Induction Immunotherapy to Promote Immunologic Priming and Enhanced Response to Neoadjuvant Pembrolizumab + Chemotherapy in Triple Negative Breast Cancer (TNBC)
Phase: PHASE2
Conditions: Breast Cancer, Breast Neoplasms
Sponsor: Providence Health & Services

Product:  MK-3475 / IRX-2  
0 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
  
 
 
TITLE: 
Induction IRX-2 immunotherapy to promote immunologic priming and enhanced 
response to neoadjuvant pembrolizumab + chemotherapy in triple negative breast 
cancer (TNBC) 
 
IND NUMBER:  146229 
 
PRINCIPAL INVESTIGATOR: David Page, MD 
 
PROTOCOL VERSION/DATE: 
Version 28-Jul-2021 
 
 
 
 
 
 
 

Product:  MK-3475 / IRX-2  
1 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
TABLE OF CONTENTS 
 
1.0 
TRIAL SUMMARY.................................................................................................... 6 
2.0 
TRIAL DESIGN.......................................................................................................... 7 
 
Trial Design ............................................................................................................. 7 
 
Trial Diagram .......................................................................................................... 8 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 9 
 
Primary Objective & Hypothesis .......................................................................... 9 
 
Secondary Objective(s) ........................................................................................... 9 
 
Exploratory Objectives ......................................................................................... 10 
4.0 
BACKGROUND & RATIONALE .......................................................................... 10 
 
Background ........................................................................................................... 10 
 Pharmaceutical and Therapeutic Background .................................................... 10 
 TNBC Background ...................................................................................... 10 
 Standard-of-care therapy for TNBC ............................................................ 10 
 Targeting PD-1 Immune Checkpoints for Cancer Treatment ...................... 11 
 Targeting PD-1 Immune Checkpoints for TNBC ........................................ 13 
 Induction Immunotherapy approaches to enhance response to chemotherapy 
and immune checkpoint therapy ......................................................................... 13 
 IRX-2 cytokine therapy as an induction therapy preceding anti-PD-1 ........ 14 
4.1.2.1.1 Delivery of IRX-2 via breast lymphatics .............................................. 15 
4.1.2.1.2 Components of IRX-2 Induction regimen ............................................ 15 
4.1.2.1.3 Preclinical rationale to combine IRX-2 with anti-PD1 ......................... 16 
4.1.2.1.4 Rationale to include IRX-2 re-induction following Treatment 1 and 
preceding Treatment 2 .......................................................................... 17 
 Summary of Clinical Activities: Pembrolizumab ............................................... 17 
 Summary of Clinical Data Supporting Pembrolizumab Use for Treatment 
of Metastatic TNBC ..................................................................................... 18 
4.1.3.1.1 KEYNOTE-012 (KN012) ..................................................................... 18 
4.1.3.1.2 Additional Ongoing Clinical Studies with Pembrolizumab in breast 
cancer .................................................................................................... 18 
 Summary of Clinical Activities: IRX-2 .............................................................. 19 

Product:  MK-3475 / IRX-2  
2 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Phase I clinical trial ...................................................................................... 19 
 Phase 2 trial in HNSCC ............................................................................... 19 
 Phase Ib Trial of IRX2 in early stage breast cancer ..................................... 22 
 Rationale for the Trial and Selected Subject Population .................................... 23 
 Rationale for Dose Selection/Regimen/Modification ......................................... 24 
 Rationale for Testing Pembrolizumab in Combination with the Selected 
TNBC Neoadjuvant Regimen ...................................................................... 24 
4.1.6.1.1 Rationale for evaluating combination immunotherapy with a 
carboplatin-sparing neoadjuvant chemotherapy background regimen
 24 
 Rationale of Pembrolizumab Dose .............................................................. 25 
 Rationale for pembrolizumab dosing and schedule during the induction 
period ........................................................................................................... 26 
 Rationale for IRX-2 dosing, delivery method, and schedule ....................... 26 
 Rationale for Dose Interval for Neoadjuvant therapy .................................. 26 
 Efficacy Endpoint ........................................................................................ 26 
 Safety Endpoints .......................................................................................... 27 
 Exploratory Biomarker Research ................................................................. 27 
 Future Biomedical Research ........................................................................ 29 
 
Benefit/Risk ........................................................................................................... 29 
5.0 
METHODOLOGY ................................................................................................... 29 
 
Entry Criteria ........................................................................................................ 29 
 Subject Inclusion Criteria.................................................................................... 29 
 Subject Exclusion Criteria .................................................................................. 31 
 
Trial Treatment(s) ................................................................................................ 32 
 Dose Modification for Pembrolizumab............................................................... 35 
 
  5.2.2   Dose Modifications for IRX-2 ………………………………………………..42 
 
  5.2.3   Dose Modifications for Chemotherapy Agents ………………………………..42 
 Timing of Dose Administration .......................................................................... 48 
 Pembrolizumab ............................................................................................ 48 
 IRX-2 ........................................................................................................... 48 
 Paclitaxel ...................................................................................................... 48 
 Cyclophosphamide ....................................................................................... 49 

Product:  MK-3475 / IRX-2  
3 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
5.2.4.4.1 Induction phase ..................................................................................... 49 
5.2.4.4.2 Neoadjuvant phase ................................................................................ 49 
 Doxorubicin ................................................................................................. 49 
 
Randomization or Treatment Allocation ............................................................ 49 
Treatment allocation/randomization will occur centrally at Providence Cancer Institute, 
details on randomization are in statistical methods. ............................................... 49 
 
Stratification .......................................................................................................... 49 
 
Concomitant Medications/Vaccinations (Allowed & Prohibited) .................... 49 
 Acceptable Concomitant Medications ................................................................ 49 
 Prohibited Concomitant Medications.................................................................. 50 
 
Rescue Medications & Supportive Care ............................................................. 51 
 Supportive Care Guidelines for Pembrolizumab ................................................ 51 
 Supportive Care Guidelines for Chemotherapy Agents ...................................... 51 
 
Diet/Activity/Other Considerations ..................................................................... 51 
 Diet ...................................................................................................................... 51 
 Contraception ...................................................................................................... 51 
 Use in Pregnancy ................................................................................................ 53 
 Use in Nursing Women ....................................................................................... 53 
 
Subject Withdrawal/Discontinuation Criteria ................................................... 53 
 Discontinuation of Treatment ............................................................................. 53 
 Withdrawal from the Trial .................................................................................. 54 
 
Subject Replacement Strategy ............................................................................. 54 
 
Beginning and End of the Trial ........................................................................... 55 
 
Clinical Criteria for Early Trial Termination ................................................... 55 
6.0 
TRIAL FLOW CHART ........................................................................................... 56 
7.0 
TRIAL PROCEDURES ........................................................................................... 68 
 
Trial Procedures ................................................................................................... 68 
 Administrative Procedures .................................................................................. 68 
 Informed Consent......................................................................................... 68 
 Inclusion/Exclusion Criteria ........................................................................ 68 
 Medical History ........................................................................................... 68 
7.1.1.3.1 Disease Details ...................................................................................... 68 

Product:  MK-3475 / IRX-2  
4 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Prior and Concomitant Medications Review ............................................... 68 
7.1.1.4.1 Prior Medications .................................................................................. 68 
7.1.1.4.2 Concomitant Medications ..................................................................... 69 
 Research Participant Registration ................................................................ 69 
 Assignment of Treatment/Randomization Number ..................................... 69 
 Trial Compliance (Medication) .................................................................... 69 
 Clinical Procedures/Assessments ........................................................................ 70 
 Adverse Event Monitoring ........................................................................... 70 
 12-Lead Electrocardiogram ......................................................................... 70 
 Echocardiography or Multigated Acquisition Scan ..................................... 70 
 Physical Examination................................................................................... 70 
7.1.2.4.1 Full Physical Examination .................................................................... 70 
7.1.2.4.2 Directed Physical Examination ............................................................. 70 
 Vital Signs .................................................................................................... 71 
 Eastern Cooperative Oncology Group Performance Status ......................... 71 
 Tumor Tissue Biopsy and Sample Collection ............................................. 71 
 Imaging Disease Assessment ....................................................................... 71 
 Definitive Surgery ........................................................................................ 71 
 Laboratory Procedures/Assessments .................................................................. 72 
 Menopausal Status ....................................................................................... 73 
 Blood Collections Samples for Exploratory Biomarker Analyses .............. 73 
 Other Procedures ................................................................................................. 73 
 Withdrawal/Discontinuation ........................................................................ 73 
 Visit Requirements .............................................................................................. 73 
 Screening...................................................................................................... 73 
 Treatment Cycles ......................................................................................... 73 
 Definitive Surgery ........................................................................................ 74 
 Post-Treatment Visits................................................................................... 74 
7.1.5.4.1 Early Discontinuation Visit .................................................................. 74 
7.1.5.4.2 Safety Follow-up Visits ........................................................................ 74 
7.1.5.4.3 Unscheduled Visit ................................................................................. 74 
7.1.5.4.4 Long Term Follow-up ........................................................................... 74 

Product:  MK-3475 / IRX-2  
5 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 74 
 Monitoring/Oversight Plan ................................................................................. 74 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 75 
 
Statistical Analysis Plan Summary ..................................................................... 75 
 
Analysis Endpoints ............................................................................................... 78 
 Efficacy Endpoints .............................................................................................. 78 
 Other Exploratory Endpoints .............................................................................. 78 
9.0 
REGULATORY AND REPORTING REQUIREMENTS ................................... 79 
 
Common Terminology Criteria for Adverse Events (CTCAE) ........................ 79 
 
Definitions .............................................................................................................. 79 
 
Adverse Event Reporting ..................................................................................... 80 
 
Continuing Review and Final Reports ................................................................ 81 
 
Protocol Amendments .......................................................................................... 81 
 
Record Retention .................................................................................................. 81 
 
Data Management ................................................................................................. 82 
10.0 
LIST OF REFERENCES ......................................................................................... 83 
APPENDICES ....................................................................................................................... 85 
 
ECOG Performance Status Scale ........................................................................ 85 
 
Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ............... 86 
 
Abbreviations ........................................................................................................ 87 
11.0 
SIGNATURES........................................................................................................... 90 
 
 

Product:  MK-3475 / IRX-2  
6 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Induction immunotherapy to promote immunologic priming and 
enhanced response to neoadjuvant pembrolizumab + chemotherapy in 
triple negative breast cancer (TNBC) 
Sponsor Product Identifiers 
 
MK-3475 (Pembrolizumab) 
IRX-2 
Trial Phase 
II 
Clinical Indication 
Neoadjuvant treatment for stage II-III TNBC 
Trial Type 
Interventional 
Type of control 
Pembrolizumab on a background of chemotherapy 
Route of administration 
Intravenous 
(pembrolizumab, 
cyclophosphamide, 
paclitaxel, 
doxorubicin), subcutaneous (IRX-2) 
Trial Blinding 
Open-label 
Treatment Groups 
 
There are two phases of therapy and randomization to treatment versus 
control: 
• 
Induction Phase 
o 
Control Arm: Pembrolizumab 
o 
Arm A: Cyclophosphamide + IRX-2 + Pembrolizumab 
o 
Subsequent arms to be added in protocol amendment 
• 
Neoadjuvant Phase 
o 
Control Arm: Pembrolizumab + Chemotherapy 
o 
Arm A: Pembrolizumab + Chemotherapy with IRX-2 re-
induction  
o 
Subsequent arms to be added in protocol amendment 
Induction phase: 
Pembrolizumab: 200 mg fixed dose, intravenously (IV) single dose on 
day 1 of the induction phase [All arms] 
IRX-2: 2mL subcutaneous (2 x 1mL subcutaneous injection) daily for 
10 days spanning days 4-21 during induction phase [Arm A] 
Cyclophosphamide: 300 mg/m2, IV single dose on day 1 of the 
induction phase [Arm A] 
Neoadjuvant Phase: 
Pembrolizumab: 200mg fixed dose, intravenously (IV) Q3W of cycles 
1-4 of the T regimen (treatment 1) and Q3W of cycles 1-4 of the AC 
regimen [All arms] 
Paclitaxel: 80 mg/m2, IV, weekly, on Days 1, 8, 15 of Cycles 1-4 of the 
paclitaxel regimen (Treatment 1) [All arms] 
Followed by: 

Product:  MK-3475 / IRX-2  
7 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
IRX-2: 2mL subcutaneous (2 x 1mL subcutaneous injection) daily for 
10 days over any 14 day period following completion of Treatment 1 
and to be completed prior to advancement to Treatment 2 [Arm A] 
Doxorubicin: 60 mg/m2, IV, Q3W, on Day 1 of Cycles 1-4 of the 
doxorubicin + cyclophosphamide (AC) regimen (Treatment 2) [All 
arms] 
Cyclophosphamide: 600 mg/m2, IV, Q3W, on Day 1 of Cycles 1-4 of 
the AC regimen (Treatment 2) [All arms] 
Note: each cycle = 21 days 
Number of trial subjects 
Estimated 30 subjects will be enrolled (additional subjects pending 
subsequent expansions). 
Estimated duration of trial 
Approximately 2 years experimental arm and Arm A, from the time the 
first subject signs the informed consent until the last subject’s last 
study-related visit. 
Duration of Participation 
Each subject will participate in the trial for approximately 34-36 weeks 
from the time the subject signs the Informed Consent Form (ICF) 
through completion of study treatment.  
After a screening phase of ~28 days, each subject will be receiving study 
treatment based on the randomization schedule for approximately 30 
weeks (induction phase plus 8 cycles neoadjuvant phase followed by 
definitive surgery 3-6 weeks after conclusion of the last cycle of the 
neoadjuvant treatment.) 
 
 
A list of abbreviations used in this document can be found in Section 10.3. 
2.0 TRIAL DESIGN 
 
Trial Design 
This is a Phase II, randomized, open-label trial to evaluate the clinical and immunologic 
activity of pembrolizumab plus chemotherapy when combined with various immunotherapy 
induction regimens as neoadjuvant therapy for triple negative breast cancer (TNBC).  
A commonly used standard neoadjuvant regimen for TNBC is a weekly taxane (e.g., paclitaxel 
80mg/m2) for 12 weeks followed by an anthracycline (e.g., doxorubicin 60 mg/m2 plus 
cyclophosphamide at 600 mg/m2 [AC]) every 3 weeks (Q3W) for 4 cycles.  
The chemotherapy regimen included in this study is built upon the aforementioned regimen.  
Pembrolizumab in combination with this regimen will be studied as part of a multi-arm study 
that randomizes subjects to receive: 
• Control Arm: (Pembro + ACT): Pembrolizumab induction (single-dose 200mg IV), 
followed by pembrolizumab Q3W + paclitaxel (T) weekly x 4 cycles, followed by 
pembrolizumab + doxorubicin + cyclophosphamide (AC) Q3W x 4 cycles as neoadjuvant 
therapy prior to surgery. 
• Arm A: (Pembro + IRX-2 + ACT): Pembrolizumab (single-dose 200mg IV) 
cyclophosphamide (single-dose 300 mg/m2 IV) + IRX-2 induction (1mL SQ x 2 daily, x 
10 days), followed by pembrolizumab Q3W + paclitaxel (T) weekly x 4 cycles, followed 
Randomization Ratio 
1:1 experimental:control for arm A   

Product:  MK-3475 / IRX-2  
8 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
by IRX-2 re-induction (1mL SQ x 2 daily, x 10 days), followed by pembrolizumab + 
doxorubicin + cyclophosphamide (AC) Q3W x 4 cycles as neoadjuvant therapy prior to 
surgery. 
• Subsequent induction therapy arms are to be included in protocol amendments. 
Note: 1 cycle = 21 days 
 
In the neoadjuvant phase, the dose and schedule of pembrolizumab will be fixed at 200 mg 
Q3W; and a commonly used AC dose/schedule will be used, i.e., doxorubicin 60 mg/m2  Q3W 
plus cyclophosphamide 600 mg/m2 Q3W.  The dose level of paclitaxel is 80 mg/m2 weekly. 
Tumor Biopsy for Translational Research: Subjects with locally advanced TNBC are 
required to submit tissue from the diagnostic biopsy, or undergo a dedicated core needle biopsy 
during the screening period. Additionally, subjects will be undergo research core needle biopsy 
at the end of the induction treatment phase and prior to commencing the neoadjuvant treatment 
phase. Tumor tissue samples will also be collected at definitive surgery for subjects who have 
not achieved a pCR. All tumor tissue samples collected at different time points during the study 
will be submitted to Providence Cancer Institute for translational research as described in more 
detail in the laboratory manual.  
Definitive surgery: Definitive surgery such as breast conservation surgery (BCS) or 
mastectomy with or without axillary lymph node dissection will be performed as part of the 
local standard of care approximately 3-6 weeks following the completion or early 
discontinuation of the treatments in the Neoadjuvant Treatment Phase. A thorough evaluation 
of breast cancer status, pathological staging per the current American Joint Committee of 
Cancer (AJCC) Edition 8 Breast Cancer Staging criteria and assessment of surgical margins 
will be performed by the local pathologist on all the tissues removed during the surgery.  
Post-surgical therapy: Subjects may receive adjuvant radiation therapy and systemic therapy 
at the discretion of the treating provider. 
Safety: Study treatment will continue until completion of study treatment, disease progression 
in the neoadjuvant phase or until recurrence (local or distance) after surgery, unacceptable 
adverse event(s), intercurrent illness that prevents further administration of study treatment, 
Investigator’s decision to withdraw the subject from study treatment, pregnancy of the subject, 
noncompliance with study treatment or procedure requirements, consent withdrawal, 
becoming lost-to-follow-up, death, or administrative reasons that require cessation of 
treatment.  Adverse events will be monitored throughout the trial and graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0.  
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
The study will be conducted in conformance with Good Clinical Practices (GCPs).  
 
