
Subjects participating may withdraw from the study at any time and for any reason. Subjects may 
be removed from the study at any time due to severe unacceptable side effects, death, patient’s 
non-compliance with the defined treatment plan, identification of recurrent/metastatic disease, 
pregnancy, or at the patient’s request to withdraw consent. 
 
5.9 
Replacement Policy 
 
5.9.1 
For Subjects 
 
Patients randomized into the study will not be replaced 
5.9.2 
For Centers 
A center may be replaced for the following administrative reasons: 
 
– Excessively slow recruitment. 
 
– Poor protocol adherence. 
 

 
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6.0 
STUDY PROCEDURES 
 
6.1 
Screening/Baseline Procedures 
 
After the patient is identified as a potentially appropriate study candidate an initial history, physical 
exam, and baseline CTCAEv.5.0 assessment will be performed. If potentially eligible, the consent 
form will be reviewed, and consent will be signed by the study candidate. 
 
Following consent, candidates will then undergo screening for eligibility for up to 28 days. Required 
components of the screening include: screening bloods, breast imaging (mammogram with 
ultrasound or MRI as indicated), cross-sectional imaging to rule out metastatic disease if AJCC 
stage III (either PET/CT or CT CAP + bone scan).  
 
Leftover tumor tissue will be collected from standard of care biopsy prior to Cycle 1, Day 1. Collection 
requirements provided in section 8.4.  
6.1.1 Informed Consent 
6.1.2 Comprehensive metabolic panel (CMP) must include the following: aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), albumin, alkaline phosphatase 
(ALP), total bilirubin, calcium, creatinine, glucose, total protein, BUN, sodium, potassium, 
chloride, bicarbonate or carbon dioxide. 
6.1.3    Complete blood cell count with differential and platelet count (CBC). 
 6.1.4   Echo or MUGA. 
6.1.5   Coagulation PT/INR and aPTT 
6.1.6 Thyroid stimulating hormone TSH with reflex to T3 and free T4 OR TSH with T3 and 
free T4 per institutional standards.  
 
6.2 
Procedures During Treatment 
6.2.1 Subjects randomized to control arm 
 
Subjects randomized to the control arm will receive standard-of-care neoadjuvant 
trastuzumab followed by pertuzumab and weekly paclitaxel, as stated on section 5.0 above. 
Before starting treatment, the tumor should be marked using the method which is standard 
locally (for example skin tattoo or surgical clip) so that the appropriate excision can be 
made should the patient experience complete clinical regression of the tumor during 
therapy. Also, patients will have a medical oncology visit and blood test collected before 
each treatment cycle. If residual disease is suspected after completion of Cycle 4, a biopsy 
can be performed at the treating physician’s discretion. If residual disease is biopsy 
confirmed, additional chemotherapy (i.e. q2weekly doxorubicin and cyclophosphamide) can 
be administered prior to surgery with clinical assessments completed on treatment days. 

 
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Additional trastuzumab and pertuzumab can be administered if surgery is delayed greater 
than 6 weeks since the last paclitaxel administration. 
 
 
In order to provide a control comparison for long-term toxicity assessment and immunologic 
laboratory correlatives, subjects will be monitored following definitive surgery (table 3). 
Following the date of surgery, subjects will be monitored with history, physical exam, toxicity 
assessment, and research bloods at 30 days and 60 days +/- 1 week after surgery. These 
visits will correspond with standard-of-care surgical oncology follow-up and/or medical 
oncology follow-up/chemotherapy treatment visits whenever feasible. Therefore, the research 
assessments may be conducted by a surgical oncologist or medical oncologist. Thus, study 
assessments will not require additional visits above and beyond the standard of care.  
 
Research bloods will be drawn at Cycle 1 Day 1 and Cycle 3 Day 1 (prior to treatment) with 
standard-of-care routine bloods, at surgery (research items completed within +/- 3 days of 
surgery), 30 and 60 days (+/- 1 week) after surgery. Research bloods (2 CPT tubes, 1 Cyto 
tube and 1 red-top tube) for immune response studies will be sent to laboratory. 
 
Optional fecal sample for microbiome analysis will be collected on Cycle 1 Day 1 and Cycle 
3 Day 1 (prior to treatment), at surgery (+/- 3 days), and at 30 and 60 days (+/- 1 week) after 
surgery. 
 
Optional fresh breast biopsies (Cedars site only) will be collected at baseline (after eligibility 
is confirmed but prior to start of treatment) and at 6 weeks (C3D1 +/- 1 week). 
 
CBC and CMP will be drawn weekly on days 1, 8 and 15 of each cycle (+/-3 days) prior to 
treatment. 
 
Echo or MUGA after last dose of paclitaxel and prior to surgery. 
 
6.2.2 Subjects randomized to intervention arm 
 
Subjects randomized to the intervention arm will receive either neoadjuvant trastuzumab, 
pertuzumab, pembrolizumab and weekly paclitaxel (Arm B) or trastuzumab, pembrolizumab 
and weekly paclitaxel (Arm C) as stated on section 5.0 above. Before starting treatment, the 
tumor should be marked using the method which is standard locally (for example skin tattoo 
or surgical clip) so that the appropriate excision can be made should the patient experience 
complete clinical regression of the tumor during therapy.  
 
Patients will have a medical oncology visit and blood test collected before each treatment 
cycle. Additional trastuzumab and pertuzumab can be administered if surgery is delayed 
greater than 6 weeks since the last paclitaxel administration.  Following the date of surgery, 
subjects will be monitored with history, physical exam, toxicity assessment, safety labs and 
research bloods 30 days +/- 1 week after surgery and again 60 days +/- 1 week. As in the 
control arm, long-term toxicity assessment and immunologic laboratory correlatives will be 
conducted during standard-of-care surgical/medical oncology follow-up appointments.  
 

 
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Research bloods will be drawn at Cycle 1 Day 1 and Cycle 3 Day 1 (prior to treatment) with 
standard-of-care routine bloods, at surgery (research items completed within +/- 3 days of 
surgery), 30 and 60 days (+/- 1 week) after surgery. Research Blood (2 CPT tubes, 1 Cyto 
tube and 1 red-top tube) for immune response studies will be sent to laboratory. 
 
Optional fecal sample for microbiome analysis will be collected on Cycle 1 Day 1 and Cycle 
3 Day 1 (prior to treatment), at surgery (+/- 3 days), and at 30 and 60 days post-surgery 
follow-up. 
 
Optional fresh breast biopsies (Cedars site only) will be collected at baseline (after eligibility 
is confirmed but prior to start of treatment) and at 6 weeks (C3D1 +/- 1 week). 
 
CBC and CMP will be drawn weekly on days 1, 8 and 15 of each cycle (+/-3 days) prior to 
each treatment. 
 
Echo or MUGA after last dose of paclitaxel and prior to surgery. 
 

 
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Table 3: Time and Events Table 
 
Pre-
study 
(28 
days) 
Cycle 1 
Day 1 
(+/- 3 
days)  
Cycle 2 
Day 1 
(+/- 3 
days) 
Cycle 3 
Day 1 
(+/- 3 
days) 
Cycle 4 
Day 1 
(+/- 3 
days) 
Surgery8 
(+/- 3 
days) 
Safety 
follow-up 
(30-days  
and 60-
days post 
-surgery 
+/- 1 
week) 
Long term-
follow-up 
and final 
study visit14  
Informed Consent 
X 
 
 
 
 
 
 
 
History and PE with 
Clinical Breast Exam 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
 
X 
X 
Toxicity evaluation1 
 
X 
X 
X 
X 
X 
X 
X 
Staging imaging2 
X 
 
 
 
 
X10 
 
 
Breast Imaging10 
X 
 
 
 
 
X 
 
X 
Safety bloodwork3 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation tests13 
X 
 
 
 
 
 
 
 
Optional fecal 
samples4 
 
X 
 
X 
 
X 
X 
 
Research blood5 
 
X 
 
X 
 
X 
X 
 
Echo or MUGA6 
X 
 
 
 
 
X 
 
X 
Neoadjuvant 
treatment7 
 
X 
X 
X 
X 
 
 
 
Tissue collection11  
X 
 
 
 
 
X 
 
 
Optional fresh breast 
biopsies (Cedars site 
only)15 
 
X 
 
X 
 
 
 
 
Pregnancy testing12 
(urine or serum) 
X 
X 
 
 
 
 
 
 
 
1. Toxicity will be evaluated using CTCAE version 5.0 until 1-year post surgery.  
2. Staging imaging will be with the discretion of the physician. For clinical stage IIB/III disease, staging with either a FDG 
PET/CT or CT chest, abdomen and pelvis and plus bone scan or PET/CT is recommended. Brain MRI is recommended 
for symptomatic patients only. 
3. Safety bloodwork consists of CBC, CMP (including: AST, ALT, albumin, ALP, total bilirubin), and TSH with reflex to 
T3 and free T4 OR TSH with T3 and free T4 per institutional standards. C1D1 safety labs are not repeated if drawn for 
screening within 7 days of treatment initiation. CBC & CMP are drawn weekly during treatment on days 1, 8, and 15 of 
each cycle. 
4. All fecal samples for microbiome analysis are optional. 
5. 2 CPT tubes, 1 Cyto-Chex BC tube, and 1 red top tube of blood will be required at all timepoints. All research blood 
draws will be performed in conjunction with safety labs in order to minimize the number of venipunctures 
6. Patients will undergo Echo or MUGA between last dose of paclitaxel and surgery date (+/- 3 days does not apply to 
these tests), then every 3 months (+/- 1 week) until completion of HER2-directed therapy. Cardiac monitoring after surgery 
will be performed per standard of care for patients receiving HER2 directed adjuvant therapy 
7. Neoadjuvant treatment: consists of treatment Arm A, Arm B, and Arm C and will start within 5 business days of 
randomization. Each cycle is 3 weeks in duration and patients receive 3 doses of weekly paclitaxel within each cycle. 