Trial Diagram 
The trial diagram is depicted in Figure 2.2-1. 

Product:  MK-3475 / IRX-2  
9 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Figure 2.2-1: Trial diagram (Control and Arm A) 
  
AC refers to doxorubicin plus cyclophosphamide. Details of treatments are listed in subsequent 
sections. Following completion of accrual of Arm A (n=15) and control arm (n=15), the trial 
may either terminate, or may continue to enroll additional arms at n=15, each randomized 1:1 
against control (n=5), with additional agents as specified in subsequent protocol amendments. 
See section 5.0 for additional treatment management guidelines.  
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
In male and female subjects at least 18 years of age with newly diagnosed, locally advanced 
TNBC:  
 
Primary Objective & Hypothesis 
1) Objective: To evaluate the rate of pCR of pembrolizumab plus chemotherapy plus 
various induction regimens using the definition of ypT0/Tis ypN0 (i.e., no invasive 
residual in breast or nodes; noninvasive breast residuals allowed) as assessed by the 
local pathologist at the time of definitive surgery in subjects with locally advanced 
TNBC. 
Hypothesis: Administration of induction immunotherapy enhances activity of 
pembrolizumab plus chemotherapy, as measured by the rate of pCR using the definition 
of ypT0/Tis ypN0 as assessed by the local pathologist at the time of definitive surgery 
in subjects with locally advanced TNBC. 
The study is considered to have met its primary objective if an induction regimen (example: 
Arm A: IRX-2) is found to have pCR rates similar or superior to historical controls of 
pembrolizumab plus carboplatin-containing chemotherapy obtained from the phase III 
KEYNOTE-522 clinical trial. 
 
Secondary Objective(s)  
1) Objective: To evaluate the rate of response using the residual cancer burden (RCB) 
index in subjects with locally advanced TNBC tumors treated with pembrolizumab plus 
chemotherapy plus various induction immunotherapy regimens. 
2) Objective: To determine the safety and tolerability of pembrolizumab in combination 
with neoadjuvant chemotherapy and various induction immunotherapy regimens in 
locally advanced TNBC subjects. 

Product:  MK-3475 / IRX-2  
10 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
3) Objective: To evaluate stromal TIL quantity1 changes of therapy, comparing baseline 
diagnostic biopsy to post-induction research biopsy core tissue specimen. 
 
Exploratory Objectives 
1) Objective: To characterize TIL phenotype and activation status at baseline and 
following induction immunotherapy and/or pembrolizumab by various assays such as 
multispectral immunofluorescence (mIHC), and/or deep sequencing (TCRseq and/or 
RNAseq/Nanostring). 
2) Objective: To evaluate for dynamic tumoral/immune cell PD-L1 expression following 
induction therapies (using assays such as mIHC, transcriptome, and/or PD-L1 assay). 
3) Objective: To identify molecular (genomic, metabolic and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic 
activity, and/or the mechanism of action of pembrolizumab+chemotherapy plus various 
induction immunotherapy regimens. 
 
4.0 BACKGROUND & RATIONALE 
 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475 and IRX-2. 
 Pharmaceutical and Therapeutic Background 
 TNBC Background 
Breast cancer is the most commonly diagnosed malignancy and the second leading cause of 
cancer death in women.  In the United States, the estimated number of new cases and death 
from breast cancer in 2018 is approximately 268,670 and 41,400, respectively.2 Triple-negative 
breast cancer, or TNBC, which is phenotypically defined by lack of estrogen receptor (ER) 
and progesterone receptor expression, and the absence of human epidermal growth factor 
receptor-2 (HER2) overexpression and/or amplification, accounts for approximately 15-20% 
of all breast cancers.3 Compared to other breast cancer subtypes, TNBC is associated with poor 
overall survival and high risk of disease recurrence relative to other tumor types. 3,4 
 Standard-of-care therapy for TNBC 
Neoadjuvant chemotherapy has emerged as the standard-of-care treatment option for locally 
advanced (i.e. stage II-III) TNBC in the United States. Systemic therapy is given prior to 
definitive surgery, which may be beneficial relative to an adjuvant approach because it allows 
for assessment of disease response by pathology review. Anthracycline/taxane-based regimens 
have been considered an important and standard part of treatment strategy for patients with 
locally advanced TNBC for both tumor control and improving the curability rate 5.  
The poor long-term outcome in TNBC was found to be driven by those who did not achieve 
pCR after neoadjuvant chemotherapy.  Patients who achieved pCR demonstrated sustained 

Product:  MK-3475 / IRX-2  
11 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
clinical benefit regardless of breast cancer subtypes 6.   Recently, a large pooled analysis 
demonstrated strong association of pCR, when defined as no tumor in both breast and lymph 
nodes (ypT0 ypN0 or ypT0/is yp N0) following neoadjuvant therapy for breast cancer, with 
improved long-term benefit as measured by EFS and OS.  Furthermore, this association was 
found to be strongest in patients with TNBC 7. 
Because of the poorer survival for patients that did not achieve pCR after neoadjuvant 
chemotherapy, there is great interest in examining whether additional therapy after surgery will 
improve the RFS for this group of patients.  The CREATE-X study demonstrated significant 
improvement in both EFS and OS for patients with HER2-negative breast cancer, positive 
lymph node and non-pCR, receiving capecitabine compared to controls 8.  In previous studies, 
the GeparTrio and GeparQuattro, the rate of pCR did not improve with the addition of 
capecitabine 9,10.  However, while previous adjuvant studies such as the GEICAM/2003-10, 
FINXX and/or CBCSG10 did not show a statistically significant improvement in RFS and/or 
OS with the addition of capecitabine in all patients, there may be a benefit in subsets of patients 
with TNBC, albeit with increased toxicities 11.  Thus, confirmation studies are needed. 
Meanwhile, current standard of care for patients who do not obtain pCR include observation, 
adjuvant capecitabine, or clinical trial participation. 
The findings that the pCR is correlated with survival have led to increased efforts in identifying 
new drugs and drug combinations that can deliver higher pCR in TNBC.  
Addition of a taxane to anthracycline-based regimen as adjuvant chemotherapy has been 
shown to improve both DFS and OS in locally-advanced breast cancer.  Currently, pCR rate 
for standard regimen with paclitaxel followed by an anthracycline and cyclophosphamide is 
about 30% 12.  Because patients without pCR have significantly worse outcomes, efforts are 
underway to find novel combinations to improve the pCR. 
 Targeting PD-1 Immune Checkpoints for Cancer Treatment  
It is widely accepted that cancer cells carry tumor-specific or tumor-associated antigens and 
therefore are immunogenic and subject to immune surveillance of the human body. However, 
cancer cells can often escape immune system’s surveillance and control via various 
mechanisms and progress into clinically evident disease, a process called cancer 
immunoediting.13 The ability of human cancer to evade the destruction of the immune system 
has recently been recognized as an emerging hallmark of cancer.  
In the adaptive immune system, cytotoxic T-lymphocytes cells (CTLs, also called CD8+ or 
effector T cells) can recognize foreign antigens presented on the surface of antigen presenting 
cells (APC) via T cell receptor (TCR) and become activated executing the cell killing function.  
TCR-mediated T cell activations are tightly controlled by co-stimulatory and co-inhibitory 
signals or pathways that are triggered by the interactions between T cell surface receptors and 
their ligands.  These inhibitory pathways, also called immune checkpoints, are crucial for 
maintaining self-tolerance and minimizing collateral tissue damage in the event of immune 
response to pathogens. Cancer can exploit immune checkpoint pathways as one of the key 
mechanisms to avoid being detected and destroyed.  Therefore, restoration of endogenous anti-
cancer immunity by immune checkpoint blockade has become an attractive strategy of cancer 
immunotherapy. 

Product:  MK-3475 / IRX-2  
12 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Among many of the agents in clinical development that target immune checkpoint pathways, 
those that target pathways controlled by programmed cell death protein 1 (PD-1) and cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) are the most advanced and have shown 
unprecedented clinical anticancer activities and durable responses across multiple solid 
tumors. Immune checkpoint inhibiting agents that have been approved by the US Food and 
Drug Administration (FDA) include ipilimumab, a full human anti-CTLA-4 monoclonal 
antibody (mAb), pembrolizumab (MK-3475), a humanized mAb targeting PD-1, and 
nivolumab, a full human mAb targeting PD-1 (see details in Yervoy® US label, Keytruda® US 
Label, and Opdivo® US label ).   
PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators.  It is a 
transmembrane receptor including an extracellular domain that resembles the immunoglobulin 
variable region, a transmembrane region, and an intracellular tail that contains separate 
potential phosphorylation sites for signaling.  Binding of PD-1 to its ligands PD-L1 (also 
named B7-H1) and/or programmed death – ligand 2 (PD-L2) (also named B7-DC) will trigger 
downstream signaling inside T cells leading to decreased cytokine production such as IL-2, 
inhibition of cell proliferation, reduced T cell effector function and survival.  Unlike CTLA-4 
which modulates the early phase of activation of naïve or memory T cells, PD-1 is expressed 
on antigen-experienced T cells in the peripheral tissues and therefore regulates the effector 
phase of the T-cell activity. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T 
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an immunoglobulin 
(IgG) superfamily member related to CD28 and cytotoxic CTLA-4, which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2).  The structures of murine PD-1 alone, and in complex with its ligands, were first 
resolved (Ref: 0422GD, 0422GF), and more recently the nuclear magnetic resonance–based 
(NMR-based) structure of the human PD-1 extracellular region and analyses of its interactions 
with its ligands were also reported. PD-1 and family members are type I transmembrane 
glycoproteins containing an IgG Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T cell stimulation, PD-1 recruits the tyrosine phosphatases Src homology 
phosphatase (SHP)-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules, such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase 70 kDa (ZAP70), which are involved in the 
CD3 T cell signaling cascade. The mechanism by which PD-1 down-modulates T cell 
responses is similar to, but distinct from, that of CTLA-4.  PD-1 was shown to be expressed 
on activated lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, T regs and 
natural killer cells (NKCs).  Expression has also been shown during thymic development on 
CD4-CD8–double negative T cells as well as subsets of macrophages and dendritic cells.  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety 
of cell types. PD-L1 is expressed at low levels on various nonhematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 

Product:  MK-3475 / IRX-2  
13 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  Both 
ligands are type I transmembrane receptors containing both IgV- and gC-like domains in the 
extracellular region and short cytoplasmic regions with no known signaling motifs.  Binding 
of either PD-1 ligand to PD-1 inhibits T cell activation triggered through the T cell receptor.  
PD-L2 is thought to control immune T cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T cell function in peripheral tissues.  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels 
of this T cell inhibitor, which, via its interaction with the PD-1 receptor on tumor-specific T 
cells, plays a critical role in immune evasion by tumors.  As a consequence, the PD-1/PD-L1 
pathway is an attractive target for therapeutic intervention in cancer. 
 Targeting PD-1 Immune Checkpoints for TNBC 
Several studies have demonstrated that the presence of tumor-infiltrating T-lymphocytes 
(TILs) correlated with better prognosis in TNBC, independent of systemic therapy.14  In 
addition, unsupervised gene expression profiling of TNBCs has identified a gene signature 
enriched for cytotoxic CD8+ T cell genes and natural killer cell (NKC) activity, which is 
predictive of good clinical outcome. These findings suggest an active role of acquired 
immunity in concurring TNBC.15 
PD-L1, which is not detected in normal breast tissue, has been reported to be expressed in 
about half of all breast cancers, particularly in hormone-receptor-negative, high grade and 
proliferative tumors.16  The presence of Treg cells, tumor PD-L1 expression, and PD-1–
positive TILs has been associated with high histologic grade, ER negativity, and prominent 
tumor lymphocytic infiltration. Recently, it is reported that PD-L1 messenger ribonucleic acid 
(mRNA) is expressed in nearly 60% of breast tumors, independently of hormone receptor 
status, and is positively correlated with PD-L1 protein expression and increased TILs.  Another 
study mining The Cancer Genome Atlas ribonucleic acid (RNA) sequencing data showed that 
PD-L1 gene expression is significantly higher in TNBCs compared to non-TNBCs, and is 
associated with Phosphatase and Tensin Homolog (PTEN) loss.  This evidence demonstrates 
that TNBCs are characterized by PD-L1 positivity and presence of TILs, and thus suggest that 
PD-1 immune checkpoint inhibition is a therapeutic strategy worthy of further investigation 
for the treatment of this aggressive breast cancer subtype. 
 Induction Immunotherapy approaches to enhance response to chemotherapy and 
immune checkpoint therapy  
Despite the above associations, TNBC remains a heterogeneous disease, with only a subset of 
tumors expressing PD-L1 and exhibiting dense baseline TIL infiltrate, suggesting that the 
addition of immune checkpoint antibodies to chemotherapy may not be an effective strategy 
for all locally advanced TNBCs. Complementary immunotherapeutic approaches are being 
explored in combination with anti-PD-1/L1 to facilitate anti-tumor immune responses. 
Examples include therapies that alter the microenvironment or cytokine milieu, or therapies 
that induce immunogenic cell death and/or antigen presentation. 
Recently, the phase II TONIC trial evaluated an induction approach whereby metastatic 
TNBCs were treated for two weeks with various therapies (radiotherapy, low-dose 
cyclophosphamide, low-dose doxorubicin, low-dose platinum) preceding anti-PD-1. In this 

Product:  MK-3475 / IRX-2  
14 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
study, clinical response appeared to be potentiated with the addition of induction low-dose 
doxorubicin and/or cisplatin.17 
The overarching goal in this protocol is to sequentially evaluate whether various candidate 
induction strategies may be used to enhance response to immune checkpoint therapy plus 
chemotherapy in locally advanced TNBC.  
 IRX-2 cytokine therapy as an induction therapy preceding anti-PD-1 
IRX-2-is a cell-derived biologic with multiple active cytokine components produced under 
pharmaceutical standards as discussed in more detail in the IB. Briefly, human leukocytes 
(“buffy coats”) pooled from multiple donors are stimulated with phytohemagglutinin and 
ciprofloxacin. Subsequently, the phytohemagglutinin, ciprofloxacin and all cellular elements 
are removed or significantly reduced, and the cell-free supernatant is filter sterilized, 
nanofiltered to clear viral particles, vialed, and frozen as IRX-2. IL-2 is the major cytokine in 
IRX-2, followed by IFN-γ, TNF-α, and interleukin 1 beta (IL-1β). These cytokines when 
studied individually enhance cell-mediated immunity via several different mechanisms 
discussed below and in the IRX-2 IB.  
Recent in vitro studies have elucidated several potential mechanisms of action of IRX-2, and 
these various mechanisms of action need not be exclusive. IRX-2 treatment of human 
monocyte-derived dendritic cells results in changes consistent with the development of mature 
activated dendritic cells. Specifically, IRX-2 increased the percentage of cells expressing 
CD83 and CCR7, markers for dendritic cell maturation and migration and increased the 
expression of multiple markers that are critical mediators of T cell activation 18. Similar results 
were obtained in a later study in cells obtained from patients with HNSCC19. Also, in an in 
vitro study of peripheral blood mononuclear cells obtained from patients with HNSSC, IRX-2 
up-regulated cytotoxicity of NK cells and did so more effectively than IL-220. 
IRX-2 can also protect T cells from activation induced cell death by reversing microvesicle 
induced inhibition of the PI3K/Akt pathway and correcting the imbalance of pro- versus anti-
apoptotic proteins induced by tumor-derived microvesicles21,22. IRX-2 was superior to 
recombinant IL-7 and IL-15 in protecting T cells from tumor-induced apoptosis. The presence 
of IRX-2 in a tumor microenvironment model promoted the induction and expansion of IFN-
γ+T-bet+ Teff and significantly decreased the induction of inducible IL-10+TGF-β+ Treg. The 
responsible mechanism involved IFN-γ+-driven T cell polarization towards Teff and 
suppression of Treg differentiation20. In the Phase 2a study in subjects with HNSSC (described 
below in Section 1.3.1), IRX-2 mediated reductions in circulating B and NKT cell numbers, 
suggesting redistribution of these cells to tissues23. A decrease in naïve T cells was also noted, 
suggesting their upregulation to memory T cells, while unchanged numbers of Tregs 
(suppressor T cells) after IRX-2 therapy indicated that IRX-2 does not expand this 
compartment, potentially benefiting anti-tumor immune responses. 
IRX-2 has been shown to induce enhanced T cell responses when administered with tumor 
antigen vaccines, raising the possibility that IRX-2 treatment in subjects with HNSCC 
enhances endogenous antigen-specific T cell responses to the tumor.24 

Product:  MK-3475 / IRX-2  
15 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
4.1.2.1.1 Delivery of IRX-2 via breast lymphatics 
The route of administration of IRX-2 takes advantage of the normal pathways of lymph node 
activation. Normally, lymphatics drain from an area of disease, such as a tumor bed, and 
antigens and other factors associated with disease migrate in the lymphatics to the regional 
nodes. By presenting the cytokine-containing biologic in the area of the tumor-draining lymph 
nodes rather than systemically, there is an opportunity to mobilize antigen presenting cells and 
enhance dendritic cell function as well as directly activate T cells to proliferate and become 
cytotoxic lymphocytes. Additionally, subcutaneous administration has been less toxic since 
the systemic cytokine drug concentration is much lower. 
Periareolar injection of radioactive colloid is an acceptable and clinically utilized technique for 
localizing sentinel lymph nodes in breast cancer25 and therefore it is assumed that periareolar 
injection of IRX-2 leads to update of the IRX-2 product into the draining lymph nodes of the 
tumor. Peri-areolar injections have been shown to be safe and feasible, with pharmacodynamic 
activity, in a pilot/phase Ib study in early stage breast cancer, which is described later in 
detail.26 
4.1.2.1.2 Components of IRX-2 Induction regimen 
The IRX-2 induction regimen being investigated in this trial includes single-dose 
cyclophosphamide (300mg/m2 IV on day 1), followed by 10 peri-areolar subcutaneous 
injections of the IRX-2 cytokine product (2 x 1mL product daily). 
The IRX-2 regimen includes cyclophosphamide, which is thought to mediate T-regulatory cell 
depletion and immunogenic cell death. Evidence indicates that cyclophosphamide inhibits 
Treg number and/or function27. Thus many clinical trials that involve immunotherapy or 
attempt to stimulate immune response to tumor antigens have employed low dose 
cyclophosphamide (300 mg/m2) as a component of the treatment regimen. This 
immunomodulatory dose is half of the typical anti-cancer dose included in the AC regimen, 
and is intended to enhance the development of cell-mediated immunity by providing contra-
suppression of tumor-associated immune suppression (to reduce the number and function of 
regulatory T cells, i.e. Treg). Pathways of local immune tolerance, escape mechanisms active 
within the tumor microenvironment and superimposed potent systemic mechanisms of immune 
tolerance have been reviewed and are discussed in more detail in the Investigator’s Brochure 
(Section 3.4.1). The use of cytotoxic chemotherapy in doses and schedules designed to 
abrogate specific mechanisms of immune tolerance in order to release the full potential of an 
antitumor immune response is discussed. Specifically, cyclophosphamide may be used to 
prime the immune system by promoting the differentiation of CD4+ T helper cells and by 
abrogating the suppressive influence of CD4+CD25+ T regulatory (Treg) cells. In the absence 
of Treg influence, high-avidity CD8+ T cells are recruited to an antigen-specific immune 
response. Cyclophosphamide also facilitates the establishment of memory CD8+ T cells. Thus 
inclusion of cyclophosphamide in combination with other immune-modulatory agents is 
supported by both pre-clinical and clinical data as reviewed in more detail by Emens (2005) 
and in the Investigator’s Brochure (Section 3.4.1). 
In previous trials, IRX-2 was co-administered with oral indomethacin and oral vitamin 
supplementation, based upon preclinical rationale the nonselective COX-1/COX-2 inhibition 
may results in reversal of immunosuppression induced by prostaglandin. However, because a 

Product:  MK-3475 / IRX-2  
16 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
number of subjects with breast cancer experienced adverse gastrointestinal effects related to 
the indomethacin requiring discontinuation of this component of the regimen, subsequent 
clinical studies of IRX-2 will not include oral indomethacin or supplements. 
4.1.2.1.3 Preclinical rationale to combine IRX-2 with anti-PD1 
Recently it has been shown that the degree of lymphocyte infiltration is an important 
prognostic factor for treatment with anti-PD-1 monoclonal antibodies 28. Furthermore, the 
degree of tumoral and/or immune cell PD-L1 expression may predict clinical benefit in the 
setting of anti-PD-1/L1 therapy. These two data provide a compelling rationale for 
consideration of IRX-2 as an induction agent. In a phase Ib trial in early stage breast cancer, 
IRX-2 induction therapy was shown to increase stromal TIL count and to increase mRNA 
transcripts of PD-L1.26. In a Phase 2 trial, IRX-2 was shown to increase T cell infiltration into 
the tumor and this correlated with overall survival in HNSCC29. We have found increases in 
PD-L1 in 4 of 7 Head and neck patients treated with neoadjuvant IRX-2 regimen as 
documented by Perkin-Elmer multiplex IHC platform. In addition similar findings were 
documented by NanoString for both PD-L1 and CTLA-4 on 3 of 7 patients. Together with 
increases in lymphocytic infiltration seen in 21 of 25 patients29 by standard IHC, a known 
important predictive parameter for response to many checkpoint inhibitors, there is a strong 
rationale for the combination. 
IRX-2 has also been shown to induce enhanced T cell responses when administered with tumor 
antigen vaccines, raising the possibility that IRX-2 treatment in patients with HNSCC enhances 
endogenous antigen-specific T-cell responses to the tumor24. 
Recently at the University of Michigan using a SCC7 model of squamous cell head and neck 
cancer, the combination of anti-PD-L1 plus IRX-2 resulted in synergistic slowing in tumor 
outgrowth relative to control or monotherapy with either IRX-2 or anti-PD-L1. In this model, 
SCC7 tumors were injected orthotopically (1 x 106  tumor cells injected into SC flanks), 
followed by IRX-2 100IU/mL at day 14 (weekly x 3) and/or anti-PD-L1 (0.03mg twice weekly 
x 3 weeks). Mice were observed before tumor sacrifice for analysis of lung/primary 
tumor/spleen and PBMCs. As shown in figure 4.1.2.1.3-1, combination therapy was associated 
with significant slowing of tumor outgrowth relative to control (PBS) or either monotherapy 
arm (unpublished, data shown below). 
 
 
 
 
 
 
 
 
 

Product:  MK-3475 / IRX-2  
17 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Figure 4.1.2.1.3-1: synergistic efficacy of IRX-2 plus anti-PD-L1 in a SCC7 orthotopic 
model 
 
4.1.2.1.4 Rationale to include IRX-2 re-induction following Treatment 1 and preceding 
Treatment 2 
No clinical or preclinical data are available to ascertain the optimal duration of IRX-2 therapy 
in the context of anti-PD-1 and/or neoadjuvant chemotherapy in breast cancer. However, IRX-
2 is known to facilitate antigen presentation and recruit immune cells.  Because Treatment 2 
constitutes a new chemotherapy type (doxorubicin and cyclophosphamide) with a unique 
potential for immunologic priming, in arm A a re-induction period of 10 days of IRX-2 
injections 
will 
be 
administered 
following 
completion 
of 
Treatment 
1 
(paclitaxel/pembrolizumab) and Treatment 2 (AC/pembrolizumab). IRX-2 will be given at 
least 1 day following completion of Treatment 1 (i.e. after cycle 4 day 15) to mitigate potential 
concerns of toxicity with concurrent therapy.  
 Summary of Clinical Activities: Pembrolizumab 
Pembrolizumab is a potent and highly selective humanized mAb of the IgG4/kappa isotype 
designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.  
Details regarding preclinical, clinical pharmacology, and clinical efficacy and safety studies 
can be found in pembrolizumab clinical IB, the US label, and the Summary of Product 
Characteristics (SmPC). 
D a y s p o st T u m o r  C e ll I n o c u la tio n
T u m o r  v o lu m e ( m m
3 )
1 0
1 5
2 0
2 5
3 0
3 5
4 0
4 5
0
2 0 0
4 0 0
6 0 0
8 0 0
1 0 0 0
1 2 0 0
1 4 0 0
1 6 0 0
In je c t S C C 7  s .c .
1 x 1 0 6/m o u s e
a n ti-m P D L 1  0 .0 3 m g /m o u s e
P B S
IR X -2  1 0 0 I U /m l
IR X -2  1 0 0 IU /m l+ a n ti-m P D L 1  0 .0 3 m g /m o u s e
p = 0 .0 2 5 5
p < 0 .0 1

Product:  MK-3475 / IRX-2  
18 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Pembrolizumab has demonstrated robust, substantial, and clinically-meaningful benefit in the 
treatment of a number of solid tumors, based on RECIST 1.1 and immune-related RECIST 
(irRECIST) recommendations. Pembrolizumab has been generally well tolerated, as expected 
based on preclinical findings and data from other anti-PD-1 monoclonal antibodies.  
Pharmacokinetics were as expected, based on pembrolizumab being an IgG mAb and based on 
preclinical data, which support dosing once every 2 or 3 weeks. 
 
 Summary of Clinical Data Supporting Pembrolizumab Use for Treatment of 
Metastatic TNBC 
4.1.3.1.1 KEYNOTE-012 (KN012)  
In Study KN012, a cohort of 32 female patients with metastatic TNBC, with PD-L1 positivity 
(defined as PD-L1 expression in ≥1% tumor cells or in stroma, using a prototype assay and the 
22C3 antibody) was enrolled and received pembrolizumab 10 mg/kg Q2W dose.  Subjects with 
a median age of 51.9 years (range: 29-72 years) and PD-L1 (+) metastatic TNBC (mTNBC) 
were enrolled in the study.  The currently available prevalence of PD-L1 positivity in mTNBC 
is 58%, as determined by this study KN012.  Most of these patients had received and 
progressed on multiple lines of therapy for advanced disease (median number of prior 
treatments for metastatic disease was 3).  Based on a data cutoff of 06-Nov-2014, 5 (15.6%) 
patients experienced at least one drug-related SAE; each of 4 patients experienced one of the 
following: Grade 3 anemia, headache, aseptic meningitis or pyrexia, and a fifth patient 
experienced Grade 5 disseminated intravascular coagulation (DIC) with thrombocytopenia and 
decreased blood fibrinogen.  Of the 27 patients with centrally confirmed measurable disease, 
1 (3.7%) patient had a complete response (CR), 4 patients (14.8%) had a confirmed partial 
response (PR), 25.9% had stable disease (SD), and 44.4% had progressive disease (PD), based 
on RECIST 1.1 as assessed by the central imaging vendor.  At this cutoff, the median duration 
of response had not been reached (range: 15 to 40+ weeks), and 3 patients (1 CR; 2 PR) were 
still on treatment after at least 11 months.  Given that the current systemic treatments had little 
effect in this setting, this result looks very promising. 
4.1.3.1.2 Additional Ongoing Clinical Studies with Pembrolizumab in breast cancer 
Two clinical studies are currently investigating the efficacy of single agent pembrolizumab as 
later line of treatment for mTNBC, namely KEYNOTE-086 (KN086), KEYNOTE-119 
(KN119), and 2 clinical studies are investigating the efficacy of combination of 
pembrolizumab with chemotherapy (KEYNOTE-355 [KN355] and KEYNOTE-173 
[KN173]). 
• KN086 (NCT02447003): A Phase II Clinical Trial of Pembrolizumab (MK-3475) as 
Monotherapy for Metastatic Triple Negative Breast Cancer (mTNBC) – (KEYNOTE-086) 
• KN119 (NCT02555657): A Randomized, Open-Label, Phase III Clinical Trial of Single 
Agent Pembrolizumab vs Single Agent Chemotherapy per Physician’s Choice for 
Metastatic Triple Negative Breast Cancer (mTNBC) – (KEYNOTE-119) 

Product:  MK-3475 / IRX-2  
19 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
• KN173 (NCT02622074): A Phase 1b Study to Evaluate safety and clinical activity of 
Pembrolizumab (MK-3475) in combination with Chemotherapy as Neoadjuvant Treatment 
for Triple Negative Breast Cancer (TNBC) - (KEYNOTE-173) 
• KN355 (NCT02819518): A Randomized, Double-Blind, Phase III Study of 
Pembrolizumab (MK-3475) plus Chemotherapy vs Placebo plus Chemotherapy for 
Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast 
Cancer – (KEYNOTE-355) 
A number of clinical trials are ongoing that evaluate pembrolizumab in the neoadjuvant or 
adjuvant setting, including the randomized comparison of neoadjuvant chemotherapy 
with/without pembrolizumab for triple negative breast cancer (KEYNOTE-522), as well as a 
randomized assessment of adjuvant pembrolizumab versus placebo in triple negative breast 
cancers not experiencing pathologic complete response (SWOG 1418). 
Ongoing clinical studies are also being conducted in melanoma, NSCLC, head and neck 
cancer, breast cancer, gastric cancer, colorectal cancer, a number of other advanced solid tumor 
indications, and hematologic malignancies.  For further details, please refer to the IB. 
 Summary of Clinical Activities: IRX-2 
 Phase I clinical trial 
IRX-2 2004-B was a multicenter, Phase 1 trial in subjects with advanced stage HSNCC who 
had progressed after surgery and/or radiation therapy that was designed to evaluate the clinical 
and laboratory safety and tolerability of the IRX-2 regimen. Results of the study are presented 
in the IB and have been published. The reported toxicities were acceptable overall and did not 
preclude proceeding to additional trials. 
 Phase 2 trial in HNSCC 
IRX-2 2005 A was a multi-center trial entitled “A Phase 2, Open-label Trial of the Safety and 
Biological Effect of Pre-operative Subcutaneous IRX-2 (with Cyclophosphamide, 
Indomethacin, and Zinc) in Subjects with Resectable Cancer of the Head and Neck.”  Results 
of the study are presented in the IB and have been published20,29-31 and are also summarized 
here.  
The study objectives were to determine the safety of the IRX-2 regimen when used as 
neoadjuvant (preoperative) therapy and to evaluate clinical, pathological, and radiographic 
tumor response and disease-free survival (DFS) and overall survival (OS). 
Changes in tumor size between baseline and immediately pre-operative, i.e. after the IRX-2 
regimen, measurements were evaluable in 23 subjects. Based on measurement of the longest 
single tumor diameter, tumor growth or shrinkage was as follows: 4 subjects had a decrease in 
tumor size, 16 subjects had no significant change, and 3 subjects had an increase in tumor 
size.30 Review of the radiologic findings in relation to the pathology finding in the resection 
specimens, however, established that lymph node or tumor enlargement due to reactive 
hyperplasia could not be distinguished from enlargement related to tumor growth. 
One subject underwent a fluorodeoxyglucose positron emission tomography (FDG-PET) CT 
scan at baseline and at completion of the IRX-2 regimen. Elevated glycolytic activity was 

Product:  MK-3475 / IRX-2  
20 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
observed in 2 lymph nodes and in the primary tumor on the baseline PET scan. At the 
completion of the IRX-2 regimen, there was a 75% decrease in glycolytic activity in these 
lesions. 
After 5 years of follow-up, median DFS and OS had not been reached. These results for both 
DFS and OS appeared to be slightly superior to those observed in a comparable group of 81 
historical controls, treated at the University of Michigan and matched for baseline 
characteristics. 
The IRX-2 regimen was tolerated with minimal toxicity. Compliance was excellent; all 
subjects completed the regimen and there were no unplanned delays in surgery as a result of 
the immunotherapy regimen. There were no reports from investigators of any unanticipated or 
unusual delays or difficulties in performing the planned resections or reconstructions or during 
the postoperative recovery.  
The most common adverse events (AEs) were headache (30%), injection site pain (22%), 
nausea 22%), constipation (15%), dizziness (15%), fatigue (11%), aspiration pneumonia 
(11%), anemia (11%) and myalgia (7%). All were Grade 1-2 except for the aspiration 
pneumonias (one Grade 3, one Grade 4) and all resolved without sequelae. There were only 
minor (Grade 1) alterations in post-treatment laboratory values. Eight serious adverse events 
(SAEs) in 7 subjects were reported during treatment and the 30-day post-operative period: 
aspiration pneumonia (n = 3), respiratory tract infection, asthma exacerbation, wound 
infection, neck abscess and alcohol withdrawal (n = 1 each); only the postoperative wound 
infection was considered related to the study treatment. Note that many of these AEs, including 
e.g. aspiration pneumonia, wound infections, alcohol withdrawal, are common in HNSCC 
subjects during their pre- and post-operative course. During treatment, several subjects noted 
decreased pain or improved swallowing and no significant progressive symptoms were noted. 
Pretreatment tumor biopsies and the tumor surgical specimens from 25 subjects were 
characterized for lymphocyte infiltration, necrosis and fibrosis using both hematoxylin and 
eosin stains and immunohistochemistry29. Kaplan-Meier estimates of overall survival are 
displayed in Figure 1 as a function of high and low lymphocyte infiltration in the surgical 
specimens after the IRX-2 immunotherapy. Eighteen subjects were in the better survival group 
and 7 were in the inferior survival group; the survival curves are significantly different (p 
<0.05). 
 