 
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Additional chemotherapy per local standard-of-care may be administered prior to surgery in patients with biopsy proven 
residual disease after study treatment. 
8. Surgery will take place 3-6 weeks after last protocol treatment dose per SOC.  
9. Vitals including height and weight to be obtained at each study visit prior to and during treatment. Once a subject 
completes study treatment, height is not required to be collected at long term follow up visits. 
10. Baseline, pre-surgery and long-term follow up breast imaging (i.e. mammography, ultrasound, and/or MRI) is 
recommended per SOC. 
11. Left-over tumor tissue will be collected from standard of care biopsy prior to C1D1 and from surgical specimen.  Fresh 
tissue will be obtained if possible, see lab manual.   
12. Must occur within 72 hours before first drug administration. If screening occurs within 72 hours of C1D1, then test will 
not be repeated. 
13. Coagulation panel to include Prothrombin time (PT/INR) and aPTT (activated partial thromboplastin time). 
14. Subjects will be followed as per standard-of-care after surgery every 3 months (+/- 1 month) for 3 years then every 6 
months (+/- 1 month) in years 4 and 5 and then annually after 5 years (up to year 10) for assessment of recurrence or 
metastatic disease. During this follow-up phase, routine bloods, physical exam, and standard-of-care follow-up imaging will 
be performed to assess for disease recurrence. Toxicity will be assessed up to 1-year post surgery. If the subject does not 
return for protocol-specified or standard-of-care visits in the long-term follow-up period, all attempts should be made to 
contact the subject via telephone for survival status in accordance with the study schedule. 
15. Optional fresh breast biopsies (Cedars patients only) will be collected at baseline (after eligibility is confirmed but before 
C1D1 treatment) and 6 weeks (+/- 1 week of cycle 3).  
6.3 
Follow-up Procedures 
Long-term follow-up and final study visit: 
 
Subjects will be followed on protocol after surgery every 3 months until 36 (+/-1) months 
from the date of surgical resection. Thereafter, every effort will be made to continue 
monitoring these subjects via standard-of-care visits, so that late recurrences can be 
identified and overall survival can be estimated. Specifically, all subjects will be followed as 
per standard-of-care after surgery every 3 months (+/- 1 month) for 3 years then every 6 
months (+/- 1 month) in years 4 and 5 and then annually after 5 years (up to year 10) for 
assessment of recurrence or metastatic disease. During this follow-up phase, routine 
bloods, physical exam, and standard-of-care follow-up imaging will be performed to assess 
for disease recurrence. Toxicity will be assessed up to 1-year post surgery. If the subject 
does not return for protocol-specified or standard-of-care visits in the long-term follow-up 
period, all attempts should be made to contact the subject via telephone for survival status 
in accordance with the study schedule.  
 
Cardiac (LVEF) monitoring while on adjuvant HER2-directed therapy should be obtained per 
standard-of-care (i.e. every 3 months while on therapy). 
 
6.4        Removal of Subjects from Study 
 
Patients can be taken off the study treatment and/or study at any time at their own request, 
or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
6.4.1 
Patient voluntarily withdraws (follow-up permitted);  
6.4.2 
Patient withdraws consent (termination of treatment and follow-up); 

 
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6.4.3 
Patient is unable to comply with protocol requirements; 
6.4.4 
Patient demonstrates disease progression (unless continued treatment with study 
drug is deemed appropriate at the discretion of the investigator); 
6.4.5 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
6.4.6 
Treating physician determines continuation on the study would not be in the 
patient’s best interest; 
 
6.4.7 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
6.4.8 
Development of second malignancy (except for basal cell carcinoma or squamous 
cell carcinoma of the skin) that requires treatment, which would interfere with this 
study; 
6.4.9 
Lost to follow-up. If a research subject cannot be located to document survival after 
a period of 20 weeks, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the follow up period must be documented. 
This will be reviewed during an interim data monitoring visit. 
 
 

 
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7.0 
ADVERSE EVENTS (AE) 
 
7.1    Definitions 
7.1.1 Adverse Event 
An adverse event is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an experimental intervention whether or not related to the intervention.  
7.1.2 Serious Adverse Events (SAE) 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
7.1.2.1 
Results in death. If death results from (progression of) the disease, the 
disease should be reported as event (SAE) itself. 
7.1.2.2 
Is life-threatening (the patient was at risk of death at the time of the 
event; it does not refer to an event that hypothetically might have 
caused death if it were more severe). 
7.1.2.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
7.1.2.4 
Results in persistent or significant disability or incapacity. 
7.1.2.5 
Is a congenital anomaly / birth defect. 
7.1.2.6 
Is an important medical event. 
 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event.” For 
example: allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; convulsions that may not result in hospitalization; development of 
drug abuse or drug dependency. 
7.1.3 
Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all 
of the following criteria: 
• 
Unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 

 
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• 
Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known to an individual or group of individuals (including research subjects, 
research staff, or others not directly involved in the research). 
 
7.1.3.1 Evaluable for toxicity  
All patients will be evaluable for toxicity from the time of their first treatment with 
study drug. 
 
7.2 Severity of Adverse Events 
All non-hematologic adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. The CTCAE current version is available at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
7.3 
 Adverse Event Monitoring  
 
The investigator or designee is responsible for ensuring that all adverse events (both serious 
and non-serious) observed by the clinical team or reported by the subject which occur after 
the subject has signed the informed consent are fully recorded in the subject’s medical 
records. Source documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations result 
in a delay or dose modification of study treatment, or judged relevant by the investigator), 
should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the following 
for all adverse events (both serious and non-serious): 
 
• 
Event term (as per CTCAE) - Descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting.  
• 
Description of the event 
• 
Date of onset and resolution 
• 
Expectedness of the toxicity 
• 
Grade of toxicity  
• 
Attribution of relatedness to the investigational agent- (this must be assigned by an 
investigator, sub-investigator, or treating physician) 
• 
Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. 
no action, received conmed or other intervention, etc. 

 
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• 
Outcome of event 
All patients experiencing an adverse event, regardless of its relationship to study drug, will 
be monitored until:  
• 
the adverse event resolves or the symptoms or signs that constitute the adverse  
 
event return to baseline 
• 
any abnormal laboratory values have returned to baseline 
• 
there is a satisfactory explanation other than the study drug for the changes  
 
observed, or death. 
 
 
7.4 Toxicity profiles of investigational agents 
 
7.4.1 Paclitaxel, Trastuzumab and Pertuzumab 
 
 This combination is FDA approved based on the results from the neoadjuvant trials, 
such as NeoSphere trial18. In this trial, the majority of the adverse events were related 
to the chemotherapy backbone, docetaxel. The association of paclitaxel, trastuzumab 
and pertuzumab has been tested in a phase II trial, also showing a good safety and 
efficacy profile54.   
 
   Because of the risk to potentiate trastuzumab cardiac toxicity, these trials had a 
careful cardiac safety follow up and procedures. There were no new signals of cardiac 
toxicity with the combination of trastuzumab, pertuzumab and docetaxel or paclitaxel. 
However, we intend to carefully follow patients for the risk of cardiac toxicity signals 
in our trial, with the association of pembrolizumab. The algorithm for continuation and 
discontinuation of study medication based on cardiac safety will be the same used 
on the NeoSphere protocol, as outlined on Appendix A and B. It will be also graded 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 
5.0. 
The 
CTCAE 
current 
version 
is 
available 
at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
Monoclonal antibodies may cause infusion-associated symptoms such as fever, 
chills, hypotension, shortness of breath, skin rash, headache, nausea, and/or 
vomiting. Such reactions typically occur during or very shortly after an infusion. 
Paclitaxel can also cause infusion-associated symptoms. 
Since trastuzumab, pertuzumab and paclitaxel are widely available drugs on daily 
practice and FDA approved for neoadjuvant breast cancer treatment, toxicity 
management should follow the current standard of care guidelines. Tables 4 and 5 
outline some of these guidelines.  
 
Dose reductions are not recommended for trastuzumab and/or pertuzumab. 
Pertuzumab should be discontinued if trastuzumab is discontinued.  
 
Delayed or missed trastuzumab and/or pertuzumab of ≥ 6 weeks, reloading dose 
should be administered per discretion of the investigator.  
 

 
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  Table 4 Dose Modification Guideline for Paclitaxel 
Toxicities 
Grade or actual 
value 
Paclitaxel  
Hematological 
Neutropenia 
ANC≥1000/mm3 
G2/G1 
No change to paclitaxel  
• 
For ANC ≤1500/mm3, prophylactic myeloid growth 
factors (filgrastim) use at the discretion of the 
investigator, 
o  Should not be given on the same day as 
chemotherapy. 
o Pegfilgrastim may not be used with paclitaxel 
due to it’s weekly dosing schedule 
ANC<1000/mm3 
G3/G4 
Hold paclitaxel until ANC ≥1000/mm3. 
G-CSF may be used between days 2–6 at discretion of 
the investigator. Pegfilgrastim may not be used with 
paclitaxel due to its weekly dosing schedule. Resume 
paclitaxel based on timing of recovery: 
• 
≤1 week: No change to paclitaxel  
• 
>1 but <3 weeks: Dose-reduce paclitaxel to 70 
mg/m2 for all subsequent cycles. 
• 
≥3 weeks: Stop paclitaxel 
Febrile neutropenia ANC ≤1000/mm3, 
fever ≥38.5°C 
G3 and G4 
Hold paclitaxel until resolved (ANC 
>1000/mm3, fever <38.5°C, and resolution of any signs 
of infection). G-CSF may be used between days 2–6 
at discretion of the investigator. Pegfilgrastim may not be 
used with paclitaxel due to its weekly dosing schedule. 
Resume paclitaxel according to number of episodes: 
• 
First episode: no change to paclitaxel. 
 
• Second episode: Reduce paclitaxel to 70 mg/m2  
for all subsequent doses. 
• 
Third 
episode: Discontinue paclitaxel 
Thrombocytopenia ≥75,000-
<100,000/mm3 
G1 
Hold paclitaxel until ≥100,000/mm3, 
resume treatment based on timing of recovery: 
• 
≤1 week—no change to paclitaxel. 
• 
>1 but <3 weeks— Reduce paclitaxel to 70 mg/m2 
for all subsequent doses. 
• 
≥3 weeks: Discontinue paclitaxel 
<75,000/mm3 
≥G2 
Hold paclitaxel until ≥100,000/mm3. 
• 
Reduce paclitaxel to 70 mg/m2 for all subsequent 
doses. 
• 
Stop paclitaxel if held for ≥ 3 weeks in a row. 

 
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Anemia 
All grades 
No change to paclitaxel  
• 
Iron studies should be done and iron should be 
replaced as indicated. 
Red blood   cell transfusions can be given at the 
investigator’s discretion. 
 