 
 
 
 
 
 
 
 

Product:  MK-3475 / IRX-2  
21 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Figure 4.1.4.2-1: Overall Survival by High and Low Lymphocyte Infiltration in the Surgical 
Resection Specimen (Study IRX-2 2005-A) 
 
 
When lymphocyte infiltration in the pretreatment biopsies was compared to that in the resected 
surgical specimen, increases in lymphocyte infiltration were seen as shown in Figure 2 (change 
in mean lymphocyte infiltration from the biopsy to the surgical specimen is shown on the y-
axis). 
 
Figure 4.1.4.2-2: Lymphocyte Infiltration (Study IRX-2 2005-A) 
 
 

Product:  MK-3475 / IRX-2  
22 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
In addition, subjects in whom the greatest increase in tumor lymphocyte infiltration from 
biopsy to surgery (n=14) was observed had a trend toward superior survival compared to 
subjects in whom no or more limited change was observed (n=11) as shown in Figure 3 (p = 
0.10) (Brooklyn Immunotherapeutics, unpublished observations). 
 
Figure 4.1.4.2-3: Overall Survival vs. Change in Lymphocyte Infiltration (Study IRX-2 2005-
A) 
 
 
 
Peripheral blood lymphocyte subsets also were monitored pre- and post-treatment with the 
IRX-2 regimen to evaluate changes induced by the IRX-2 regimen (summarized in Section 
4.1.4.2 above and in the IB). The IRX-2 regimen-mediated reductions in B and NKT cell 
numbers in the blood suggested a redistribution of these cells to tissues while the unchanged 
numbers of Tregs after IRX-2 therapy indicated that IRX-2 does not expand this compartment, 
potentially benefiting anti-tumor immune responses. 
 Phase Ib Trial of IRX2 in early stage breast cancer 
A phase Ib trial evaluating safety and feasibility of IRX2 in stage I-III (any histology) breast 
cancer has completed accrual. Preliminary results were presented at SITC 2017 and ACSO 
2018.26 The primary outcome of the study was to evaluate the safety/tolerability of IRX2 
during 
a 
pre-surgical 
window-of-opportunity 
in 
patients 
for 
whom 
surgical 
lumpectomy/mastectomy was planned. In this study, all 16 subjects (n=16/16, 100%) tolerated 

Product:  MK-3475 / IRX-2  
23 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
the therapy without dose interruption or reduction of the IRX-2 product. No unexpected 
surgical complications or delays were observed. 
Pharmacodynamic assessment of the tumor bed and PBMCs was conducted. All patients 
(n=16/16) completed and tolerated the regimen with no surgical delays or treatment-attributed 
grade III/IV toxicities. Common adverse events (occurring in >15% subjects) attributed to 
IRX-2 injections were: injection site reaction (grade 1,  n=8/16), bruising (grade 1, n=7/16), 
and pain (grade 1, n=3/16). Common adverse events attributed to low-dose cyclophosphamide 
were: fatigue (grade 1, n=5/16) and nausea (grade 1/2, n=3/16). Treatment was associated with 
an increase in sTIL score (Wilcoxon signed-rank p=.04), with 4/10 sTIL-low tumors (0-10% 
score) re-categorized to sTIL-moderate (11-50% score). Increases in PD-L1 RNA expression 
were observed (Wilcoxon signed-rank p=.04) in 12/16 tumors (median 57% increase, range: -
53% to 185% increase), as well as increases in Nanostring cell signatures (natural killer cell 
and Th1 signatures). In blood, increases in CD4 and CD8 effector T-cell activation (ICOS, 
HLA-DR, and CD38) and T-reg depletion were observed. 
 Rationale for the Trial and Selected Subject Population 
It is well known that TNBC has the worst prognosis and is the most difficult to treat among 
the breast cancer subtypes. Recent clinical trials data support the possibility that 
pembrolizumab may increase pathologic complete response rates when combined with 
standard-of-care neoadjuvant paclitaxel, doxorubicin, and cyclophosphamide.32. These 
findings are being confirmed in a large placebo-controlled study evaluating neoadjuvant 
paclitaxel, carboplatin, doxorubicin, and cyclophosphamide, +/- pembrolizumab versus 
placebo (Merck KEYNOTE-522).  
Anticipating that the addition of pembrolizumab improves outcome in KEYNOTE-522, one 
future direction will be to incorporate induction immunotherapy approaches to enhance 
immune response. If proven, such an approach may allow for de-escalation of the 
chemotherapy backbone, thereby reducing toxicity and morbidity associated with curative-
intent therapy in this disease. 
Because the addition of carboplatin is not a universally accepted standard treatment for locally 
advanced TNBC (owing to disparate data on long term survival outcomes), and because the 
addition of carboplatin substantially increases the likelihood of hematologic toxicities and 
other toxicities, the rationale of this trial is to evaluate the efficacy and tolerability of various 
immunotherapy/chemotherapy combination approaches that omit carboplatin. The trial is 
designed to offer preliminary point estimates of pCR rates, which could be compared to 
contemporary trials data from the I-SPY-2 and KEYNOTE-522 trial. Furthermore, 
randomization to pembrolizumab-only induction arm will afford an opportunity to conduct a 
comparative analysis of immunologic activity, as measured by serial blood and tissue biopsy 
following induction immunotherapy.  
Arm 2 of the trial will evaluate whether the addition of IRX-2 to pembrolizumab is associated 
with favorable pCR rates and favorable immunologic activity. Subsequent induction agents 
will be studied in future arms of the study. Arm 1 (control) will enroll in an ongoing fashion). 

Product:  MK-3475 / IRX-2  
24 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Rationale for Dose Selection/Regimen/Modification 
 Rationale for Testing Pembrolizumab in Combination with the Selected TNBC 
Neoadjuvant Regimen 
The rationale for testing pembrolizumab in combination with the selected chemotherapy 
regimens is as follows. Pembrolizumab functions as an immune checkpoint blockade by 
targeting PD-1, which helps to restore the endogenous anti-cancer immunity.  Pembrolizumab 
has shown significant clinical anti-cancer activity across multiple tumor types including 
melanoma, NSCLC, head and neck cancer, bladder cancer and has gained FDA approval for 
treating advanced melanoma, head and neck, and NCSLC.  Preliminary data have also shown 
promising clinical activity of pembrolizumab in metastatic TNBC patients who have failed 
multiple prior treatments.  Therefore, further testing of pembrolizumab in both the metastatic 
and early stage such as a neoadjuvant and/or adjuvant setting is warranted.  
Pembrolizumab relies on a functional immune system to exert its anti-tumor effect.  
Theoretically, an even greater tumor cell reduction might be achieved by enhancing the antigen 
presentation via administration of pembrolizumab in combination with standard cytotoxic 
chemotherapy, provided that the immune suppression by some of these agents (e.g., 
cyclophosphamide) do not significantly compromise the anti-tumor effect of pembrolizumab.  
Optimal supportive care may alleviate some of these potential negative impacts. 
4.1.6.1.1 Rationale for evaluating combination immunotherapy with a carboplatin-
sparing neoadjuvant chemotherapy background regimen 
Across 2 randomized trials, adding carboplatin in combination with weekly paclitaxel at 80 
mg/m2 versus paclitaxel alone followed by the standard anthracycline/cyclophosphamide 
combination has shown increased pCR rates as neoadjuvant treatment for TNBC via 2 
randomized trials using either weekly carboplatin at AUC 2 (the Phase II GeparSixto trial), 
(Ref: 047FC8) or carboplatin at AUC 6 Q3W (the Phase III CALGB 40603 trial).  Due to 
toxicity, in the GeparSixto trial, the dose of carboplatin was reduced to AUC 1.5. A meta-
analysis by Petrelli et al to compare TNBC patients who received carboplatin vs. those who 
did not receive carboplatin in the neoadjuvant setting, showed the risk of not having a pCR for 
those without carboplatin was 1.45 (95% CI, 1.25-1.68, p<0.0001) compared to those who 
have received carboplatin. Based upon the potential for improved pCR rates, the phase III 
KEYNOTE-522 study is evaluating whether the addition of pembrolizumab may improve the 
reponse to a neoadjuvant regimen containing paclitaxel, carboplatin, doxorubicin, and 
cyclophosphamide. 
However, despite trials showing improved pCR with carboplatin, there are still limited 
prospective data confirming that the addition of carboplatin improves long term survival or 
recurrence free survival. Furthermore, hematologic toxicities are significantly higher with the 
addition of carboplatin. For example, in the CALGB 40603 study the carboplatin AUC 6 Q3W 
plus weekly paclitaxel 80 mg/m2 arm showed statistically significant increase in Grade 3/4 
neutropenia (56% vs. 22%) and Grade 3/4 thrombocytopenia (20% vs. 4%) compared to 
paclitaxel alone arm.  

Product:  MK-3475 / IRX-2  
25 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Because of the lack of long-term survival data and because of the increased toxicities, it may 
be of interest to evaluate combination immunotherapy approaches with a carboplatin-sparing 
chemotherapy backbone. This study will estimate the pCR rate of a chemotherapy backbone 
regimen of weekly paclitaxel, doxorubicin, and cyclophosphamide, but omitting carboplatin 
and adding a secondary immunotherapy agent. The goal is to achieve pCR rates that are similar 
to carboplatin-containing chemo-immunotherapy, but without the added toxicities of 
carboplatin.   
Refer to the Investigator’s Brochure for additional preclinical and clinical data. 
 Rationale of Pembrolizumab Dose 
The optimal duration of pembrolizumab has not been tested, and therefore for this trial, 
pembrolizumab will only be given during the neoadjuvant phase and will not be continued 
beyond surgery. If during the trial pembrolizumab is demonstrated to improve long-term 
outcomes when administered beyond surgery, the protocol may be amended to allow for 
extended pembrolizumab dosing. 
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of data 
generated in the Keytruda development program, 200 mg Q3W is the appropriate dose of 
pembrolizumab across all indications and regardless of tumor type. As outlined below, this 
dose is justified by:  
• 
Clinical data from 8 randomized studies demonstrating flat dose- and exposure- 
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W) 
• 
Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications, and 
• 
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically based 
pharmacokinetic [PBPK] analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled with 
melanoma and non-small cell lung cancer, covering different disease settings (treatment naïve, 
previously treated, PD-L1 enriched and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W 
vs. 10 mg/kg Q3W (KN001 B2, KN001 D, KN002, KN010 and KN021), and 3 studies 
compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 
mg fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, 
flat dose-/exposure-response relationships were also observed in other tumor types including 
head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These findings 
are consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 

Product:  MK-3475 / IRX-2  
26 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Secondly, 
a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other subject covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected 
for evaluation across all pembrolizumab protocols. 
 Rationale for pembrolizumab dosing and schedule during the induction period 
The pembrolizumab dose during induction period will be 200mg IV on day 1, similar to the 
neoadjuvant period. Subjects will advance to the neoadjuvant phase after at least 2 weeks 
following pembrolizumab dosing, but no more than 26 days. Pembrolizumab has been studied 
and demonstrated to be safe at doses up to 10mg/kg q2wk. 
 Rationale for IRX-2 dosing, delivery method, and schedule 
The IRX-2 dosing schedule and regimen are directly informed by a preceding phase Ib study 
in ESBC that demonstrated safety/tolerability of the regimen, as well as an associated 
expansion of TILs and PD-L1 expression within the tumor26. Cyclophosphamide will be given 
at 300mg IV on day 1, followed by the IRX-2 biologic administered on days 4-21 (daily on 
any 10 days, 2 x 1mL daily).  
A re-induction period of IRX-2 will occur following completion of treatment 1 
(paclitaxel/pembrolizumab) and preceding initiation of treatment 2 (AC/pembrolizumab). This 
will consist of only IRX-2 biologic (daily on any 10 days, 2 x 1mL daily). The rationale is that 
pre-treatment with IRX-2 may enhance the microenvironment of the residual tumor and 
draining lymph nodes, and facilitate priming associated with the initiation of AC 
chemotherapy.  
 Rationale for Dose Interval for Neoadjuvant therapy 
The standard neoadjuvant treatment is typically 4 cycles of taxane (12 × weekly dosing) 
followed by 4 cycles of anthracycline/cyclophosphamide combination (e.g., doxorubicin 
60 mg/m2 + cyclophosphamide 600 mg/m2 Q3W).  This trial will test the new combination 
using the same dosing interval and schedule, with the inclusion of an induction immunotherapy 
Rationale for Endpoints 
 Efficacy Endpoint 
pCR is considered a surrogate measure of long-term survival in patients with TNBC, and is 
considered by the FDA as a viable surrogate for event free survival following the FDA 

Product:  MK-3475 / IRX-2  
27 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
guidance on “Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-
Stage Breast Cancer”. Patients who achieved pCR have demonstrated sustained clinical benefit 
regardless of breast cancer subtypes. Recently, a large pooled analysis demonstrated strong 
association of pCR, when defined as no tumor in both breast and lymph nodes (ypT0 ypN0 or 
ypT0/is yp N0) following neoadjuvant therapy for breast cancer, with improved long-term 
benefit as measured by event-free survival and overall survival.7. 
Following these data, the study will use pCR to preliminary evaluate whether various 
combination therapies are meritorious for further study in a larger trial.  
 Safety Endpoints 
Safety parameters such as incidence of AE/SAEs (including fatal SAEs), immune-related AEs 
(irAEs) and laboratory abnormalities, rates of dose interruption and discontinuation due to 
AEs, and ECI are important endpoints for safety and tolerability evaluations. 
 Exploratory Biomarker Research 
Cancer immunotherapies represent an important and novel class of anti-tumor agents.  
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs in 
treating patients.  Thus, to aid future patients, it is important to investigate the determinants of 
response or resistance to cancer immunotherapy as well as determinants of adverse events in 
the course of our clinical trials.  These efforts will identify novel predictive/pharmacodynamic 
biomarkers and generate information that will better guide single-agent and combination 
therapy with immuno-oncology drugs.  To identify novel biomarkers, we will collect 
biospecimens (blood components, tumor material, etc.) to support analyses of cellular 
components (e.g., protein, deoxyribonucleic acid [DNA], RNA, metabolites) and other 
circulating molecules.  Investigations may include but are not limited to: 
Germline (blood) Genetic Analyses (e.g., SNP Analyses, Whole Exome Sequencing, 
Whole Genome Sequencing) 
This research will evaluate whether genetic variation within a clinical trial population 
correlates with response to the treatment(s) under evaluation.  If genetic variation is found to 
predict efficacy or adverse events, the data might inform optimal use of therapies in the patient 
population.  Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.  Finally, microsatellite instability 
(MSI) may be evaluated as this is an important biomarker for some cancers (i.e., colorectal 
cancer).  
Genetic (DNA) Analyses from Tumor 
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (i.e., mutations, methylation 
status, microsatellite instability).  Key molecular changes of interest to immune-oncology drug 
development include the mutational burden of tumors and the clonality of T-cells in the tumor 
microenvironment.  Increased mutational burden (sometimes referred to as a “hyper-mutated” 
state) may generate neo-antigen presentation in the tumor microenvironment.  To conduct this 
type of research, it is important to identify tumor-specific mutations that occur across all genes 
in the tumor genome.  Thus, genome wide approaches may be used for this effort.  Note that 