 
Toxicities 
Grade or actual 
value 
Paclitaxel  
Non-Hematological 
Nausea/Vomiting 
Grade 1 or 2 
No change to paclitaxel  
≥ Grade 3 
Hold paclitaxel until resolved to≤ Grade 1. 
• 
Resume paclitaxel with modification of premedication 
• 
Second episode ≥ Grade 3 despite maximum 
supportive care, reduce paclitaxel to 70 mg/m2 for all 
subsequent cycles 
Mucositis/Stomatitis Grade 1 or 2 
No change to paclitaxel  
≥ Grade 3 
Hold paclitaxel until resolved to ≤ Grade 1. 
• 
Resume paclitaxel at previous dose with modification 
of premedication 
• 
Second episode ≥ Grade 3 despite maximum 
supportive care, reduce paclitaxel to 70 mg/m2 for all 
subsequent cycles 
Neurotoxicity 
Grade 1–2 
No change to paclitaxel  
Grade 3 
Hold   paclitaxel until   neuropathy improves to ≤ Grade 2. 
• 
Resume paclitaxel dose reduced to 70 mg/m2 for all 
subsequent doses. 
• 
Discontinue paclitaxel if held for ≥ 3 weeks in a row. 
Grade 4 
Discontinue paclitaxel if held for ≥ 3 weeks in a row 
(see general instruction below). 
Hepatic 
Grade 1 
• 
No change to paclitaxel  
Grade 2 or 3 
• 
Bilirubin fractionation should be performed if total 
bilirubin > 1.5xULN. Dose may continue if isolated 
bilirubinemia is mostly indirect such as in subject with 
Gilbert 
• 
Hold paclitaxel until resolved to Grade 1 and resume 
the dose at previous level. 
• 
Discontinue paclitaxel if held for ≥ 3 weeks in a row. 

 
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Grade 4 
• 
Discontinue paclitaxel.  
Note all concurrent ALT/AST >3xULN and Total 
bilirubin > 2xULN should be discontinued and 
evaluated (by the investigator) for potential drug 
induced liver injury. 
Anaphylaxis 
/hypersensitivity 
Mild 
• 
Complete paclitaxel infusion w/medication. 
Moderate 
• 
Stop infusion and treat per standard practice. 
• 
Resume infusion at half of the infusion speed 
if symptoms resolve. 
• 
Stop if symptoms recur. 
Severe 
• 
Stop infusion immediately and discontinue treatment. 
Other significant 
toxicities excluding 
fatigue, alopecia 
and leukopenia at 
discretion of the 
investigators 
Grade 2 
• 
Hold paclitaxel until resolved to ≤ Grade 1. 
• 
Resume at the previous dose and increase 
supportive care measure, if available. 
≥ Grade 3 
• 
Hold paclitaxel and discuss with sponsor medical 
monitor for further instructions. 
• 
If ≥ Grade 3 toxicity recurs upon re-challenge, 
discontinue treatment permanently. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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If nab-paclitaxel is substituted per protocol section 5.0, do not administer nab-paclitaxel if baseline ANC less 
than 1,500/mcL. Refer to local standard practice and prescribing information for detailed information about 
management of nab-paclitaxel related toxicity and dose adjustment. 
Table 5 Actions to be taken in case of Pertuzumab and Trastuzumab related toxicity 
Toxicity related to study treatment 
Action 
1. Non-hematological, Grade 1 or 2 
(NCI-CTCAE; excluding cardiac*) toxicity 
2. Non-hematological, Grade 3 or 4 
(NCI-CTCAE; excluding cardiac*) toxicity 
3. Recurrence of non-hematological, Grade 3 
or 4 (NCI-CTCAE; excluding cardiac*) 
toxicity upon re-challenge 
4. Cardiac toxicity (asymptomatic drop in 
LVEF or symptomatic congestive heart 
failure) 
5. Cardiac 
toxicity 
(NCI-CTCAE; 
other 
cardiac toxicities not covered by treatment 
algorithm in C) 
6. Hematological toxicity – Neutropenia 
Continue with study treatment 
Hold study treatment (all medication in the 
cycle) until recovery to Grade ≤ 2. 
Toxicity resolved to Grade ≤ 2 within a maximum 
of 2 weeks calculated from last administration: 
Resume study treatment. 
Toxicity did NOT resolve to Grade ≤ 2 within a 
maximum of 2 weeks calculated from last 
administration: Discontinue the related study 
medication 
(pertuzumab 
or 
trastuzumab) 
permanently. Continue treatment as deemed 
suitable by local investigator. 
Discontinue the related study medication 
(pertuzumab or trastuzumab) permanently. 
Continue treatment as deemed suitable by 
local investigator. 
 
Study treatment (all medication in the cycle) to 
be held, continued or resumed according to 
the algorithm depicted in C. 
Related study medication (pertuzumab or 
trastuzumab) to be discontinued permanently 
in case of symptomatic CHF. 
Actions must follow rules 1. to 3. for non-
hematological toxicities. 
Hold study treatment (all medication in the 
cycle) until neutrophils ≥ 1.5 x 109/L. 
 
 
 

 
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7.4.2 
Pembrolizumab  
 
Pembrolizumab is an FDA-approved agent on formulary for the treatment of metastatic 
melanoma, metastatic non-small cell lung carcinoma, head and neck squamous cell 
carcinoma, Hodgkin Lymphoma, metastatic urothelial carcinoma, metastatic gastric 
cancer and microsatellite instability-high metastatic cancer. It is investigational for use 
in breast cancer. The following list of toxicities and supportive care guidelines were 
taken from the investigator’s brochure 201769, based upon Sponsor’s Reference Safety 
Dataset (RSD), a pooled data from monotherapy clinical trials (n=2799).  
 
 
7.4.3 
Pembrolizumab and chemotherapy  
 
In the Keynote 173 Trial, 20 patients with triple negative breast cancer suited to 
neoadjuvant therapy used pembrolizumab at a dose of 200mg every 3 weeks, together 
with nab-paclitaxel 125mg/m2 for 4 cycles; then pembrolizumab 200mg every 3 weeks 
together with doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 for another 4 
cycles (Cohort A, 10 patients). The Cohort B was the same regimen, but added 
carboplatin AUC 6 with the pembrolizumab and nab-paclitaxel part (10 patients). In 
terms of grade 3 and 4 toxicity, 50-80% of the patients experienced neutropenia, 10% 
anemia, 30% nausea, 10% vomiting, 10% fatigue, 10% decreased appetite, 10-20% 
febrile neutropenia and 10% pyrexia, 20% Grade 3 liver enzymes increase, 30% 
immune-mediated adverse events (hyperthyroidism, hypothyroidism and thyroiditis). 2 
patients discontinued treatment because of toxicity. No reports of death due to 
treatment related adverse events. No reports of cardiac toxicity. Dose modifications 
(reductions, interruptions or withdrawals) were reported in 90% of patients. Most of the 
adverse events were related to the chemotherapy backbone, considered very toxic, as 
shown on other neoadjuvant chemotherapy trials.   
 
 
 

 
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Table 6 Dose modification and toxicity management guidelines for immune-related AEs associated 
with pembrolizumab monotherapy and IO combinations 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. 
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to 
≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAE 
v5.0) 
Action With 
Pembrolizum
ab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonit
is  
Grade 2 
Withhold  
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Add prophylactic 
antibiotics for opportunistic 
infections 
•  Monitor participants for signs 
and symptoms of pneumonitis 
•  Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 
4  
Permanentl
y 
discontinue 
Diarrhea/C
olitis  
Grade 2 or 
3 
Withhold 
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
•  Monitor participants for signs 
and symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation (ie, 
peritoneal signs and ileus) 
•  Participants with ≥Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis 
•  Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion 
Recurrent 
Grade 3 or 
Grade 4 
Permanentl
y 
discontinue 

 
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irAEs 
Toxicity 
Grade 
(CTCAE 
v5.0) 
Action With 
Pembrolizum
ab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
AST or 
ALT 
Elevation 
or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returned to baseline or is stable) 
Grade 3 b 
or 4 c 
Permanentl
y 
discontinue 
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
T1DM or 
Hyperglyc
emia 
New onset 
T1DM or  
Grade 3 or 
4 
hyperglyc
emia 
associated 
with 
evidence 
of β-cell 
failure 
Withhold d 
•  Initiate insulin replacement 
therapy for participants with 
T1DM 
•  Administer 
antihyperglycemic in 
participants with 
hyperglycemia 
 
•  Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysi
tis 
Grade 2 
Withhold 
•  Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated 
•  Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 
4 
Withhold or 
permanentl
y 
discontinue 
d 
Hyperthyr
oidism 
Grade 2 
Continue 
•  Treat with nonselective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate 
•  Monitor for signs and symptoms 
of thyroid disorders 
Grade 3 or 
4 
Withhold or 
permanentl
y 
discontinue 
d 
Hypothyro
idism 
Grade 2, 3 
or 4 
Continue 
•  Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care 
•  Monitor for signs and symptoms 
of thyroid disorders 
Nephritis: 
Grade 2 
Withhold 
•  Administer corticosteroids 
•  Monitor changes of renal 

 
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irAEs 
Toxicity 
Grade 
(CTCAE 
v5.0) 
Action With 
Pembrolizum
ab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
grading 
according 
to 
increased 
creatinine 
or acute 
kidney 
injury 
Grade 3 or 
4 
Permanentl
y 
discontinue 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper 
function 
Neurologi
cal 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 
4 
Permanentl
y 
discontinue 
Myocarditi
s 
Grade 1 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 2, 3 
or 4 
Permanentl
y 
discontinue 
Exfoliative 
Dermatolo
gic 
Condition
s 
Suspected 
SJS, TEN, 
or DRESS 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed 
SJS, TEN, 
or DRESS 
Permanentl
y 
discontinue 
All Other 
irAEs 
Persistent 
Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue 
based on 
the event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanentl
y 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; 
CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and 
Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; 
ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 

 
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irAEs 
Toxicity 
Grade 
(CTCAE 
v5.0) 
Action With 
Pembrolizum
ab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
a 
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b 
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c 
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d 
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e 
Events that require discontinuation include, but are not limited to: encephalitis and other clinically 
important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 
 
 
 
 
 

 
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Table 7: Pembrolizumab Infusion reaction dose modification and treatment guidelines 
 
 

 
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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 participant is deemed 
medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g. 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 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 
participant should be premedicated for the 
next scheduled dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment 
Participant may be 
premedicated with 
diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine) and 
acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic) per 
institutional standards. 

 
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Grades 3 or 4 
Grade 3: 
Prolonged (i.e. not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g. 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should 
be used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v 5.0 
(CTCAE) at http://ctep.cancer.gov 
 
 
 
7.5 Reporting Requirements for Adverse Events 
7.5.1 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE VERSION 5.0).  
 
Step 2: Grade the adverse event using the NCI CTCAE VERSION 5.0 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
 
Attribution categories are as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and is 

 
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attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
 
 
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
 
• the current known adverse events listed in the Agent Information Section of this 
protocol; 
• the drug package insert; 
• the current Investigator’s Brochure 
 
7.5.2 
Expedited Reporting 
7.5.2.1 The Medical Monitor must be notified by study staff or co-investigators within 24 
hours of learning of any serious adverse events, regardless of attribution, occurring 
during the study or within 1-year post surgery. 
 
Adam Matthew Brufsky, MD, PhD, FACP 
brufskyam@upmc.edu 
412-641-6500 
 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC): 
Serious Adverse Events and UPIRSOs at all sites, which occur in research subjects on 
protocols for which the SCCC is the DSMC of record require reporting to the DSMC 
regardless of whether IRB reporting is required. All SAEs occurring during the protocol-
specified monitoring period and all UPIRSOs should be submitted to the SCCC DSMC 
within 5 business days of the study team members awareness of the event(s). In addition, 
for participating centers other than UTSW, local IRB guidance should be followed for local 
reporting of serious adverse events or unanticipated problems.  
 
The UTSW study PI is responsible for ensuring SAEs/UPIRSOs are submitted to the SCCC 
DSMC Coordinator. This may be facilitated by the IIT project manager, study team, sub-site 
or other designee. Hardcopies or electronic versions of the eIRB Reportable Event report; 
FDA Form #3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be submitted to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines if immediate 
action is required.  Follow-up eIRB reports, and all subsequent SAE or UPIRSO 
documentation that is available are also submitted to the DSMC Chair who determines if 
further action is required.  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the UTSW study PI or designee ensures that all 

 
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participating sites are notified of the event and resulting action, according to FDA guidance 
for expedited reporting. DSMC Chairperson reviews all SAEs and UPIRSOs upon receipt 
from the DSMC Coordinator.  The DSMC Chairperson determines whether action is 
required and either takes action immediately, convenes a special DSMC session (physical 
or electronic), or defers the action until a regularly scheduled DSMC meeting.  
 
 
Should you need to discuss any SAE (initial/follow up reports) contact: 
Heather McArthur (Telephone): 214-645-9380 
Heather.McArthur@utsouthwestern.edu 
 
 
Lead Site (UTSW): 
Send all SAE initial and follow up reporting to 
the following contacts below: 
 
• 
Heather McArthur, MD 
Heather.McArthur@utsouthwestern.edu 
 
• 
Meredith Carter 
Meredith.Carter@utsouthwestern.edu 
 
• 
Stephanie Rice 
Stephanie.Rice@utsouthwestern.edu 
 
 
• 
UTSW SCCC Data Safety Monitoring 
Committee: 
Report through InfoReady SAE form 
(link below) 
[http://utsouthwestern.infoready4.com] 
SCCDSMC@utsouthwestern.edu 
 
 
 
 
 
Within 24 hours of 
learning of the 
event 
 
SAE report form 
Sub Sites 
Send all SAE initial and follow up reporting to 
the following contacts below: 
 
• 
Heather McArthur, MD 
Heather.McArthur@utsouthwestern.edu 
 
• 
Meredith Carter 
Meredith.Carter@utsouthwestern.edu 
 
• 
Stephanie Rice 
Stephanie.Rice@utsouthwestern.edu 
Within 24 hours of 
learning of the 
event 
SAE report form; 
MedWatch 3400A if 
applicable 
 

 
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Lead Site: 
UTSW Institutional Review Board  
Submit a Reportable event within eIRB with a 
copy of the final sponsor report determination 
as attached supporting documentation 
 
Medical Monitor reporting 
Refer to section 7.5.2.1 
 
Merck reporting 
Refer to section 7.6.6-7.6.8 
 
Submit within time 
specified per policy 
Submit required 
documentation per 
policy 
Subsite: 
Local IRB submission per policy 
 
Medical Monitor reporting 
Refer to section 7.5.2.1 
 
Merck reporting 
Refer to section 7.6.6-7.6.8 
 
Submit within time 
specified per policy 
Submit documentation 
per policy 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) 
to the UTSW HRPP 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT 
Southwestern IRB. Additional reporting requirements apply for research relying on a non-
UT Southwestern IRB. 
According to UTSW HRPP policy, UPIRSOs are incidents, experiences, outcomes, etc. that 
meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally not expected in a subject’s 
underlying condition or not expected as a risk of the study; therefore, not included in the 
investigator’s brochure, protocol, or informed consent document),AND 
2. Probably or definitely related to participation in the research, AND 
3. Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects 
(UADEs) and death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW HRPP within 5 working days of study 
team awareness. 
 

 
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For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of study team awareness. Investigators must 
report to their relying IRB according to the relying IRB’s policy. In addition, the external 
IRB’s responses or determinations on these local events must be submitted to the UT 
Southwestern IRB within 10 working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, and 
submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/hrpp/quality-assurance/ 
 
7.5.2.2 
Reporting to the Institutional Review Board (IRB) 
The IRB must be notified per institutional standard of “any unanticipated problems 
involving risk to subjects or others.” 
1. Any serious event (injuries, side effects, deaths or other problems), which in 
the opinion of the Principal Investigator was unanticipated, involved risk to 
subjects or others, and was possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved protocol 
that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
4. Any new information (e.g. publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or others. 
Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the Principal Investigator. 
7.6   Sponsor Reporting Requirements 
 7.6.1 Collection of Safety Information  
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of investigational product, whether or not considered related to the 
investigational product. 
 

 
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All AEs, SAEs and other reportable safety events that occur after the consent form is signed, 
but before treatment allocation/randomization, must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including, but not limited to, washout or discontinuation of usual therapy, diet, or a procedure.  
 
● All AEs from the time of treatment allocation/randomization through 1-year post surgery 
must be reported by the investigator.  
 
● All AEs meeting serious criteria from the time of treatment allocation/randomization through 
90 days following cessation of study treatment or 30 days following cessation of study 
treatment, if the participant initiates new anticancer therapy (whichever is earlier), must be 
reported by the investigator.  
 
● All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment or 30 days 
following cessation of study treatment, if the participant initiates new anticancer therapy, must 
be reported by the investigator.  
 
● Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator, if the event is 
considered to be drug-related. 
 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the investigator 
must promptly notify Merck. 
 
7.6.2 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:  
 
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
“note” below for exceptions) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization, but, based upon appropriate medical 

 
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and scientific judgment, may jeopardize the subject or may require intervention [e.g. 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Although overdose and cancer are not always serious by regulatory definition, these events 
should be reported on an SAE form and sent to Merck in an expedited manner. For purposes 
of this study, 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. In the event of overdose, the participant 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 Medical Monitor and within 2 working days to Merck Global Safety (Attn: 
Worldwide Product Safety; FAX 215-661-6229) utilizing Merck’s Global Safety Intake 
Form.   
NOTE: The following hospitalizations are not considered SAEs in Merck clinical studies: 
 
• a visit to the emergency room or other hospital department for less than 24 hours that does 
not result in admission (unless considered an “important medical event” or a life-threatening 
event); 
• elective surgery, planned before signing consent; 
• admissions as per protocol for a planned medical/surgical procedure; 
• routine health assessment requiring admission for baseline/trending of health status (e.g. 
routine colonoscopy); 
• medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study (appropriate documentation is required in these cases); 

 
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• admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g. lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
Note that all pregnancies, regardless of outcome, must be reported to the sponsor on a 
Pregnancy Surveillance Form, not an SAE form. All pregnancies must be reported and 
followed to outcome, including pregnancies that occur in the female partner of a male study 
subject. See Section 8.4 for instructions on reporting pregnancies. 
 
7.6.3 Non-serious Adverse Events 
All adverse events that are not classified as serious. 
 
7.6.4 Assignment of Adverse Event Intensity and Relationship to Investigational 
Product 
All adverse events, including those that are serious, will be graded according to the National 
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE), Version 5.0. 
The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used for adverse events: 
 
• Definite: There is a reasonable causal relationship between the investigational product and 
the AE. The event responds to withdrawal of investigational product (de-challenge) and 
recurs with re-challenge when clinically feasible. 
• Probable: There is a reasonable causal relationship between the investigational product 
and the AE. The event responds to de-challenge. Re-challenge is not required. 
• Possible: There is reasonable causal relationship between the investigational product and 
the AE. De-challenge information is lacking or unclear. 
• Not likely: There is a temporal relationship to investigational product administration, but 
there is not a reasonable causal relationship between the investigational product and the AE. 
• Not Related: There is not a temporal relationship to investigational product administration 
(too early or late or investigational product not taken), or there is a reasonable causal 
relationship between non-investigational product, concurrent disease or circumstance and the 
AE. 
The expression “reasonable causal relationship” is meant to convey in general that there are 
facts (e.g. evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 
7.6.5 Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.) 

 
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If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, duration, 
intensity, seriousness, relationship to investigational product, action taken, and treatment 
required. If treatment for the AE was administered, it should be recorded in the medical record. 
The investigator shall supply the sponsor and Ethics Committee with any additional requested 
information, notably for reported deaths of subjects. 
 
7.6.6 Collection and Reporting for Serious Adverse Events 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety if it causes the participant to be 
excluded from the trial, or it is the result of a protocol-specified intervention, including, but not 
limited to, washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 1-year post surgery, 
any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause whether or not related to the Merck product, must be reported within 24 hours to the 
Medical Monitor and within 2 working days to Merck Global Safety utilizing Merck’s Global Safety 
Intake Form.   
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229 
Additionally, any serious adverse event considered by an investigator who is a qualified physician 
to be related to Merck product that is brought to the attention of the investigator at any time 
following consent through the end of the specified safety follow-up period specified in the 
paragraph above or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
 
 
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 215-661-6229) at the time of submission to FDA. 
 
 
7.6.7 Handling of Expedited Safety Reports 
In accordance with local regulations, Merck will notify investigators of all SAEs that are suspected 
(certainly, probably or possibly related to the investigational product) and unexpected (i.e. not 
previously described in the Investigator Brochure). In the European Union (EU), an event meeting 
these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). 
Investigator notification of these events will be in the form of an expedited safety report (ESR).  