Product:  MK-3475 / IRX-2  
28 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
in order to understand tumor-specific mutations; it is necessary to compare the tumor genome 
with the germline genome.  Microsatellite instability (MSI) may also be evaluated as this is an 
important biomarker for some cancers (i.e., colorectal cancer).  
Tumor and Blood RNA Analyses 
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies.  
Pembrolizumab induces a response in tumors that likely reflects an inflamed/ immune 
phenotype.  Specific immune-related gene sets (such as those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified.  Individual 
genes related to the immune system may also be evaluated (e.g., IL-10).  MicroRNA profiling 
may also be pursued. 
Proteomics and Immunohistochemistry using Blood or Tumor 
Tumor and blood samples from this study may undergo proteomic analyses (e.g., PD-L1 
immunohistochemistry [IHC]).  PD-L1 protein level in tumor sections, assessed by IHC, has 
been shown to correlate with response to pembrolizumab in patients with NSCLC, and an IVD 
device has been developed for use with pembrolizumab in NSCLC.  Preliminary data indicate 
that this association may also be true in additional cancer types (i.e., TNBC, H&N, and gastric).  
Additional tumor or blood-derived proteins may also correlate with response to 
pembrolizumab.  Therefore, tumor tissue may be subjected to proteomic analyses using a 
variety of platforms that could include but are not limited to immunoassays, liquid 
chromatography/mass spectrometry.  This approach could identify novel protein biomarkers 
that could aid in patient selection for pembrolizumab (MK-3475) therapy. 
Anti-drug Antibodies (ADA) 
A portion of scheduled research sera obtained before and during therapy from patients in the 
IRX treatment arm will be stored according to manufacturer’s instructions in case it becomes 
necessary to perform immunogenicity testing for anti-drug antibodies (ADA).  
Other Blood Derived Biomarkers 
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood.  Assays such as enzyme-linked immunoassay 
measure such proteins in serum.  Correlation of expression with response to pembrolizumab 
therapy may identify new approaches for predictive biomarkers in blood, representing a major 
advance from today’s reliance on assessing tumor biomarkers.  This research would serve to 
develop such assays for future clinical use. 
Translational Research 
The tumor microenvironments before treatment and after the combinations will be 
characterized, and this may include the presence and changes of TILs, immune-related mRNA 
expression signatures, and PD-L1 expression.  In addition, tumor genetic profiling such as 
genetic testing for mutational burden based on tumor samples collected at Screening will be 
performed.  Additional translational research may include T cell clonality, neoantigen 
expression, presence and changes in circulating tumor markers such as circulating tumor DNA 
(ctDNA), and serum microRNA (miRNA) and protein changes at Screening and following 

Product:  MK-3475 / IRX-2  
29 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
treatment.  Correlation of clinical response (pCR and ORR) to tumor/ circulating markers at 
Screening and after treatments may be evaluated. 
 Future Biomedical Research 
The investigator will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research. 
 
Benefit/Risk 
Relative to standard-of-care, subjects in clinical trials generally cannot expect to receive direct 
benefit from treatment during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine. Additional 
details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and Informed Consent documents. 
5.0 METHODOLOGY 
 
Entry Criteria 
 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent for the trial. The subject may 
also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research. 
2. Be a male or female subject ≥18 years of age on day of signing informed consent. 
3. Have locally confirmed TNBC, as defined by the most recent ASCO/CAP guidelines. 
4. Have previously untreated locally advanced non-metastatic (M0) TNBC defined as the 
following combined primary tumor (T) and regional lymph node (N) staging per the 
current AJCC Version 8 staging criteria for breast cancer staging criteria as assessed 
by the investigator based on radiological and/or clinical assessment:  
• T1c, N1-N2 
• T2, N0-N2 
• T3, N0-N2 
• T4a-d, N0-N2  
Note: bilateral tumors (i.e., synchronous cancers in both breasts) and/or multi-focal 
(ie, 2, separate lesions in the same quadrant)/multi-centric (ie, 2 separate lesions in 
different quadrants) tumors are allowed, as well as inflammatory breast cancer, and 
the tumor with the most advanced T stage should be used to assess the eligibility.  

Product:  MK-3475 / IRX-2  
30 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
5. Provide a core needle biopsy consisting of at least 1 separate tumor-bearing cores from 
the primary tumor at screening for translational research (archival is acceptable if 
sufficient tumor is available; slides are acceptable if at least 15 are available). Also 
agree to on study biopsy post induction therapy and prior to initiating combination 
pembrolizumab and paclitaxel.   
6. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
assessed within 14 days of treatment initiation. 
7. Demonstrate adequate organ function as defined in Table 5.1.1-1. All screening labs 
should be performed within 14 days of treatment initiation. 
Table 5.1.1-1 Adequate Organ Function Laboratory Values 
Organ System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 cells/µL without granulocyte colony-stimulating 
factor (G-CSF) support within 2 weeks prior to the first 
dose of study treatment  
Platelet count 
≥100,000/µL without transfusion within 2 weeks prior to 
the first dose of study treatment  
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency 
Renal 
 
Serum creatinine OR 
Calculated creatinine clearance (CrCl) 
(calculated per institutional standard) 
≤1.5 X upper limit of normal (ULN) OR 
≥50 mL/min  
Hepatic 
 
Total bilirubin 
≤1.5 X ULN OR  
Direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5 X ULN 
Aspartate aminotransferase [AST 
(SGOT)] and alanine aminotransferase 
[ALT (SGPT)] 
≤2.5 X ULN  
Albumin 
≥3.0 g/dL 
Lactate dehydrogenase (LDH) 
<2.5 X ULN 
Coagulation 
International Normalized Ratio (INR) or 
prothrombin time (PT)  
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or aPTT/PTT is within therapeutic 
range of intended use of anticoagulants 
Activated partial thromboplastin time 
(aPTT) or partial thromboplastin time 
(PTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or aPTT/PTT is within therapeutic 
range of intended use of anticoagulants 
 
8. Have left ventricular ejection fraction (LVEF) of ≥50% or ≥ institution lower limit of 
normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition 
(MUGA) scan performed at screening. 

Product:  MK-3475 / IRX-2  
31 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
9. Males and female subjects of childbearing potential (Section 5.7.2 – Contraception) 
must be willing to use an adequate method of contraception as outlined in Section 5.7.2 
– Contraception, for the course of the study through 12 months after the last dose of 
study medication for subjects who have received cyclophosphamide, and 6 months 
after the last dose of study medication for subjects who did not. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
10. Female subject of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or borderline a serum pregnancy test will be required. 
 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has a history of invasive malignancy ≤5 years prior to signing informed consent except 
for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.  
2. Has received prior chemotherapy, targeted therapy, and radiation therapy within the 
past 12 months. 
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with 
an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, 
CD137) or has previously participated in MK-3475 clinical trials. 
4. Is currently participating in or has participated in an interventional clinical trial with an 
investigational compound or device within 4 weeks of the first dose of treatment in this 
current trial.  
Note: subject should be excluded if he/she received an investigational agent with anti-
cancer or anti-proliferative intent within the last 12 months. 
5. Has received a live vaccine within 30 days of the first dose of study treatment. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines, and are not allowed. 
6. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment. 
7. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  
8. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
9. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 

Product:  MK-3475 / IRX-2  
32 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
10. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.  
11. Has an active infection requiring systemic therapy. 
12. 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 
13. Has a history or current evidence of any condition, therapy, lab abnormality or other 
circumstance that might expose the subject to risk by participating in the trial, confound 
the results of the trial, or interfere with the subject’s participation for the full duration 
of the trial in the opinion of the Investigator. 
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial in the opinion of the Investigator. 
15. Is pregnant or breastfeeding, or expecting to conceive children within the projected 
duration of the trial, starting with the screening visit through 12 months after the last 
dose of trial treatment for subjects who have received cyclophosphamide, and for 6 
months after the last dose of study medication for subjects who have not. 
16. Has a known hypersensitivity to the components of the study therapy or its analogs. 
17. Has a known history of active TB (Bacillus Tuberculosis). 
18. Allergy to ciprofloxacin (or other quinolones). 
19. History of allogeneic stem cell and/or solid organ transplant. 
 
Trial Treatment(s)  
The treatments to be used in this trial are outlined in the below tables: 
Table 5.2-1: Trial treatments: Control Arm 
Drug 
Dose/ 
Potency 
Dose 
Frequenc
y 
Route of 
Administration 
Dosing Time of each 
3-week cycle 
Use 
Pembrolizumab 
(MK-3475) 
200 mg 
Q3W 
IV infusion 
Day 1 in the Induction 
Phase; 
Day 
1 
of 
Cycles 
in 
the 
Neoadjuvant Phases 
(8 cycles) 
Experimental 
Paclitaxel 
80 mg/m2 
Weekly 
IV Infusion 
Days 1, 8, 15 of 
Cycles 
1-4 
of 
Treatment 1 
Standard 
of 
care 
Doxorubicin  
60 mg/m2  
Q3W 
IV Injection  
Day 1 of Cycles 1-4 
of Treatment 2 
Standard 
of 
care 

Product:  MK-3475 / IRX-2  
33 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Drug 
Dose/ 
Potency 
Dose 
Frequenc
y 
Route of 
Administration 
Dosing Time of each 
3-week cycle 
Use 
Cyclophosphamide 
 
600 mg/m2 
Q3W 
IV Infusion 
Day 1 of Cycles 1-4 of 
Treatment 2 
Standard 
of 
care 
Abbreviations: IV = intravenous; Q3W = every 3 weeks 
 
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. 
Table 5.2-2 Trial Treatments: Arm A  
Drug 
Dose/ 
Potency 
Dose 
Frequenc
y 
Route of 
Administration 
Dosing Time of each 
3-week cycle 
Use 
Pembrolizumab 
(MK-3475) 
200 mg 
Q3W 
IV infusion 
Day 1 in the Induction 
Phase; 
Day 
1 
of 
Cycles 
in 
the 
Neoadjuvant Phases 
(8 cycles) 
Experimental 
IRX-2 
2mL (230 
units 
of 
IL-2) 
Daily x 10 
days 
Two 
1mL 
subcutaneous 
periareolar 
injections 
Any 10 days over 
days 
4-21 
of 
the 
induction Phase, and 
daily for 10 days over 
any 14 day period 
following completion 
of Treatment 1 and to 
be completed prior to 
advancement 
to 
Treatment 2. 
Experimental 
Paclitaxel 
80 mg/m2 
Weekly 
IV Infusion 
Days 1, 8, 15 of 
Cycles 
1-4 
of 
Treatment 1 
Standard 
of 
care 
Doxorubicin  
60 mg/m2  
Q3W 
IV Injection  
Day 1 of Cycles 1-4 
of Treatment 2 
Standard 
of 
care 
Cyclophosphamide 
 
300mg/m2 
 
 
600 
mg/m2 
Once 
 
 
Q3W 
IV Infusion 
 
 
IV Infusion 
Day 
1 
(Induction 
Phase) 
 
Day 1 of Cycles 1-4 of 
Treatment 2 
Experimental 
 
Standard 
of 
care 
Abbreviations: IV = intravenous; Q3W = every 3 weeks 
 

Product:  MK-3475 / IRX-2  
34 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
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. 
Trial Treatment should begin within 3 business days of randomization. 
Pembrolizumab will be provided by Merck. IRX-2 will be provided by Brooklyn 
Immunotherapeutics, or locally by the trial site. 
Pembrolizumab Storage 
Pembrolizumab (MK-3475) Powder for Solution for Infusion vials should be stored at 
refrigerated conditions 2 – 8 °C (36 - 46 ºF). Prior to reconstitution, the vial of lyophilized 
powder can be out of refrigeration (temperatures at or below 25°C (77°F)) for up to 24 hours. 
 
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a cumulative time 
of up to 6 hours. The 6 hour countdown begins when the vial is pierced, and includes room 
temperature storage of reconstituted drug product solution in vials, room temperature storage 
of admixture solutions in the IV bags and the duration of infusion. (Please note this 6 hour 
timeframe is to provide a microbial control strategy. The microbial clock only starts when the 
product stopper is pierced and not when the vial is removed from the refrigerator.) 
In addition, reconstituted vials and/or IV bags may be stored under refrigeration at 2 °C to 8 
°C (36 °F to 46 °F), total cumulative storage time at room temperature and refrigeration should 
not exceed 24 hours. 
If refrigerated, allow the vials and/or IV bags to come to room temperature prior to use. 
 
IRX-2 Storage 
Each subcutaneous injection of IRX-2 comes in 1.0 ml frozen vials from the manufacturer.  
IRX-2 must be stored frozen at a range of −15∘C to –50∘ C until the date on the expiry label.  
Vials should be thawed at room temperature prior to administration.  In some cases, it may 
take as long as 60 minutes for small precipitates in the vial to go into solution; this is 
acceptable. Please refer to the Investigator’s Brochure for detailed information on IRX-2 
preparation and administration. 
The vials MAY NOT be returned to the freezer or refrigerator once placed at room temperature.  
The prepared drug for injection must be used within 24 hours of removing the vial from frozen 
storage. 
 
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations. 

Product:  MK-3475 / IRX-2  
35 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Dose Modification for Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab 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 trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, 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. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided in 
the below tables.  
 

Product:  MK-3475 / IRX-2  
36 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Table 5.2.1-1 Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE 
management 
with 
corticosteroid 
and/or 
other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of pneumonitis 
• 
Evaluate 
participants 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add 
prophylactic 
antibiotics 
for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus). 

Product:  MK-3475 / IRX-2  
37 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Grade 4 
Permanently 
discontinue 
• 
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. 
AST 
/ 
ALT 
elevation 
or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly 
onset 
T1DM or  
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement therapy 
for participants with T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold 
or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  

Product:  MK-3475 / IRX-2  
38 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
• Treat with non-selective beta-
blockers 
(eg, 
propranolol) 
or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate 
thyroid 
replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis 
and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 
1-2 
mg/kg 
or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All 
other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold 
or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include 
and 
not 
limited to:  Gullain-
Barre 
Syndrome, 
encephalitis 
Grade 
4 
or 
recurrent Grade 3  
Permanently 
discontinue 

Product:  MK-3475 / IRX-2  
39 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
Dose Modification and Toxicity Management of Infusion Reactions Related to Pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Suggested dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are 
provided in the below table. 
 
Table 5.2.1-2 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 

Product:  MK-3475 / IRX-2  
40 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
NCI CTCAE 
v5.0 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 1.5h (± 30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg po (or equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or equivalent dose of analgesic). 

Product:  MK-3475 / IRX-2  
41 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
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 v5.0 (CTCAE) at http://ctep.cancer.gov 

Product:  MK-3475 / IRX-2  
42 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Other Allowed Dose Interruptions for 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. Subjects should be 
placed back on study therapy within 6 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the subject's 
study record.   
 Dose Modifications for IRX-2 
Based upon the relative safety of IRX-2 in the phase Ib pilot study in breast cancer, as well as 
in a number of preceding phase I/II clinical trials in head/neck cancer (as well as in a number 
of ongoing trials in other indications), dose reductions or discontinuations are not expected to 
be necessary. 
Because dose reductions have not been previously studied, no dose reductions of IRX-2 will 
be allowed on this protocol. 
IRX-2 doses may be delayed or discontinued at any time if unanticipated and intolerable 
toxicities emerge. Subjects requiring a delay of more than 7 days due to toxicity should 
discontinue IRX-2 permanently and advance to biopsy and the neoadjuvant phase of treatment, 
and should not receive re-induction IRX-2. Subjects who require IRX-2 discontinuation for 
any reason should advance to biopsy and the neoadjuvant phase of treatment, and should not 
receive re-induction IRX-2. 
 Dose Modifications for Chemotherapy Agents 
Suggested dose modifications and guidelines for growth factor support for paclitaxel are 
detailed in table 5.2.3-1 and for doxorubicin and cyclophosphamide table 5.2.3-2 
Of note, primary prophylaxis with growth factor support is allowed with chemotherapy. Local 
guidelines related to treatment holds and dose reduction for chemotherapy should be followed, 
if different than the recommendations outlined in table 5.2.3-1 and -2. 