 
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Other important findings which may be reported by the sponsor as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with study 
procedures that could modify the conduct of the study, lack of efficacy that poses significant 
hazard to study subjects, clinically significant safety finding from a nonclinical (e.g. animal) study, 
important safety recommendations from a study data monitoring committee or sponsor decision 
to end or temporarily halt a clinical study for safety reasons. 
Upon receiving an ESR from Merck, the investigator must review and retain the ESR with the 
Investigator Brochure. Where required by local regulations or when there is a central IRB/IEC for 
the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. The investigator should also 
comply with the IRB/IEC procedures for reporting any other safety information.  
In addition, suspected serious adverse reactions (whether expected or unexpected) shall be 
reported by Merck to the relevant competent health authorities in all concerned countries 
according to local regulations (either as expedited and/or in aggregate reports). 
 
7.6.8  Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI or follow up to an ECI that occurs to any participant must be 
reported within 2 working days to Merck Global Safety, if it causes the participant to be excluded 
from the trial or is the result of a protocol-specified intervention including, but not limited to, 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment or 30 days following cessation of treatment, if the participant initiates new 
anticancer therapy (whichever is earlier), any ECI or follow up to an ECI, whether or not related 
to Merck product, must be reported within 2 working days to Merck Global Safety. 
 
Events of clinical interest for this trial include: 
 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms 
or abnormal laboratory results;  
 
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal 
and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of 
normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 

 
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7.6.9 Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course of the 
study, in a manner such that risk of failure is minimized (See appendix C). Before enrolling 
WOCBP in this clinical study, the investigator must review the guideline about study 
participation for WOCBP which can be found in the GCP Manual for Investigators. The topics 
include the following: 
 
• 
General Information 
• 
 Informed Consent Form 
• 
Pregnancy Prevention Information Sheet 
• 
Drug Interactions with Hormonal Contraceptives 
• 
Contraceptives in Current Use 
• 
Guidelines for the Follow-up of a Reported Pregnancy. 
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during study participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form documenting this discussion. 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving study 
treatment. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of 
HCG. If the pregnancy test is positive, the subject must not receive study treatment and must not 
be enrolled in the study. 
In addition, all WOCBP should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g. dose tapering, if necessary, for 
subject safety). The investigator must immediately notify Merck of this event and record the 
pregnancy on the Pregnancy Surveillance Form (not an SAE form). Initial information on a 
pregnancy must be reported immediately to Merck, and the outcome information provided once 
the outcome is known. Completed Pregnancy Surveillance Forms must be forwarded to Merck 
according to SAE reporting procedures. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g. x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered, if indicated. In addition, the investigator must report 
to Merck and follow-up on information regarding the course of the pregnancy, including prenatal 
and neonatal outcome. Infants should be followed for a minimum of 8 weeks. 
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 215-661-6229). 

 
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7.6.10 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded in the medical record. 
8.0 
CORRELATIVES/SPECIAL STUDIES  
 
Exploratory correlative studies will be performed to characterize the immunologic response of the 
intervention, to correlate immunologic laboratory parameters with clinical efficacy and toxicity, and to 
evaluate the utility of diagnostic imaging. Breast cancer tissue specimens, axillary lymph nodes 
specimens when available, peripheral blood samples, and optional fecal samples will be studied.  
 
8.1 Peripheral blood correlatives 
The rationale use of immunotherapy in the localized breast cancer setting requires a thorough 
assessment of potential predictive biomarkers. Potential biomarkers of pembrolizumab activity in the 
neoadjuvant HER2+ setting will be assessed by comparing blood-based immune markers among the 
three different arms of the study at baseline and on treatment. 
 
Whole blood (8 mL) will be separated by centrifugation into a cellular fraction and plasma. 
• 
The fraction of stem/progenitor cell, lymphocyte, and myeloid populations of total circulating 
mononuclear cells will be counted by flow cytometry using the following markers: CD3, CD4, CD8, 
CD14, CD25, CD34, CD45, CD56, CD127, and CD133. 
• 
The following plasma biomarkers will be assessed: granulocyte-macrophage colony stimulating 
factor, interferon gamma, tumor necrosis factor alpha, interleukin-1b, IL-2, IL-6, IL-8, IL-10, and 
IL-12 heterodimer p70 (using a 9-plex Inflammatory Factor array). 
• 
Surface molecules involved in immune recognition (PD-1 expression and other markers of 
differentiation, memory, and exhaustion) will also be assessed. 
• 
Potential exploratory analyses will include: 
a) identification of circulating antigens, 
b) analysis of antibody response (quantitative antibody titer and qualitative antibody binding), and 
c) analysis of genomic or protein polymorphisms that may affect immune function and response 
to pembrolizumab. 
 
In addition, circulating tumor DNA (ctDNA) will be assessed at baseline and on treatment utilizing a 
16 gene next generation sequencing-based panel covering key breast cancer genes to describe 
therapy-induced genomic changes. A total of 20 mL of blood will be collected at each timepoint for 
ctDNA analysis. For those with detectable ctDNA, the mean allelic fraction will be calculated at 
baseline and on treatment. 
 
Descriptive statistics will be used to summarize biomarker values at protocol-specific time points. The 
Wilcoxon ranked sum test will be used to evaluate the difference of baseline biomarker values 
between patients who did or did not experience a pathologic complete response. 
 
2 (8 mL) CPT (Red/Green tiger top) tubes, 1 (6mL) red top tube, and 1 (5mL) Cyto-Chex BCT tube.  
 

 
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Other assays to be performed include: 
 
• T-cell receptor DNA deep sequencing for clonal T-cell repertoire analysis. 
• Serology Assays: to identify for humoral reactivity against putative TAAs such as NY-ESO-1 
or MUC1. Microarray analyses may also be conducted to screen for novel TAA reactivity. 
• Determination of cell counts, for example absolute lymphocyte count and eosinophil count. 
 
8.2 Tumor specimen correlatives 
Exploratory studies on core biopsy and surgical tissue to evaluate treatment response include, but 
are not limited to: 
 
• Evaluation of cell proliferation by Ki-67; 
• Expression of the PD-L1 inhibitory molecule (Ghebeh 2007);  
• Lymphocyte infiltration including perivascular infiltration; 
• Immunohistochemistry (IHC) staining to further define particular lymphocytic populations 
such as T-regulatory cells (Tregs) (CD4+CD25+FOXP3+), effector T-cells and the ratio 
between Tregs and effector T-cells (CD4+/CD8+);  
• Immunohistochemistry (IHC) staining to identify subsets of dendritic cell (DC) populations 
(i.e. tolerogenic versus immunogenic) and to explore the impact of different treatment arms 
on the ratio between them; 
• Sentinel or non-sentinel lymph node tissue, where available, will also be evaluated by 
immune profiling as described above; 
• Tumoral DNA exome sequencing and RNA expression profiling to determine whether tumor 
mutational landscape correlates with immunologic response; 
• T-cell receptor DNA deep sequencing for clonal T-cell repertoire analysis. 
 
8.3 Optional Fecal Samples for Microbiome Analysis: 
In conjunction with Dr. Stephen Shiao (Radiation Oncology, Cedars-Sinai), optional fecal 
samples will undergo microbiome analysis. Kits for sample collection will be provided to all 
participants who opt to participate in this optional part of the trial, upon registration to the trial. 
Each kit will be provided with a pre-labeled box to be shipped back by the patient for analysis to 
the laboratory of the CSMC PI who will be conducting this analysis: 
 
Dr. Stephen Shiao 
 
 
Cedars-Sinai Medical Center 
 
110 N. George Burns Rd #D4094D 
 
Los Angeles, CA 90048 
 
All specimens will contain subject ID, study visit, and date of collection. The shipping and receipt 
of specimens will be tracked in a database and by emails sent to Dr. Shiao and the PI.  
 
8.4 Sample Collection / Specimen Banking 

 
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Research bloods to be used for flow cytometry analysis, measurement of circulating cytokines, 
and TCR sequencing will be collected prior to initiation of neoadjuvant treatment, after two 
cycles and before surgery. Samples will be frozen and stored for subsequent analysis. 
 
Tumor tissue will be obtained from a standard of care biopsy and surgery. Biopsy and collection 
will be conducted prior to C1D1 neoadjuvant treatment and from surgical specimen. For a fresh 
biopsy, at least 2 cores (1cm each) will be collected. One will be frozen for flow cytometry 
analysis and MerFISH and the other will be paraffin embedded for TIL score, mIHC, and TCR 
sequencing. For the ER+ cohort, if archived tissue is used in lieu of the first research biopsy, 
flow cytometry and MerFISH will not be conducted on this sample as fresh or frozen tissue is 
required for these studies. For archival tissue samples, a tissue block is preferred, but, if 
unavailable, 4 unstained slides and 1 H&E slide are acceptable.   
All blood and tissue samples will need to be shipped to the laboratory who will be conducting 
this analysis. All specimens will need to be labeled according to subject ID, date of collection 
and study visit. The shipping and receipt of specimens will be tracked in a database and by 
emails sent to the lab and the PI. The corresponding study lab manual has further specimen 
labeling and shipping directions.   
 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
This is a phase 2 randomized 3 arm trial wherein eligible patients will be randomized in a 1:1:1 ratio 
between the 2 experimental arms of chemotherapy plus HER2 directed therapy and Pembrolizumab 
(arms B and C), or standard of care neoadjuvant chemotherapy and HER2 directed therapy (arm 
A). The primary endpoint is pathological complete response rate (pCR) in the breast and axilla 
(ypT0/Tis ypN0). 
   
Because biomarkers/correlatives are presently not clearly defined in cancer immunotherapy studies, 
we have designed our study to allow a rigorous evaluation of serial pathology specimen collections. 
These serial evaluations collected in a randomized study will allow a unique opportunity to evaluate 
the impact of the proposed intervention by comparing pathology specimens for treated and 
untreated patients.  These exploratory correlative studies are an integral component of this study 
and are expected to inform future studies.    
9.1 Sample Size Estimation 
 
 
The literature suggests that pCR rates in breast and axilla for patients treated with neoadjuvant 
trastuzumab, pertuzumab and chemotherapy ranges from 39% to 51.9%16,17. There is no data 
informing pCR rates on HER2 positive breast cancer patients treated with combination 
chemotherapy, HER2 directed therapy and pembrolizumab. In a different patient population, triple 
negative breast cancer, the addition of pembrolizumab to neoadjuvant chemotherapy increased 
pCR rates from 50% to 80%30.   
 
The rate of pCR in the breast and axilla in the control group (SCO THP Arm A) is expected to be 
50% (per NeoSphere). We assume the treatment group will achieve a pCR rate of 73%. With a 
trial design 1:1:1 in THP+pembrolizumab (THP-K) vs. TH+pembrolizumab (TH-K) vs. THP, for 
alpha=0.05 and power=80%, 55 patients are required for each arm.  

 
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To account for a 5% loss to follow up during the trial, we decided to add 3 patients per arm (58 
patients/arm). Due to the binary nature of the primary endpoint, patients who discontinue study 
therapy without undergoing surgery will be considered as a non-responder (non-pCR). A total of 
174 patients will be enrolled in this trial.   
 
9.2 
Patients Clinical Characteristics  
 
Patient’s demographic and clinical characteristics at the baseline, including age, medical history 
and conditions, tumor descriptors (grade, histology, tumor size, nodal involvement, etc.) and 
any other study-appropriate data, such as date of initial diagnosis, will be summarized by each 
arm. 
 
9.3 
Study Outcomes 
 
9.3.1 Primary Endpoints  
 
The primary endpoint will be the pCR rate in the breast and axilla (ypT0/Tis ypN0). The rate 
will be calculated and compared between the modified intent-to-treat study groups and 
patient’s clinical characteristics. 
 
9.3.2 Secondary Endpoints 
 
Second endpoints include event-free survival (EFS),  Invasive Disease Free Survival 
(IDFS), Overall Survival (OS), pathological invasive and in situ complete response in breast 
and axilla (ypT0 ypN0), pathologic invasive complete response in the breast only (ypT0/is), 
residual cancer burden index, breast conserving surgery rates (proportion of patients who 
achieved breast conserving surgery out of the intent-to-treat population) and safety. These 
endpoints will be calculated and be compared between study groups. The proportion of 
patients who achieved breast conserving surgery will be tabulated.  
 
9.3.3 Exploratory Analyses  
 
We will perform the exploratory analyses to explore the potential findings for this trial.  
These analyses will be reported primarily using graphs, descriptive statistics and 
nonparametric tests where warranted. Specifically, we will characterize and evaluate the 
magnitude of immune effect as conferred by pre-operative pembrolizumab. Immune 
response in the experimental arm will be measured by the fold-increase of peripheral blood 
CD4+ T-cells expressing ICOS, a marker of T-cell activation, by flow cytometry. The 
potential associations between individual biomarkers and efficacy and safety outcomes will 
be summarized for all patients by treatment arm, and exploratory markers reported by 
subgroup, whenever possible. 
 

 
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9.3.4 Interim Analyses  
 
Stopping rules for safety 
To ensure the safety of the experimental regimens, interim analyses for safety will be 
performed. Specifically, safety will be evaluated after every 15th patient has received at 
least one dose of treatment on study in each of the experimental arms (i.e. in the safety 
population).  
 
A serious adverse event (SAE) is defined as the occurrence of any of the following events: 
 
1. a life threating adverse event, 
2. death due to treatment or  
3. a grade 3/4 AE necessitating a delay in surgery of ≥6 weeks after the last dose of study 
drug.   
 
An experimental arm will be considered unsafe if there is statistical evidence that the rate of 
SAEs θ exceeds 10%. Specifically, an experimental arm is considered unsafe if the 
posterior probability that θ > 0.1 given the data is more than 0.95;  
P(θ > 0.1 | data) > 0.95. A noninformative prior distribution for θ will be used. 
 
If one of the experimental arms is deemed unsafe, the decision to continue enrollment to 
the other 2 arms will be made at the discretion of the PI together with the sponsor. 
We will use a Bayesian sequential design by checking the decision rule to declare an arm as 
unsafe after 15, 30, and 45 patients are evaluable for safety. Table 8 gives the stopping rules 
for the design at each look and column 2 gives the maximum number of patients with SAE in 
order for the trial to proceed. For example, if 5 or more patients had SAEs after enrolling 15 
patients, the arm is considered unsafe. The third column gives the probability of stopping the 
trial when in fact, the true θ = 0.10. This is the equivalent of the Bayesian type I error 
probability. The target type I error probability was set at 0.05.  
 
Number of  
Patients 
Number to 
Continue 
Probability to  
Stop 
Cumulative Probability 
to Stop 
15 
4 
0.013 
0.013 
30 
6 
0.019 
0.032 
45 
8 
0.016 
0.048 
Table 8.  Stopping rules based on three interim looks. Number to continue is the maximum 
number of SAEs for not declaring an arm as unsafe. 
 
Table 9 gives the design operating characteristics under selected values of the true rate of 
SAEs θ. It gives the probability of declaring an arm as unsafe under the alternative 
hypothesis, the expected sample size, and the average sample size given that the arm was 
declared unsafe. For example, if the true value of θ is 0.3, then there is a 96% chance that 
the trial is declared unsafe and the average sample size is about 25. On the other hand, there 
is a small chance of declaring the trial unsafe if θ is small; 4.8% chance of declaring the arm 
unsafe when in fact θ = 0.1. 
 
True Value 
of θ 
Probability to  
Stop 
Expected 
N 
Expected 
N given that we Stopped 
0.10 
0.048 
53.85 
31.14 

 
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0.30 
0.96 
25.41 
24.15 
0.50 
0.999 
15.9 
15.90 
Table 9.  Design operating characteristics under different scenarios for the true probability 
of SAE θ.  
 
Arm C stopping rule for efficacy 
The TH-K arm will be stopped early if the pCR rate is less than 40%. The expected pCR 
rate for the control arm A (THP) is 50%. The stopping rule will be assessed after the first 20 
patients on the TH-K arm have completed surgery. Out of 20 patients, if 8 patients do not 
achieve pCR, regardless of hormone receptor-status, the TH-K arm will be stopped. The 
assessment will be rolling. Subjects can continue to enroll on the TH-K arm and treatment 
will not be stopped while the stopping rule is assessed. If the stopping rule is met, no 
additional patients will be randomized to the TH-K arm. Patients already on the TH-K arm 
will be permitted to continue. 
 
9.4 
Statistical Analyses 
The primary endpoint pCR rate will be calculated and compared using the Cochran-Mantel-
Haenszel test adjusting for the two stratification factors between the arms. Exact 95% 
confidence intervals for the difference in pCR rates between the arms will be constructed 
using the unconditional distribution of two binomials distributions70. A logistic regression 
model will be used to evaluate the treatment effect while adjusted for the factors (e.g. 
hormone receptor status, age, stage, LVI, grade).  
 
The second endpoint rate will be compared using methods like those described for the 
primary endpoint. In addition, the second endpoint will also be analyzed using the survival 
analysis method. The survival rate and pattern will be compared using Kaplan-Meier and 
stratified log-rank test between the arms. The hazard ratio for each event and 95% 
confidence interval between each will be estimated using Cox hazard proportional regression 
model while adjusting the confounding factors.  
 
The efficacy and safety outcomes for exploratory analyses will be summarized using 
descriptive statistical analyses. 
 
All analyses will be performed for Intent-to-Treat (ITT), modified Intent-to-Treat (m-ITT), and 
Safety population based on the following definition: 
 
- 
ITT population: all randomized subjects will be included in the ITT population. 
- 
Modified ITT population: all randomized subjects that received any amount of the study 
drug will be included in the m-ITT population.  
- 
Safety population: includes all subjects in the study who received at least 1 dose or any 
partial dose of pembrolizumab. 
 
9.5 
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Randomization will be conducted using a web-based randomization system. Randomization 
will be accomplished by the method of random permuted block. Eligible patients will be 
randomized in a 1:1:1 ratio between the experimental arm and control arm. Patients will be 
randomized and assigned a unique randomization number. As confirmation, the investigator 
will be provided a written verification of each patient’s registration. Treatment should occur 
within 5 working days of the patient being randomized into the study. No patient may begin 
treatment prior to randomization and assignment of a medication number. 
 
The patient randomization numbers are to be allocated dynamically in the order in which the 
patients are enrolled. The dynamic allocation will be stratified by hormone receptor status 
(positive or negative) and lymph nodes status (positive or negative). 
10.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
 
10.1 
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. 
 
Pembrolizumab will be provided by Merck as summarized in Table 10. 
 
Table 10. Product Description 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
10.2 
Packaging and Labeling Information 
 
Supplies will be labeled in accordance with regulatory requirements. 
 
10.3 Clinical Supplies Disclosure 
 
This trial is open-label, therefore, the participant, 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. 
 
10.4 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. 

 
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Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
10.5 Returns and Reconciliation 
 
The investigator and site are responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the participants 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. 
 
11.0 
STUDY MANAGEMENT 
11.1 Conflict of Interest 
Any reportable conflict of interest will be disclosed to the IRB of record and will be outlined 
in the Informed Consent Form. Conflict of interest will be defined by a situation in which a 
study investigator is involved in an interest, financial or otherwise, which could affect the 
decision-making of that individual as it relates to this study. 
11.2  Institutional Review Board (IRB) Approval and Consent  
 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent 
form must include all the relevant elements currently required by the FDA Regulations and 
local or state regulations. Once this essential information has been provided to the patient 
and the investigator is assured that the patient understands the implications of participating 
in the study, the patient will be asked to give consent to participate in the study by signing 
an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 

 
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11.3 Registration Procedures 
 
All subjects that sign informed consent will be assigned a subject number sequentially by 
their date of consent and listed on the study specific site dedicated screening log.  Those 
subjects that do not pass the screening phase will be listed as screen failures on the site 
screening logs. The study team will also track all subjects who sign consent using OnCore.  
 
Issues that would cause treatment delays after registration should be discussed with the 
Principal Investigator (PI). If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be canceled. The Study Coordinator 
should be notified of cancellations as soon as possible. 
 
Assignment of Subject ID: The study team will track all subjects who sign consent on a 
subject screening/enrollment log using a unique screening ID (S001, S002, etc.). Subjects 
found to be ineligible will be recorded as screen failures. Subjects found to be eligible will 
be registered in Clinical Studio and assigned a three-digit numeric ID. 
 
A) Eligibility Verification 
 
Prior to registration, all subjects must undergo eligibility verification by UTSW. The following 
documents will be completed and provided for review: 
 
• 
Copy of applicable source documents (i.e. pathology report and cTNM staging 
redacted to remove PHI) 
• 
Eligibility checklist (signed by investigator) 
• 
Signed patient consent form with applicable HIPAA language. 
• 
HIPAA authorization form 
 
B) Registration 
 
After eligibility is verified, registration is completed as follows: 
 
Using the EDC system Clinical Studio, site investigator or staff will login and enter 
subject required information for registration and a study ID will be generated: Protocol 
#-AAA (site number)-BBB (unique subject ID); 
• 
Notify the investigational pharmacy and treating physicians that a subject has gone 
on study and of the anticipated treatment start date. 
 