Product:  MK-3475 / IRX-2  
43 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Table 5.2.3-1: Dose Modification Guideline for Paclitaxel 
Toxicities 
Grade or actual 
value 
Paclitaxel 
Hematological 
Neutropenia 
≥1000/mm3 
Grade 2/Grade 1 
No change to paclitaxel 
• 
For ANC ≤1500/mm3, prophylactic myeloid growth 
factors (filgrastim) may be used 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 its weekly dosing schedule 
<1000/mm3  
Grade 3/Grade 4 
Hold paclitaxel until ANC ≥1000/mm3.  
Prophylactic 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 (see general instruction below) 
Febrile neutropenia 
ANC ≤1000/mm3, 
fever ≥38.5°C  
Grade 3 and 
Grade 4 
Hold paclitaxel until resolved (ANC >1000/mm3, fever 
<38.5°C, and resolution of any signs of infection). 
Prophylactic 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. Consider adding 
prophylactic GCSF for subsequent cycles. 
• 
Second episode: Reduce paclitaxel to 70 mg/ for all 
subsequent doses.  
• 
Third episode: Discontinue paclitaxel (see general 
instruction below) 
Thrombocytopenia 
75-<100,000/mm3  
Grade 1 
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 (see general instruction 
below) 
<75,000/mm3 
≥Grade 2 
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, (see general 
instruction below) 
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.  
Nausea/Vomiting 
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 

Product:  MK-3475 / IRX-2  
44 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
• 
Second episode ≥Grade 3 despite with 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 with 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, (see 
general instruction below) 
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 resolve to Grade 1 and resume the 
dose at previous level 
• 
Discontinue paclitaxel if held for ≥3 weeks in a row, (see 
general instruction below) 
 
Grade 4 
• 
Discontinue paclitaxel (see general instruction below) 
Note all concurrent ALT/AST >3×ULN and Total 
bilirubin >2×ULN should be discontinued and evaluated 
for potential Hy’s law 
Anaphylaxis 
/hypersensitivity 
Mild  
• 
Complete paclitaxel infusion, observe until symptom 
resolved 
Moderate 
• 
Stop infusion and treat per standard practice 
• 
Resume infusion at half of the infusion speed if symptom 
resolve 
• 
Stop if symptom recurs 
Severe 
• 
Stop infusion immediately and discontinue treatment (see 
general instruction below) 
Other significant 
toxicities excluding 
fatigue, alopecia and 
leukopenia at 
discretion of the 
investigators 
Grade 2 
• 
Hold paclitaxel until resolve 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 rechallenge, discontinue 
treatment permanently 

Product:  MK-3475 / IRX-2  
45 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Table 5.2.3-2: Dose Modification Guideline for Doxorubicin and Cyclophosphamide (AC) 
Toxicities 
Grade or actual 
value 
Doxorubicin and cyclophosphamide 
Hematological 
Neutropenia 
≥1000/mm3  
(Grade 2/Grade 1) 
No change to AC 
• 
For ANC ≤1500/mm3, prophylactic myeloid growth 
factors (filgrastim or pegfilgrastim) may be used at the 
discretion of the investigator. 
<1000/mm3  
Grade 3/Grade 4 
Hold AC until ANC ≥1000/mm3.  
• 
Prophylactic myeloid growth factors (filgrastim or 
pegfilgrastim) may be used at the discretion of the 
investigator 
Resume AC based on timing of recovery: 
• 
<1 week: No change to AC  
• 
≥1 but <3 weeks: Reduce AC by 20% for all subsequent 
cycles.  
• 
≥3 weeks: discontinue AC (see general instruction below) 
Febrile neutropenia 
ANC ≤1000/mm3, 
fever ≥38.5°C 
Grade 3 and 
Grade 4 
Hold AC until resolved (ANC >1000/mm3, fever <38.5°C, and 
resolution of any signs of infection 
• 
Prophylactic myeloid growth factors (filgrastim or 
pegfilgrastim) may be used at the discretion of the 
investigator. 
Resume AC according to number of episodes: 
• 
First episode: no change to AC. 
• 
Second episode: Reduce AC by 20% for all subsequent 
cycles  
• 
Third episode: Discontinue AC (see general instruction 
below) 
Thrombocytopenia 
75–
<100,000/mm3 
Grade 1 
Hold AC until ≥100,000/mm3, resume AC based on timing of 
recovery: 
• 
≤1 week — no change to AC. 
• 
>1 but <3 weeks — Reduce AC by 20% for all subsequent 
cycles 
• 
≥3 weeks: Discontinue AC (see general instruction below) 
<75,000/mm3 
≥Grade 2 
Hold AC until ≥100,000/mm3.  
• 
Reduce AC or EC by 20% for all subsequent cycles 
• 
Discontinue AC if held for ≥3 weeks in a row, (see general 
instruction below) 
Anemia  
All grades 
No change to AC  
• 
Iron studies should be done and iron should be replaced as 
indicated. 
• 
Red blood cell transfusions can be given at the investigator’s 
discretion.  
Nausea/Vomiting 
Grade 1 or 2 
No change to AC  
≥Grade 3 
Hold AC until resolved to ≤Grade 1.  
• 
Resume AC at previous dose with modification of 
premedication 
• 
Second episode ≥Grade 3 despite with maximum supportive 
care, reduce AC by 20% for all subsequent cycles  
Mucositis/Stomatitis 
Grade 1 or 2 
No change to AC  
≥Grade 3 
Hold AC until resolved to ≤Grade 1.  

Product:  MK-3475 / IRX-2  
46 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 
Instruction on Discontinuation of a Component or Entire Regimen  
During the first part of the combination therapy, if 1 or more than 1 component must be 
discontinued or delayed due to toxicity, the investigator can select 1 of the following options 
at his/her own discretion for the subject (table 5.2.3-1 and -2). 
• If paclitaxel is discontinued due to toxicity related to paclitaxel,  
o Option 1 Stop the first part of the neoadjuvant chemotherapy (pembrolizumab + 
paclitaxel); start and complete the AC regimen as planned per protocol, then 
followed by surgery..  
o Option 2 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. 
• 
Resume AC at previous dose with modification of 
premedication 
• 
Second episode ≥Grade 3 despite with maximum supportive 
care, reduce AC by 20% for all subsequent cycles  
Hepatic 
Grade 1 
• 
No change to AC  
≥Grade 2 or 3 
• 
Hold AC until resolve to Grade 1 and resume the dose at 
previous level 
• 
Discontinue AC if held for ≥3 weeks in a row, (see general 
instruction below) 
Grade 4  
• 
Discontinue AC (see general instruction below) 
Note all concurrent ALT/AST >3×ULN and Total bilirubin 
>2×ULN should be discontinued and evaluated for potential 
Hy’s law 
Cardiac toxicity  
Grade 1 or 2 
• 
No change to AC  
≥Grade 3 
• 
Discontinue doxorubicin (see general instruction below) 
Anaphylaxis/ 
hypersensitivity 
Mild  
• 
Complete AC infusion, observe until symptom resolved 
Moderate 
• 
Stop infusion and treat per standard practice 
• 
Resume infusion at half of the infusion speed if symptom 
resolve 
• 
Stop if symptom recurs 
Severe 
• 
Stop infusion immediately and discontinue treatment (see 
general instruction below) 
Other significant 
toxicities excluding 
fatigue, alopecia 
and leukopenia at 
discretion of the 
investigators 
Grade 2 
• 
Hold AC until resolve to ≤Grade 1 
• 
Resume at the previous dose and increase supportive care 
measure, if available 
≥Grade 3 
• 
Hold AC and discuss with sponsor medical monitor for 
further instructions 
• 
If ≥Grade 3 toxicity recurs upon rechallenge, discontinue 
treatment permanently 

Product:  MK-3475 / IRX-2  
47 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
o Option 3 In cases nab-paclitaxel may not be immediately feasible (insurance auth), 
option 1 may be followed, with subsequent completion of taxane after receipt of 
AC. 
o If taxane doses are held or skipped, if feasible the full course of taxane therapy 
should be completed thereafter.    
o In arm A, IRX2 reinduction is intended to be administered following treatment 1 
and preceding treatment 2. However, in the above instances, re-induction may be 
held/omitted or delayed at the discretion of the PI 
• If only pembrolizumab is discontinued due to pembrolizumab toxicity, 
o Continue with paclitaxel regimen alone as planned per protocol, then start and 
complete the AC regimen as planned per protocol, then followed by surgery.   
o IRX-2 re-induction may be administered if thought to be safe after review of 
scenario with principal investigator 
• If only IRX-2 is discontinued due to IRX-2 toxicity 
o Continue with other therapies per protocol, then followed by surgery 
 
During the second part of the combination therapy, if one or more than one component should 
be discontinued, the investigator can select 1 of the following options at his/her own discretion 
for the subject: 
• If doxorubicin and/or cyclophosphamide are discontinued due to doxorubicin and/or 
cyclophosphamide toxicity,  
o Discontinue all study treatment including pembrolizumab and proceed with 
surgery.   
• If only pembrolizumab is discontinued due to pembrolizumab toxicity, 
o Continue doxorubicin and cyclophosphamide for the remaining cycles as planned 
per protocol, and followed by surgery.   
Subjects who are discontinued from the study treatment and continue with another neoadjuvant 
treatment prior to the definitive surgery will be evaluable for pCR, but will be considered non-
pCR. In these cases, pathology response at the time of definitive surgery will be evaluated and 
reported for exploratory/descriptive purposes.  
Instruction on Making up Missed Doses:  
If a dose delay does not require discontinuation of chemotherapy, subjects may resume 
treatment with the next scheduled dose in the regimen and continue on treatment to complete 
the full number of cycles per protocol. 

Product:  MK-3475 / IRX-2  
48 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Timing of Dose Administration 
On each trial treatment dosing day, trial treatments should be administered after all procedures/ 
assessments have been completed as listed in the Section 6 – Trial Flow Chart.  
Refer to the product label for detailed instructions on preparation and administration 
precautions on combination chemotherapy agents included in the trial: paclitaxel, doxorubicin, 
and cyclophosphamide. 
 Pembrolizumab 
For the induction phase, pembrolizumab is administered on day 1 of therapy. For the 
neoadjuvant phase, pembrolizumab will be administered on Cycle 1 Day 1  (with a window of 
+5 days) as the first trial treatment; for Cycles 1-4 of the Neoadjuvant Treatment Phase 
(Treatment 1) every 3 weeks (± 2 days); and for Cycles 1-4 of the Neoadjuvant Treatment 
Phase (Treatment 2) every 3 weeks (+/- 3 days. Trial treatments should be administered in 
accordance with the schedules provided in Section 6 – Trial Flow Chart. 
On Day 1 of each Cycle, a fixed dose of 200 mg pembrolizumab will be administered as a 
30 minute IV infusion. Sites should make every effort to target infusion timing to be as close 
to 30 minutes as possible. However, given the variability of infusion pumps from site to site, 
a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 
30 minutes: -5 min/+10 min). 
When pembrolizumab is administered on the same day with chemotherapy agents, 
pembrolizumab should be administered prior to chemotherapy agents.  
 
 IRX-2  
IRX-2 should be administered as two subcutaneous injections of 1 mL each, in the periareolar 
region of the affected breast. Each injection should be given subcutaneously approximately 1 
cm from the outer margin of the areola. A 4-6 mm, 28-30 gauge needle is recommended; 
injections should consistently enter the fat just underneath the skin. The first injection should 
be administered on the same axis as the tumor location as identified by physical exam, 
mammography or ultrasound. The second injection on the same day should be rotated 90 
degrees clockwise to the first injection. On the second day of IRX-2 injections, the first 
injection should be again administered on the same axis as the tumor location, but the second 
injection should be rotated 90 degrees counter-clockwise to the first injection, i.e. to maximize 
the likelihood of drug delivery to the lymphatics, the location of the second injection each day 
should be alternated between clockwise and counter-clockwise from the primary injection site. 
Each injection site each day should be gently massaged for one minute to promote entry into 
lymphatics. 
 
 Paclitaxel  
Paclitaxel, at a dose level of 80 mg/m2, will be administered on Days 1, 8, and 15 during Cycles 
1-4 of the paclitaxel regimen (Treatment 1) as IV infusion as instructed per product label. 

Product:  MK-3475 / IRX-2  
49 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Paclitaxel should be administered after pembrolizumab. Additional premedication should be 
administered as per standard practice. It is preferable that dexamethasone be tapered and 
discontinued by cycle 2 if no infusion reactions are incurred. 
 Cyclophosphamide 
5.2.4.4.1 Induction phase 
Cyclophosphamide will be administered at a dose level of 300mg/m2 intravenously on day 1 
[arm A only],  as instructed per product label. The relatively low dose of cyclophosphamide 
has low to moderate emetic risk per NCCN Guidelines. Use of corticosteroids as an antiemetic 
is neither required nor permitted because of its potential immunosuppressive effect. An 
antiemetic regimen of lorazepam and a serotonin (5-HT3) antagonist is recommended. 
5.2.4.4.2 Neoadjuvant phase 
Cyclophosphamide at a dose level of 600 mg/m2 will be administered intravenously as 
instructed per product label on Day 1 of Cycles 1-4 of the AC regimen (Treatment 2) following 
the administration of pembrolizumab. Additional premedication should be administered as per 
standard practice. 
 Doxorubicin  
Doxorubicin at a dose level of 60 mg/m2 should be administered IV push on Day 1 of Cycles 1-
4 of the AC regimen (Treatment 2) as instructed per product label following the administration 
of pembrolizumab. Additional premedication should be administered as per standard practice. 
Doxorubicin should be avoided for subjects who had previous exposure to doxorubicin of more 
than 200 mg/m2. 
 
Randomization or Treatment Allocation 
Treatment allocation/randomization will occur centrally at Providence Cancer Institute, details 
on randomization are in statistical methods. 
 
Stratification 
Patients will not be stratified. 
 
Concomitant Medications/Vaccinations (Allowed & Prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required. The investigator should discuss any questions regarding this with the Coordinating 
Center Principal Investigator. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician. However, the decision to continue 
the subject on trial therapy or vaccination schedule requires the mutual agreement of the 
treating investigator, the Coordinating Center Principal Investigator and the subject. 
  Acceptable Concomitant Medications 

Product:  MK-3475 / IRX-2  
50 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF.  Note: the use of GnRH therapy (eg, goserelin 
acetate [Zolodex®]) for ovarian preservation and bisphosphonates or rank ligand inhibitors to 
prevent osteopenia or osteoporosis is allowed during chemotherapy. 
Supportive care is permitted for managing drug-related toxicities. See guidelines in Section 5.6 
–Rescue Medications & Supportive Care for more details.  
All prior medications received within 30 days before the screening visit, and all new 
concomitant medications given from the screening visit through the safety follow-up visit 
should be recorded. After the Adjuvant Phase safety follow-up visit, record all medications 
administered for the treatment of SAEs and ECIs as defined in Section 9.1 - Common 
Terminology Criteria for Adverse Events (CTCAE) and Section 9.2 - Definitions. 
 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies from the time of screening until 
completion of all study treatments (subsequent off study treatments may be administered prior 
to surgery if a biopsy is performed and there is histologic confirmation of residual disease 
following all treatments on this study): 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents not specified in this protocol  
• Radiation therapy. (Post-operative radiation therapy is acceptable according to the 
standard of care, as applicable.) 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella, zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
• Glucocorticoids for any purpose other than to modulate symptoms from an irAE of 
suspected immunologic etiology or for use as a pre-medication for chemotherapeutic 
agents specified in the protocol.  
o Note: Inhaled steroids are allowed for management of asthma. 
o Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to 
IV contrast dye) is permitted. 

Product:  MK-3475 / IRX-2  
51 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Subjects who are discontinued from the study treatment and continue with another neoadjuvant 
treatment prior to the definitive surgery will be considered treatment failures and will not be 
evaluable for pCR. Subjects may receive other medications that the investigator deems to be 
medically necessary. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy may be required. 
The Exclusion Criteria describes other prior medications prohibited during study treatment. 
Site staff should refer to the local product label for permitted and prohibited medications, as 
well as, drug interactions for each chemotherapy agent used as trial treatment. 
 