Oversight by the site principal investigator is required throughout the entire registration 
process. 
 
C) Randomization 
 
This is an unblinded randomized comparison of standard neoadjuvant HER2 directed care 
versus neoadjuvant HER2 directed care and pembrolizumab. After eligibility is established 
and immediately after consent is obtained, patients will be registered and randomized within 
Clinical Studio. 

 
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Randomization will be conducted using a web-based randomization system within the EDC 
system Clinical Studio at the time of registration. Randomization will be accomplished by 
the method of random permuted block. Eligible patients will be randomized in a 1:1:1 ratio 
between the experimental arm and control arm. 
   
11.4 Data Management and Quality Control and Reporting 
The data will be entered into a HIPAA-compliant database. The Study Staff will be 
responsible for data processing, in accordance with procedural documentation. Database 
lock will occur once quality assurance procedures have been completed. 
 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
 
11.5 Data and Safety Monitoring 
 
11.5.1 
Data Monitoring and Quality Assurance 
The study project manager will perform the site evaluation visits for all potential sites 
approved by the sponsor. A study monitor will be assigned to the study.  
 
The First Visit will occur within 8-12 weeks of 1st patient enrolled at the site. The study 
monitor with or without the Manager, Clinical Operations will arrange a visit to the site. This 
initial visit is intended to ensure that: 
• 
The study is being conducted according to the protocol 
• 
Confirm the following: 
• Eligibility of enrolled patients 
• Site has received all study supplies and staff understand re-ordering process 
• Study drug is properly stored and inventoried 
• The site staff understands how to complete the eCRFs and all required forms 
 
The study monitor will schedule a site visit approximately every 16 weeks throughout the 
enrollment period and approximately every 24 weeks during the follow-up period. The visits 
may alternate between three and four days. Frequency may change depending on patient 
enrollment, deviations, safety concerns, quality of data and/or quantity of outstanding data. 
Interim visits will continue to occur after the last patient is enrolled at an interval based on 
the number of active patients and outstanding data per site. Monitoring intervals may also 
fluctuate by frequency based on necessity and efficiency of visits. 
 
Remote monitoring will be conducted to review recruitment activity, ongoing data 
completion, to issue queries or resolve queries. If remote access to site EMR is not 
possible, sites will be required to send redacted source documents to study monitor. 
Remote monitoring will be determined by prior agreement amongst the site and sponsor. 
 
Approximately every 2-4 weeks, the assigned  project manager will review the EDC for 
completion and accuracy of critical safety data. The site is expected to upload de-identified 
source documents to the EDC, to allow for a satisfactory review of laboratory assessments, 

 
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physical exams, vitals, dosing information, adverse events and concomitant medications to 
ensure protocol compliance. 
 
 
 
11.5.2 
Safety Monitoring 
 
Safety, data and progress oversight will be provided by the Lead PI with the assistance of 
Medical Monitor and an Institutional Data Safety Monitoring Committee (DSMC). The UTSW 
Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring Committee 
(DSMC) is responsible for monitoring data quality and patient safety for all UTSW SCCC 
clinical trials.  As part of that responsibility, the DSMC reviews all serious adverse events and 
UPIRSOs in real time as they are reported and reviews adverse events on a quarterly basis.  
The quality assurance activity for the Clinical Research Office provides for periodic auditing 
of clinical research documents to ensure data integrity and regulatory compliance.  A copy of 
the DSMC plan is available upon request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing 
clinical trials, for which it serves as the DSMC of record. The Quality Assurance Coordinator 
(QAC) works as part of the DSMC to conduct regular audits based on the level of risk. Audit 
findings are reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of investigational 
agent, device or intervention being studied; and monitoring required to ensure the safety of 
study subjects based on the associated risks of the study. Protocol-specific DSMC plans must 
be consistent with these principles. UTSW will maintain continuous monitoring for the 
duration of the study by reviewing all subject data through in-person and remote monitoring 
visits (by study monitor) and spot check review by the project manager team. 
 
 
 
11.6 Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring/auditing logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). 
 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. Government agency regulations and directives require that the study 
investigator must retain all study documentation pertaining to the conduct of a clinical trial. 
Study documents should be kept on file per local guidelines. 
 
11.7 Adherence to Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, a planned deviation must be sent to 

 
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the Medical Monitor; the study shall be conducted exactly as described in the approved 
protocol. 
 
11.7.1 
Emergency Modifications 
Investigators may implement a deviation from the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB or Sponsor (UTSW) 
approval. 
11.7.2 Protocol Exceptions and Eligibility Waivers  
 
An exception is an anticipated or planned deviation from the IRB-approved research 
protocol. This protocol does not allow for protocol exceptions: any conduct that 
does not follow the protocol is considered a deviation as stated above.  
 
Eligibility Waivers (EW) 
In general, subjects who do not meet the eligibility requirements should not be 
enrolled. For this protocol, eligibility waivers will not be granted.  
 
11.7.3 Other Protocol Deviations 
Logistical deviations from the protocol (e.g. minor changes to the study schedule for 
an individual subject) do not require prior IRB approval unless the deviation has the 
potential to affect the subject’s safety. Such planned deviations that do meet this 
definition and do not affect the subject’s safety should be noted in the subject’s 
research record. 
 
Unintentional deviations from the protocol that might affect subject safety or study 
integrity should be reported to the IRB per institutional standards. 
11.8 
Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment of 
all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and 
all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion. 
 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms and/or into a HIPAA-compliant study 
database. Periodically, monitoring visits will be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of data. At 
the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
 
 
 

 
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12.0  
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13.0 APPENDICES 
 
Appendix A: Criteria for New York Heart Association Functional Classification 
 
 
Functional capacity (four classes) 
 
Class I: 
     No limitation of physical activity. 
 
Ordinary physical activity does not cause fatigue, palpitation or dyspnea. 
 
 
Class II: 
     Slight limitation of physical activity. 
 
Comfortable at rest, but ordinary physical activity results in fatigue, palpitation or dyspnea. 
 
 
 
Class III: 
  Marked limitation of physical activity. 
 
Comfortable at rest, but less than ordinary activity causes fatigue, palpitation or dyspnea. 
 
Class IV:    
Unable to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest. If any 
physical activity is undertaken, discomfort is increased. 
 
 
 
 
 

 
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Appendix B 
Algorithm for Continuation and Discontinuation of Trastuzumab and Pertuzumab Based on LVEF Assessment in 
Asymptomatic Patients 
 
 
LVEF < 50% 
LVEF ≥ 50% 
 
 
 
 
 
 
LVEF ≤ 44%* 
LVEF 45% - 49% 
CONTINUE trastuzumab and pertuzumab 
 
 
HOLD trastuzumab and pertuzumab and repeat LVEF in 3 
weeks 
Decrease of ≥ 10 EF points 
from baseline* 
Decrease of < 10 EF points from baseline 
 
 

 
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LVEF ≤ 44% OR LVEF 45% - 49% and 
decrease of ≥ 10 points from baseline 
LVEF 45% - 49% and a 
decrease of < 10 points 
from baseline OR 
LVEF > 49% 
 
HOLD trastuzumab and 
pertuzumab and repeat LVEF in 3 
weeks 
 
CONTINUE 
trastuzumab and pertuzumab and repeat LVEF 
in 3 weeks 
 
 
 
STOP trastuzumab and pertuzumab** 
 
RESUME trastuzumab and 
pertuzumab 
LVEF ≤ 44% 
OR 
LVEF 45% - 49% and decrease 
of ≥ 10 points from baseline 
LVEF 45% - 49% and decrease of 
< 10 points from baseline OR 
LVEF > 49 % 
 
 
 
 
 
 
 
EF = ejection fraction; LVEF = left ventricular ejection fraction. 
STOP trastuzumab and 
pertuzumab** 
RESUME trastuzumab and pertuzumab 
 
* Report as AE – Reporting term ‘Left ventricular systolic dysfunction’ 
 
** Report as AE (eCRF AE eform) and Non-Serious Event of Special Interest (SAE form) Reporting term ‘Left ventricular systolic dysfunction’ 
Note: LVEF assessment results must be available before/or on the day of the next scheduled trastuzumab and pertuzumab/placebo equivalent administration. 
 
 
 
 

 
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Appendix C: Contraceptive Guidance and Pregnancy Testing 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● Premenarchal 
● Premenopausal female with 1 of the following: 
○Documented hysterectomy 
○Documented bilateral salpingectomy 
○Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
●Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal range is required.  
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
 
Contraception Requirements 
 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined time frame in section 5.6:  
●Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on 
a long term and persistent basis) and agree to remain abstinent 
●Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per 
year as described in Table 11 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration. 
 
Female Participants: 
 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 11 during the protocol-defined time frame in Section 5.6.   
 

 
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Table 11 
Highly Effective Contraceptive Methods That Have Low User Dependency 
 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.  
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation. 
  
 

 
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Appendix D: SUMMARY OF CHANGES 
 
Amendment 1 Protocol Version 2 dated 10Jan2019:  
changes made to version 1 dated 25Sep 2018 
1. Title page:  
a. updated co-investigators to include Dr. Stephen Shiao and removed Dr. Kollman and 
Wachsman. 
b. NCT number added 
2. List of abbreviations: EDC added 
3. Eligibility, 4.1 Inclusion Criteria: 
a. Clarification of criteria #2 
b. Type of criteria #4 to state greater than or equal to 18 years of age 
c. Criteria #8 clarified from provided tissue to confirmation of adequate tissue.  Section 8.1 
reference added. 
d. Criteria #9 removed the ECOG requirement of completion within 7 days of randomization  
4. Eligibility, 4.2 Exclusion Criteria: 
a. #8 clarified to specify that a malignancy other than the current breast cancer diagnosis 
b. #13 updated to include specific hepatitis panel tests to confirm eligibility 
5. Section 5.1 Treatment Dosage and Administration: Pertuzumab administration clarified to state that 
the observational period following infusion is recommended (per FDA approved guidelines), but not 
required and may be performed per institutional standards. 
Subsequent cycle observation period was removed.  
6. Section 5.2 Dose Modifications and Delays: Clarified dosing delays and timing regarding holds and 
restarting or discontinuing treatment 
7. Section 5.3 Method of Assigning Subjects to Treatment Groups: updated to include the new EDC 
Clinical Studio.  Clarification of working days as business days. 
8. Section 5.4 Excluded Therapies updated to include Proton Pump Inhibitor guidelines during 
treatment 
9. Section 5.5 Other Modalities, etc.: Surgery timing added to confirm procedure at 5 weeks (+/-1 week) 
following completion of protocol treatment.  
10. Section 6.0 Study Procedures: 
a. Screening time clarified to 28 days 
b. CMP labs clarified to state tests that must be included 
c. Coagulation test added to screening 
d. Research blood and optional fecal sample moved from screening to C1D1 
e. Clarification of the timing of research blood and optional fecal samples during treatment 
f. 
Research blood specimen tube and timing updated 
g. Timing of CBC added as drawn weekly days 1, 8 and 15 (+/- 3 days) for every cycle during 
treatment 
11. Table 3, Time and Events Table: updated to reflect the changes listed above.   
a. Clarified that safety labs utilized for screening do not need to be repeated on C1D1 if 
completed within 7 days of treatment initiation 