Rescue Medications & Supportive Care 
 Supportive Care Guidelines for Pembrolizumab 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined along with the dose modification 
guidelines in Section 5.2.1. 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 Section 5.2.1 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. 
 Supportive Care Guidelines for Chemotherapy Agents 
Instructions regarding supportive care for the chemotherapeutic agents administered in this 
study can be found in the local product label for each agent. Infusion reactions and injection 
site reactions will be managed by the investigators according to the local product labels. 
 
Diet/Activity/Other Considerations 
 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  

Product:  MK-3475 / IRX-2  
52 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either:  
1. postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
2. have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
 
OR  
3. has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant (or 
getting their partner pregnant) while receiving study drug and for 12 months after the last dose 
of study drug for subjects who have received cyclophosphamide, and for 6 months after the 
last dose of study medication for subjects who have not, by complying with one of the 
following:  
1. practice abstinence† from heterosexual activity;  
OR  
2. use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡: 
1. Single method (one of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a female subject’s male partner  
• contraceptive rod implanted into the skin 
2. Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)  
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 

Product:  MK-3475 / IRX-2  
53 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
† Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception.  
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 12 months after 
the last dose of trial therapy for subjects who have received cyclophosphamide, and for 6 
months after the last dose of study medication for subjects who have not. If there is any 
question that a subject of childbearing potential will not reliably comply with the requirements 
for contraception, that subject should not be entered into the study. 
 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from study treatment.  
 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
Subject Withdrawal/Discontinuation Criteria 
 Discontinuation of Treatment 
Discontinuation of treatment does not represent withdrawal from the trial. 
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the subject 
has discontinued treatment.  Therefore, all subjects who discontinue trial treatment prior to 
completion of the treatment will still continue to participate in the trial as specified in Section 
6.0 - Trial Flow Chart and Section 7.1.4.1.  
Subjects may discontinue treatment at any time for any reason or be dropped from treatment 
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator if treatment is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
procedures to be performed at treatment discontinuation are provided in Section 7.1.4 – Other 
Procedures. 
A subject must be discontinued from treatment, but continue to be monitored in the trial for 
any of the following reasons: 
o Unacceptable adverse experiences as described in Section 9.1 - Common Terminology 
Criteria for Adverse Events (CTCAE) and Section 9.2 - Definitions. 

Product:  MK-3475 / IRX-2  
54 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
o The subject or subject’s legally acceptable representative requests to discontinue 
treatment. 
o Intercurrent illness that prevents further administration of treatment 
o Investigator’s decision to withdraw the subject from study treatment due to disease 
progression or other reasons.  
o The subject has a confirmed positive serum pregnancy test 
o Noncompliance with trial treatment or procedure requirements 
The Early Discontinuation and Safety Follow-up visit procedures are listed in Section 6 – Trial 
Flow Chart and Section 7.1.5 – Visit Requirements. Following completion of treatment, each 
subject will be followed for 30 days for any adverse events (SAEs will be collected for 90 days 
after completion of treatment or 30 days following completion of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, as described in Section 9.3 –Adverse 
Event Reporting). 
  
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment. 
 Withdrawal from the Trial 
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial. 
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits. 
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 – 
Other Procedures. 
 
Subject Replacement Strategy 
Subjects will be replaced in the following scenarios: 
• Discontinuation from trial treatment or withdraws from the trial without receipt of at 
least a partial dose of therapy. In the case that a subject withdraws prior to receipt of at 
least a partial dose, the subject will not be evaluable and will be replaced. 
• Additional subjects may be randomized to ensure that at least n=15 viable paired tumor 
specimens are available for experimental arms, and n=10 viable paired tumor 
specimens are available for control arm.    
 

Product:  MK-3475 / IRX-2  
55 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Beginning and End of the Trial 
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related visit, withdraws from the trial 
or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator). 
 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below  
1. Quality or quantity of data recording is inaccurate or incomplete as assessed by the 
Sponsor 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of decision to no longer supply study drug, ample notification will be provided so 
that appropriate adjustments to subject treatment can be made. 
Further recruitment in the study or at (a) particular study site(s) may be stopped due to 
insufficient compliance with the protocol, GCP, and/or other applicable regulatory 
requirements or procedure-related problems or if the number of discontinuations for 
administrative reasons is too high. 

Product:  MK-3475 / IRX-2  
56 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
6.0 TRIAL FLOW CHART 
Table 6.0-1: Control Arm Flow Chart 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definitive 
Surgery 
Early 
Discon 
Visit 
(c)  
Follow-
up 
Treatment 1 
Treatment 2 
(Paclitaxel) 
(AC) 
Treatment Cycle: 
Screening 
D1 
D8 
+/- 
2d 
D15 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-
C4 
D1 
C2-
C4 
D8, 
D15 
C1D1 
C2D1 
C3D1 
C4D1 
 
 
 
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery.  
 
 
D8 
D15 
Scheduling Window 
(Days) 
-28 to 0 
  
 
 
  
±2 
±2 
±2 
±2 
±3 
±3 
±3 
±3 
±7 
Surgery 
  
±30 
Informed Consent (d)  
X 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion 
Criteria 
X 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
Demographics and 
Medical History 
X 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
Prior and Concomitant 
Medication Review (e)  
X 
  
 
 
X 
  
  
X 
  
X 
X 
X 
X 
X 
  
X 
Treatment 
allocation/randomization 
X (w)  
  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
Clinical/Pathological 
tumor staging 
X  
  
 
 
  
  
  
  
  
  
  
  
  
  
 X 
  
Pembrolizumab 
  
X 
 
 
X 
  
  
X 
  
X 
X 
X 
X 
  
  
  
Paclitaxel  
  
  
 
 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
Doxorubicin   
  
  
 
 
  
  
  
  
  
X 
X 
X 
X 
  
  
  
Cyclophosphamide  
  
  
 
 
  
  
  
  
  
X 
X 
X 
X 
  
  
  

Product:  MK-3475 / IRX-2  
57 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definitive 
Surgery 
Early 
Discon 
Visit 
(c)  
Follow-
up 
Treatment 1 
Treatment 2 
(Paclitaxel) 
(AC) 
Treatment Cycle: 
Screening 
D1 
D8 
+/- 
2d 
D15 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-
C4 
D1 
C2-
C4 
D8, 
D15 
C1D1 
C2D1 
C3D1 
C4D1 
 
 
 
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery.  
 
 
D8 
D15 
Review Adverse Events 
(f) 
X 
X  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
12-Lead ECG (Locally 
performed) 
X 
  
 
 
  
  
  
  
  
X (g) 
  
  
  
X 
  
X (x) 
MUGA or ECHO for 
LVEF Assessment 
X 
  
 
 
  
  
  
  
  
X (g) 
  
  
  
X 
  
X (x) 
  
Full Physical 
Examination 
X 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
Directed Physical 
Examination 
  
  
 
 
X 
  
  
X 
  
X 
X 
X 
X 
X 
  
X 
Vital Signs, Height and 
Weight (h) 
X 
  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
ECOG Performance 
Status (i) 
X 
  
 
 
X 
  
  
X 
  
X 
X 
X 
X 
X 
  
X 
Pregnancy Test – Urine 
or Serum β-HCG (j) 
X 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
Blood for menopausal 
status (if applicable) (k) 
X 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
PT/INR and aPTT/ PTT 
(l,n) 
X 
  
 
 
  
  
  
  
  
  
  
  
  
X 
  
X 
CBC with Differential 
(m,n,o,q) 
X 
X 
(q)
  
X (q) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Chemistry Panel (m,n,o) 
X 
  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 

Product:  MK-3475 / IRX-2  
58 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definitive 
Surgery 
Early 
Discon 
Visit 
(c)  
Follow-
up 
Treatment 1 
Treatment 2 
(Paclitaxel) 
(AC) 
Treatment Cycle: 
Screening 
D1 
D8 
+/- 
2d 
D15 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-
C4 
D1 
C2-
C4 
D8, 
D15 
C1D1 
C2D1 
C3D1 
C4D1 
 
 
 
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery.  
 
 
D8 
D15 
Urinalysis (m,n,o) 
X 
  
 
 
  
  
  
X 
  
X 
  
  
X 
X 
 
X 
T3, FT4 and TSH 
(m,n,o) 
X 
  
 
 
  
  
  
  
  
X 
  
  
  
X 
  
X 
Cortisol (m,n,u) 
X 
  
 
 
  
  
  
  
  
  
  
  
  
  
 
  
    
Troponin (m,n,v) 
X 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
LDH (m,n) 
X 
  
 
 
  
  
  
  
  
  
  
  
  
X 
  
X 
Assessment of disease 
progression (p) 
  
  
 
 
  
  
  
X 
  
X 
X 
X 
X 
X 
  
X 
X 
Blood for Biomarker 
Analysis (q)  
  
X 
(q)  
X(q) 
 
X (q)  
  
  
X 
(q)  
  
X (q)  
X (q)  
  
  
X (q)  
  
X (q)  
pCR assessment  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
X 
  
Core tumor tissue 
biopsy for translational 
research (s) 
X (s) 
  
 
X(s) 
  
  
  
  
  
  
  
  
  
* (s) 
X (r,t) 
  
Definitive surgery 
  
  
 
 
  
  
  
  
  
  
  
  
  
  
X (r,t) 
  
Survival 
X 
AC = doxorubicin + cyclophosphamide; CBC = Complete Blood Count; Discon = discontinuation; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECHO = Echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; PRO = Patient Reported Outcomes; ; FFPE = formalin-fixed paraffin-embedded; FT4=Free thyroxine 4; HCG = human chorionic 
gonadotropin; LDH = Lactate Dehydrogenase; LVEF = Left ventricular ejection fraction; MUGA = Multigated Acquisition; NCI = National Cancer Institute; pCR = Pathological 
Complete Response; PT/INR = Prothrombin Time/International Normalized Ratio; aPTT/PTT= Activated  Prothrombin Time/Partial thromboplastin time; RNA = ribonucleic acid; T3 = 
Triiodothyronine; TNBC = Triple-negative Breast Cancer; TSH = Thyroid stimulating hormone. 

Product:  MK-3475 / IRX-2  
59 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definitive 
Surgery 
Early 
Discon 
Visit 
(c)  
Follow-
up 
Treatment 1 
Treatment 2 
(Paclitaxel) 
(AC) 
Treatment Cycle: 
Screening 
D1 
D8 
+/- 
2d 
D15 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-
C4 
D1 
C2-
C4 
D8, 
D15 
C1D1 
C2D1 
C3D1 
C4D1 
 
 
 
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery.  
 
 
D8 
D15 
a. In general, assessments/procedures are performed on Day 1 of each cycle prior to dosing of any study treatment (or prior to weekly dosing of paclitaxel) unless otherwise specified. 
Each treatment cycle is 3 weeks (21 days). If the treatment is delayed, all procedures should be performed based on the new dosing schedule.  
b. The 30-Day Safety Follow-Up visit should be performed within 30 days +/- 7 days after last dose of chemotherapy. If surgery is scheduled to occur less than 30 days after the end of 
Neoadjuvant Treatment Phase, the Safety Follow-up Visit should occur before surgery. If patient is to receive another treatment for their breast cancer prior to surgery and following end 
of study treatment, the 30 Day Safety Follow-up should be performed prior to initiation of new treatment.  If an Early Discontinuation Visit occurs, then every attempt should be made to 
perform a 30-Day Safety Follow-Up visit (30 days ± 7 days). 
c. The Early Discontinuation Visit should be conducted if subject discontinues all protocol-specified treatment after Treatment 1 Cycle 1 through 30 Day Safety Follow-up. 
d. Written consent must be obtained prior to performing any protocol-specified procedures. If the signature falls outside of the 28 day screening window, the consent form does not need 
to be resigned. Results of a test performed prior to the subject signing consent as part of routine clinical management are acceptable in lieu of a screening test, if performed within the 
specified time frame (e.g., within 28 days prior to the first dose of trial treatment).  
e. Prior medications – Record all medications taken within 30 days prior to the screening visit. Concomitant medications – Enter new medications started during the screening period 
through the Safety Follow-up Visit or Early Discontinuation, whichever is earlier. Record all medications taken for AEs 
f. AEs and laboratory safety measurements will be graded per NCI CTCAE Version 5.0. All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness. 
g. After Treatment 1 Cycle 4, and prior to dosing the subject with AC, the 12-lead ECG and MUGA/ECHO must be performed to ensure adequate cardiac function. If taxane aborted 
early due to toxicity, the 12-lead EKG and MUGA/ECHO are not required prior to starting AC and should be obtained at Investigator discretion. 
h. Vital signs to include temperature, pulse, respiratory rate and blood pressure. Height will be measured at screening only; weight will be measured at baseline and preceding each dose 
of chemotherapy/pembrolizumab. Vital signs will be collected during treatment cycle. 

Product:  MK-3475 / IRX-2  
60 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definitive 
Surgery 
Early 
Discon 
Visit 
(c)  
Follow-
up 
Treatment 1 
Treatment 2 
(Paclitaxel) 
(AC) 
Treatment Cycle: 
Screening 
D1 
D8 
+/- 
2d 
D15 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-
C4 
D1 
C2-
C4 
D8, 
D15 
C1D1 
C2D1 
C3D1 
C4D1 
 
 
 
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery.  
 
 
D8 
D15 
i. ECOG performance status at Screening to be performed within 14 days prior to of the first dose of trial treatment. ECOG performance status will also be performed prior to the start of 
every treatment cycle, at 30-Day follow-up visits, and at the Early Discontinuation visit.  
j. For women of childbearing potential, a serum or urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results are positive 
or cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Monthly pregnancy testing should be conducted as per local 
regulations where applicable. 
k. Blood for menopausal status may be required for certain subjects as described in Section 7.1.3.1 – Menopausal Status.  
l. Coagulation factors (PT/INR and aPTT/PTT) should be tested within 14 days of treatment initiation and at the time points specified.  Additional testing to be conducted as clinically 
indicated for subjects taking anticoagulant therapy. 
m. After Treatment 1 Cycle 1, pre-dose lab samples can be collected up to 72 hours prior to the scheduled time point. 
n. Screening laboratory samples will be collected within 14 days prior to study treatment initiation. 
o. Unresolved abnormal labs that are drug-related AEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs are within normal range. 
p. Assessment includes (per local or institutional guidelines): disease progression that precludes definitive surgery, local or distant recurrence, development of a second primary 
malignancy, or death. 

Product:  MK-3475 / IRX-2  
61 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definitive 
Surgery 
Early 
Discon 
Visit 
(c)  
Follow-
up 
Treatment 1 
Treatment 2 
(Paclitaxel) 
(AC) 
Treatment Cycle: 
Screening 
D1 
D8 
+/- 
2d 
D15 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-
C4 
D1 
C2-
C4 
D8, 
D15 
C1D1 
C2D1 
C3D1 
C4D1 
 
 
 
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery.  
 