 
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b. Clarified that pregnancy test will need to be repeated if completed over 72 hours prior to 
treatment initiation 
c. Breast imaging added at screening, surgery and follow up 
d. Staging imaging timepoints clarified 
e. Vitals added to screening, before dosing visits, surgery and during follow up 
f. 
Footnotes clarified throughout chart 
12. Section 6.3 Follow up Procedures: SOC f/u visit to occur every 3 months (+/- 1 week) 
13. Section 7.5.2 Expedited Reporting: updated to include coordinating center/outside contracted 
CRO, Oncotherapeutics and contact information 
a. Section 7.5.2.2: clarified that IRB must be notified per institutional standard 
14. Section 7.6.2  SAEs: the following language was added: Progression of the cancer under study is 
not considered an adverse event unless it results in hospitalization or death. 
15. Section 7.6.2 and 7.6.6 udpated to  include Merck global safety reporting to include PI, 
Oncotherapeutics and Merck as recipients in overdoes and SAE and other safety information 
reports utilizing the Merck global safety intake form. 
16. FDA MEDWATCH reporting requirements for IND reporting removed.  This study is IND exempt 
17. Section 8.0 Correlatives: 
a. Blood collection tubes updated as: 2 (8 mL) CPT (Red/Green tiger top) tubes, 1 (6mL) 
red top tube, and 1 (5mL) Cyto-Chex BCT tube. 
b. Sample instructions added: All research blood (and tissue) samples will need to be 
shipped to the laboratory of the CSMC PI who will be conducting this analysis.  All 
specimens will need to be labeled according to subject ID, date of collection and study 
visit. The shipping and receipt of specimens will be tracked in a database and by 
emails sent to Dr. Shiao and the PI.  The corresponding study lab manual has further 
specimen labeling and shipping directions.   
c. Archival tissue samples updated to state: For archival tissue samples, a tissue block is 
preferred, but it unavailable 4 unstained slides and 1 H&E slide is acceptable.   
18. Section 11.3 Registration Procedures: updated to include screening log, and removal of review 
procedures of log by investigator and CRC.  Clinical studio EDC added as registration tool.  
Registration/Randomization procedures and eligibility verification updated to reflect new 
procedures with Oncotherapeutics and EDC, Clinical Studio. 
19. Section 11.5 Data and Safety Monitoring: Language updated to reflect the data monitoring plan 
and safety review by Oncotherapeutics. 
20. Section 11.7 Adherence to protocol, the following modifications were made: Emergency 
modifications, protocol exceptions and planned deviations request must be sent to PI and Medical 
Monitor.  Medical Monitor contact information included.  Eligibility waivers updated to reflect PI 
policy that none will be granted.  Protocol amendments process removed from protocol.  Site 
specific deviation language was removed.  
21. Formatting updates and changes throughout the document 
 
 
 
Amendment 2 Protocol Version 3 dated 03Mar2020:  
changes made to version 2 dated 10Jan2019 
1. List of abbreviations: added missing abbreviations. 

 
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2. Her2 changed to HER2 throughout the document for consistency. 
3. Typo corrections, formatting updates, and changes throughout the document. 
4. Study schema: clarified use of additional therapy for biopsy proven residual disease. 
5. Study summary: clarified study duration, study centers, and safety and efficacy analyses. 
6. Background and rationale: 
a. Changed “programmed death ligand 1” to “programmed cell death ligand 1”; 
b. Changed “programmed death 1” to “programmed cell death protein 1”; 
c. Changed “cytotoxic T lymphocyte-associated antigen 4” to cytotoxic T lymphocyte-associated protein 4”. 
7. Section 2.4.2 Secondary Efficacy Endpoints: changed “Any evidence of ipsilateral or contralateral disease in sit will 
not be identified as progressive disease.” to “All in situ cancer events (ipsilateral or contralateral DCIS, ipsilateral or 
contralateral LCIS and all in situ cancer of non-breast sites) are excluded as an event in the endpoint.”. 
8. Section 2.4.3 Exploratory Endpoints: changed serial peripheral blood and optional fecal sample collection to “as per 
schedule in Table 3”. 
9. Section 3.1 Overview of the Study Design: 
a. Added “Patients with biopsy-proven residual disease after completing the study treatment may receive 
additional chemotherapy (i.e. four cycles of adriamycin + cyclophosphamide administered every two 
weeks) prior to surgery at the treating physician discretion and should be seen in follow-up at each 
additional treatment prior to surgery.”; 
b. Clarified follow up visit schedule to every 3 months until 36 months after surgery and every 6 months in 
year 4 and 5, then annually until year 10 after surgery. 
10. Section 5.1 Treatment Dosage and Administration: Paclitaxel administration clarified to state that additional 
premedication should be administered as per standard practice. 
11. Section 5.4 Concomitant Medication and Treatment: 
a. Removed acetaminophen from Allowed Therapies because same as paracetamol (duplication); 
b. Added corticosteroids for immune related adverse events, thyroid medications, and gonadotropin-releasing 
hormone analog/antagonists to the Allowed Therapies; 
c. Clarified excluded anti-cancer therapies to allow exception for ddAC administration in patients with residual 
disease before surgery; 
d. Removed steroids and corticosteroids from the Excluded Therapies. 
12. Section 6.0 Study Procedures: 
a. Clarified screening/baseline procedures; 
b. Added carbon dioxide as an option within CMP labs; 
c. Hepatitis B, Hepatitis C and HIV tests removed; 
d. TSH + free T3 and T4 changed to THS to reflex T4 or TSH with T4 per institutional standards; 
e. Modified section 6.2.1 Subjects randomized to control arm to include ddAC chemotherapy for patients with 
residual disease after Cycle 4;  
f. 
Research blood and optional fecal sample moved from C2D1 to C3D1; 
g. Added optional fecal sample collection at 30and 60 days after surgery; 
h. Clarified Echo and MUGA timing. 
i. 
Clarified long-term follow-up schedule 
j. 
Table 3, Time and Events Table updated to reflect the changes listed above and footnotes clarified 
throughout chart. 
13. Table 4: clarified guideline for paclitaxel use in case of grade 4 hepatic toxicity. 
14. Table 7: clarified guidelines for premedication at subsequent doses of pembrolizumab in case of grade 2 infusion 
reaction. 

 
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15. Section 8.1 Peripheral blood correlatives: updated to list specific blood correlative assays to be conducted. 
16. Section 9.3.4 Interim Analyses: added Arm C stopping rule for efficacy. 
17. Section 11.3: added cTNM staging to source documents to obtain for eligibility verification. 
18. Section 11.5.2 Safety Monitoring: Language updated to reflect the additional data and safety monitoring by an 
Institutional Data Safety Monitoring Committee with a frequency of 6 months. 
19. Appendix C: Table 9 changed to Table 11. 
20. Removed Performance Status at surgery in Schedule of Events. 
21. Clarified duration of toxicity assessment through 1-year post surgery. 
22. Updated acceptable forms of trastuzumab throughout the document. 
23. Added allowance of nab-paclitaxel.  
24. Increased long-term follow-up to year 10. 
 
Protocol Version 4 dated 08DEC2020: 
1. Addition of Torrance sub-investigators. 
2. Clarified TSH per PI to read: TSH with reflex to T3 and free T4 OR TSH with T3 and free T4. 
3. Removed section 7.5.3 
 
Protocol Version 5 dated 24MAR2021: 
1. Revise Exclusion Criteria #5 (vaccines) per Merck revised Protocol Template. 
2. Revise Exclusion Criteria #10 (pneumonitis) to include interstitial lung disease per Merck revised 
Protocol Template. 
3. Revise Section 5.2.3 and Table 6 per Merck revised Protocol Template.  
4. Added Optional fresh breast biopsies for analysis (Cedars patients only) at baseline and week 6. 
 
 
Protocol Version 5.1 dated 16JUN2021: 
Cover page: Principal Investigator changed from Dr. Heather McArthur to Dr. Reva Basho. 
 
Protocol Version 6.0 dated 23May2022: 
Cover page- updated to reflect UTSW as lead site 
Section 11.5.2 – Updated to reflect UTSW SCCC DSMC standard template language for safety 
monitoring 
Minor clarifications about lost to follow up contact and vital sign collection during long term follow up 
 
Protocol Version 7.0 dated 22Feb2023: 
Cover page updated to reflect current protocol version and date  
Signature page updated to reflect current protocol version and date  
Study Summary:  Addition of New Mexico Cancer Center as subsite 
Inclusion Criterium 10: Removal of language regarding screening lab collection time period to align with 
schedule of events 

 
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Section 6.2.1 Removal of clinical breast exam and mammogram language after completion of cycle 4 of 
treatment 
 
Protocol Version 8.0 dated 14Dec2023: 
1. Cover page updated to reflect current protocol version and date  
2. Signature page updated to reflect current protocol version and date  
3. Section 7.5.2 Removal of VP of Oncotherapeutics as contact for SAE reporting and updated SAE 
reporting table  
4. Section 7.6.2 Removal of Oncotherapeutics as contact for SAE reporting  
5. Section 7.6.6 Removal of coordinating center Oncotherapeutics as contact for overdose reporting  
6. Section 8.4 Updated sample collection to remove incorrect laboratory address  
6. Section 11.3 Replacement of Oncotherapeutics with UTSW 
7. Section 11.5 Replacement of Oncotherapeutics with IIT project manager; replacement of CRA with Study  
Monitor; replacement of Oncotherapeutics with Sponsor; removal of ‘and follow specifications deemed 
appropriate by both Sponsor and Oncotherapeutics.’ 
8. Section 11.5.2 Removal of Oncotherapeutics; replacement of CRO with UTSW; replacement of CRA 
with study monitor  
9. Section 11.7 Removal of Oncotherapeutics 
10. Section 11.7.1 Removal of Oncotherapeutics