 
D8 
D15 
q. Blood for exploratory biomarkers (Three 10cc green top tube, one 5cc cytochex tube, and one SST tube; CPT tube acceptable as alternative to green top if the green top 
is not feasible) will be collected on Induction day 1, day 8 +/- 2 days, at pre-dose on Day 1 of Cycles 1 and 2 of Treatment 1 (paclitaxel),  Day 1 of Cycles 1 and 2 of 
Treatment 2 (AC), and at Early Discontinuation or safety follow-up visit (within 30 days +/- 7 days of last chemo) . A CBC must be collected on all days that research 
blood is collected. See Laboratory Manual. Any leftover samples from the blood studies will be stored for future biomedical research. 
 
r. If feasible, a tumor tissue sample will also be collected at definitive surgery for subjects who have not achieved a pathological complete response (pCR) 
s. During screening, formalin-fixed paraffin-embedded (FFPE) tumor tissue samples or slides obtained at subject’s initial diagnosis maybe submitted and used to satisfy the baseline 
requirement if sufficient tissue for analysis is available). Induction Phase biopsy to be collected within 7 days prior to starting Treatment 1. *In certain cases, a post-treatment biopsy will 
be conducted per the treating physician if clinically indicated to confirm the presence of residual disease burden, and to guide subsequent therapy in the neoadjuvant setting. In this case, 
remaining tissue may be used for research purposes following confirmation of residual disease. 
t. Detailed pathological staging of all tumor tissue collected during definitive surgery for determination of pCR. 
u. Cortisol to be determined in the morning. 
v. Troponin to be measured at screening and then as clinically indicated. 
w. Induction Day 1 must occur within 3 business days of randomization 
x. ECG and ECHO/MUGA need not be repeated at early discontinuation if performed within previous 12 weeks 
 
 
 
 

Product:  MK-3475 / IRX-2  
62 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Table 6.0-2: Arm A (IRX-2) Flow Chart 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definiti
ve 
Surgery 
Early 
Discon 
Visit (c)  
Follow-
up 
Treatment 1 (Paclitaxel) 
IRX-2 
Reindu
ction 
Treatment 2 
(AC) 
Treatment Cycle: 
Screening  
D1 
Any 10 
days 
between 
day 4-
21 
Within 
7 days 
of last 
IRX-2 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-C4 
 
C2-C4 
 
Any 10 
days 
over 14 
day 
window  
C1 
C2 
C3 
C4 
  
  
  
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery. 
D8 
D15 
D1 
 
D8, D15 
 
D1 
D1 
D1 
D1 
Scheduling Window 
(Days) 
-28 to 0 
  
  
  
  
±2 
±2 
±2 
±2 
  
  
±3 
±3 
±3 
±3 
±7 
Surgery 
  
±30 
Informed Consent (d)  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion 
Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics and 
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior and Concomitant 
Medication Review (e)  
X 
  
  
  
X 
  
  
X 
  
  
  
X 
X 
X 
X 
X 
  
X 
Treatment 
allocation/randomization 
 X(x) 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical/Pathological 
tumor staging 
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 X 
  
Pembrolizumab 
  
X 
  
  
X 
  
  
X 
  
  
  
X 
X 
X 
X 
  
  
  
Paclitaxel   
  
  
  
  
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
Doxorubicin   
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
  
  
  
Cyclophosphamide  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
  
  
  
Induction 
Cyclophosphamide  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRX-2 
  
  
X 
  
  
  
  
  
   
X (w) 
  
  
  
  
  
  
  

Product:  MK-3475 / IRX-2  
63 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definiti
ve 
Surgery 
Early 
Discon 
Visit (c)  
Follow-
up 
Treatment 1 (Paclitaxel) 
IRX-2 
Reindu
ction 
Treatment 2 
(AC) 
Treatment Cycle: 
Screening  
D1 
Any 10 
days 
between 
day 4-
21 
Within 
7 days 
of last 
IRX-2 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-C4 
 
C2-C4 
 
Any 10 
days 
over 14 
day 
window  
C1 
C2 
C3 
C4 
  
  
  
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery. 
D8 
D15 
D1 
 
D8, D15 
 
D1 
D1 
D1 
D1 
Review Adverse Events 
(f) 
X 
 X 
X  
 X 
X 
X 
X 
X 
 
X  
X  
X 
X 
X 
X 
X 
  
X 
12-Lead ECG (Locally 
performed) 
X 
  
  
  
  
  
  
  
  
  
  
X 
(g) 
  
  
  
X 
  
X (y) 
MUGA or ECHO for 
LVEF Assessment 
X 
  
  
  
  
  
  
  
  
  
  
X 
(g) 
  
  
  
X 
  
X (y) 
Full Physical 
Examination 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Directed Physical 
Examination 
  
  
  
  
X 
  
  
X 
  
  
  
X 
X 
X 
X 
X 
  
X 
Vital Signs, Height and 
Weight (h) 
X 
  
  
  
X 
X 
X 
X 
X 
  
  
X 
X 
X 
X 
X 
  
X 
ECOG Performance 
Status (i) 
X 
  
  
  
X 
  
  
X 
  
  
  
X 
X 
X 
X 
X 
  
X 
Pregnancy Test – Urine 
or Serum β-HCG (j) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood for menopausal 
status (if applicable) (k) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PT/INR and aPTT/ PTT 
(l,n) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
X 
CBC with Differential 
(m,n,o,q) 
X 
 X
(q) 
X(q)  
  
X  
X 
X 
X 
X 
  
 X(q) 
X 
X 
X 
X 
X 
 
X 
Chemistry Panel (m,n,o) 
X 
  
  
  
X  
X 
X 
X 
X 
  
  
X 
X 
X 
X 
X 
 
X 
Urinalysis (m,n,o) 
X 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
X 
X 
 
X 

Product:  MK-3475 / IRX-2  
64 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definiti
ve 
Surgery 
Early 
Discon 
Visit (c)  
Follow-
up 
Treatment 1 (Paclitaxel) 
IRX-2 
Reindu
ction 
Treatment 2 
(AC) 
Treatment Cycle: 
Screening  
D1 
Any 10 
days 
between 
day 4-
21 
Within 
7 days 
of last 
IRX-2 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-C4 
 
C2-C4 
 
Any 10 
days 
over 14 
day 
window  
C1 
C2 
C3 
C4 
  
  
  
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery. 
D8 
D15 
D1 
 
D8, D15 
 
D1 
D1 
D1 
D1 
T3, FT4 and TSH 
(m,n,o) 
X 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
X 
  
X 
Cortisol (m,n,u) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Troponin (m,n,v) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
LDH m,n) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
X 
Assessment of disease 
progression (p) 
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
X 
X 
X 
  
X 
X 
Blood for Biomarker 
Analysis (q)  
  
X 
(q)  
X (q)  
  
X (q)  
  
  
X (q)  
  
  
X(q)  
X 
(q)  
X 
(q)  
  
  
X (q)  
  
X (q)  
pCR assessment  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Core tumor tissue biopsy 
for translational research 
(s) 
X (s) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
* (s)  
X (r,t) 
  
Definitive surgery 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X (r,t) 
  
Survival 
X 
AC = doxorubicin + cyclophosphamide; CBC = Complete Blood Count; Discon = discontinuation; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECHO = Echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; PRO = Patient Reported Outcomes; ; FFPE = formalin-fixed paraffin-embedded; FT4=Free thyroxine 4; HCG = human chorionic 
gonadotropin; LDH = Lactate Dehydrogenase; LVEF = Left ventricular ejection fraction; MUGA = Multigated Acquisition; NCI = National Cancer Institute; pCR = Pathological 
Complete Response; PT/INR = Prothrombin Time/International Normalized Ratio; aPTT/PTT= Activated  Prothrombin Time/Partial thromboplastin time; RNA = ribonucleic acid; T3 = 
Triiodothyronine; TNBC = Triple-negative Breast Cancer; TSH = Thyroid stimulating hormone. 

Product:  MK-3475 / IRX-2  
65 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definiti
ve 
Surgery 
Early 
Discon 
Visit (c)  
Follow-
up 
Treatment 1 (Paclitaxel) 
IRX-2 
Reindu
ction 
Treatment 2 
(AC) 
Treatment Cycle: 
Screening  
D1 
Any 10 
days 
between 
day 4-
21 
Within 
7 days 
of last 
IRX-2 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-C4 
 
C2-C4 
 
Any 10 
days 
over 14 
day 
window  
C1 
C2 
C3 
C4 
  
  
  
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery. 
D8 
D15 
D1 
 
D8, D15 
 
D1 
D1 
D1 
D1 
a. In general, assessments/procedures are performed on Day 1 of each cycle prior to dosing of any study treatment (or prior to weekly dosing of paclitaxel) unless otherwise specified. 
Each treatment cycle is 3 weeks (21 days). If the treatment is delayed, all procedures should be performed based on the new dosing schedule.  
b. The 30-Day Safety Follow-Up visit should be performed within 30 days +/- 7 days after last dose of chemotherapy. If surgery is scheduled to occur less than 30 days after the end of 
Neoadjuvant Treatment Phase, the Safety Follow-up Visit should occur before surgery.  If patient is to receive another treatment for their breast cancer prior to surgery and following end 
of study treatment, the 30 Day Safety Follow-up should be performed prior to initiation of new treatment.  If an Early Discontinuation Visit occurs, then every attempt should be made to 
perform a 30-Day Safety Follow-Up visit (30 days ± 7 days). 
c. The Early Discontinuation Visit should be conducted if subject discontinues all protocol-specified treatment after Treatment 1 Cycle 1 through 30 Day Safety Follow-up.. 
d. Written consent must be obtained prior to performing any protocol-specified procedures. If the signature falls outside of the 28 day screening window, the consent form does not need 
to be resigned. Results of a test performed prior to the subject signing consent as part of routine clinical management are acceptable in lieu of a screening test, if performed within the 
specified time frame (e.g., within 28 days prior to the first dose of trial treatment).  
e. Prior medications – Record all medications taken within 30 days prior to the screening visit. Concomitant medications – Enter new medications started during the screening period 
through the Safety Follow-up Visit or Early Discontinuation, whichever is earlier. Record all medications taken for AEs 
f. AEs and laboratory safety measurements will be graded per NCI CTCAE Version 5.0. All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness. 
g. After Treatment 1 Cycle 4, and prior to dosing the subject with AC, the 12-lead ECG and MUGA/ECHO must be performed to ensure adequate cardiac function. If  taxane aborted 
early due to toxicity, the 12-lead EKG and MUGA/ECHO are not required prior to starting AC and should be obtained at Investigator discretion. 
h. Vital signs to include temperature, pulse, respiratory rate and blood pressure. Height will be measured at screening only; weight will be measured at baseline and at each cycle. Vital 
signs will be collected during treatment cycle. 

Product:  MK-3475 / IRX-2  
66 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definiti
ve 
Surgery 
Early 
Discon 
Visit (c)  
Follow-
up 
Treatment 1 (Paclitaxel) 
IRX-2 
Reindu
ction 
Treatment 2 
(AC) 
Treatment Cycle: 
Screening  
D1 
Any 10 
days 
between 
day 4-
21 
Within 
7 days 
of last 
IRX-2 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-C4 
 
C2-C4 
 
Any 10 
days 
over 14 
day 
window  
C1 
C2 
C3 
C4 
  
  
  
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery. 
D8 
D15 
D1 
 
D8, D15 
 
D1 
D1 
D1 
D1 
i. ECOG performance status at Screening to be performed within 14 days prior to of the first dose of trial treatment. ECOG performance status will also be performed prior to the start of 
every treatment cycle, at 30-Day follow-up visits, and at the Early Discontinuation visit.  
j. For women of childbearing potential, a serum or urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results are positive or 
cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Monthly pregnancy testing should be conducted as per local 
regulations where applicable. 
k. Blood for menopausal status may be required for certain subjects as described in Section 7.1.3.1 – Menopausal Status.  
l. Coagulation factors (PT/INR and aPTT/PTT) should be tested within 14 days of treatment initiation and at the time points specified.  Additional testing to be conducted as clinically 
indicated for subjects taking anticoagulant therapy. 
m. After Treatment 1 Cycle 1, pre-dose lab samples can be collected up to 72 hours prior to the scheduled time point. 
n. Screening laboratory samples will be collected within 14 days prior to study treatment initiation. 
o. Unresolved abnormal labs that are drug-related AEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs are within normal range. 
p. Assessment includes (per local or institutional guidelines): disease progression that precludes definitive surgery, local or distant recurrence, development of a second primary 
malignancy, or death. 

Product:  MK-3475 / IRX-2  
67 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Trial Period: 
Screening 
Phase 
Induction Phase 
Neoadjuvant Treatment Phase (a) 
30 Day 
Safety 
Follow-
Up (b) 
Definiti
ve 
Surgery 
Early 
Discon 
Visit (c)  
Follow-
up 
Treatment 1 (Paclitaxel) 
IRX-2 
Reindu
ction 
Treatment 2 
(AC) 
Treatment Cycle: 
Screening  
D1 
Any 10 
days 
between 
day 4-
21 
Within 
7 days 
of last 
IRX-2 
C1D1 (21 
days +/- 
5d of D1 
induction) 
C1 
C1 
C2-C4 
 
C2-C4 
 
Any 10 
days 
over 14 
day 
window  
C1 
C2 
C3 
C4 
  
  
  
Q3mos 
for 3 
years, 
then 
Q6mos 
for 5 
years 
from 
definitive 
surgery. 
D8 
D15 
D1 
 
D8, D15 
 
D1 
D1 
D1 
D1 
q. Blood for exploratory biomarkers (Three 10cc green top tube, one 5cc cytochex tube, and one SST tube; CPT tube acceptable as alternative to green top if the green top is not feasible) 
will be collected on Induction day 1 (before cyclophosphamide), at pre-dose on day 8 +/- 2 days, at pre-dose on Day 1 of Cycles 1 and 2 of Treatment 1 (paclitaxel),  Day 1 pre-dose of 
IRX-2 re-induction, Day 1 pre-dose of Cycles 1 and 2 of Treatment 2 (AC), and at Early Discontinuation or safety follow-up (30 day from last chemo +/- 7 days). Serum obtained at each 
of these time points will be stored to allow for anti-drug antibody (ADA) testing if necessary. A CBC must be collected on all days that research bloods are collected. See Laboratory 
Manual. Any leftover samples from the blood studies will be stored for future biomedical research. 
r. If feasible, a tumor tissue sample will also be collected at definitive surgery for subjects who have not achieved a pathological complete response (pCR) 
s. During screening, formalin-fixed paraffin-embedded (FFPE) tumor tissue samples or slides obtained at subject’s initial diagnosis maybe submitted and used to satisfy the baseline 
requirement if sufficient tissue for analysis is available). *In certain cases, a post-treatment biopsy will be conducted per the treating physician if clinically indicated to confirm the 
presence of residual disease burden, and to guide subsequent therapy in the neoadjuvant setting. In this case, remaining tissue may be used for research purposes following confirmation 
of residual disease. 
t. Detailed pathological staging of all tumor tissue collected during definitive surgery for determination of pCR. 
u. Cortisol to be determined in the morning. 
v. Troponin to be measured at screening and then as clinically indicated. 
w. IRX-2 re-induction consists of IRX-2 injections, may commence as early as 1 day after last dose of treatment 1 (1 day after c4d15 paclitaxel/pembrolizumab), and should be completed 
prior to commencing treatment 2. Please refer to Section 5.0 for guidance in setting of early termination of taxane. 
x. Induction day 1 must occur within 3 business days of randomization. 
y. ECG and ECHO/MUGA need not be repeated at early discontinuation if performed within previous 12 weeks 

Product:  MK-3475 / IRX-2  
68 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
7.0 TRIAL PROCEDURES 
 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
for reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 Administrative Procedures 
 Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. A copy of the signed and dated consent form 
should be given to the subject before participation in the trial. 
 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Any autoimmune disorders, 
regardless of onset date, should be recorded.  
7.1.1.3.1 Disease Details 
Details regarding subject’s TNBC diagnosis and status at baseline must be thoroughly 
evaluated by the investigator or qualified designee and recorded. 
 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days prior to screening visit. 

Product:  MK-3475 / IRX-2  
69 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record all concomitant medication, if any, taken by 
the subject within 30 days before the first dose of trial treatment through the Adjuvant 
Treatment Phase Safety Follow-up Visit. All medications related to reportable AEs, SAEs and 
ECIs, including AEs and SAEs following the Adjuvant Treatment Phase, 30-day Safety 
Follow-up Visit, and Early Discontinuation visit should be recorded. 
 Research Participant Registration 
To register a patient, email the Data Management Office of the Providence Cancer Institute at 
OREACRIRandomization@providence.org with the following information: 
• Investigator's name 
• Patient's initials and date of birth 
• Eligibility Verification 
• Date of first dose. 
Patients must meet all of the eligibility requirements and undergo all pre-study procedures. If 
a patient enrolls in the study, but does not receive study therapy, the patient’s enrollment may 
be canceled. Reasons for cancellation will be documented in writing. Any patient whose 
enrollment was canceled before receiving study therapy will be replaced.  
Assignment of Study Numbers: 
Study Numbers will be assigned at enrollment based on order of enrollment. For example: 
• MFH is the 4th patient enrolled to study. Study Number PMI – 04 
• B-A is 9th patient enrolled to study. Study Number PMI - 09 
All case report forms, study reports, and laboratory samples for research tests, including 
immune parameters or pharmacokinetics, will be labeled with the full patient study number. 
 Assignment of Treatment/Randomization Number 
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject. A single subject cannot 
be assigned more than 1 treatment/randomization number. Study treatment should begin on the 
day of randomization or, at most, within 3 days post randomization. Randomization will occur 
via the Data Management Office of the Providence Cancer Institute.  
 Trial Compliance (Medication) 
Interruptions from the protocol specified treatment for greater than 6 weeks between doses 
require consultation with the principal investigator.  
Administration of trial medication will be overseen by the investigator and/or trial staff. The 
total volume of IRX-2, pembrolizumab alone and/or combination product infused will be 

Product:  MK-3475 / IRX-2  
70 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
compared to the total volume prepared to determine compliance with each dose of 
pembrolizumab and/or combination product administered. 
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual. 
Refer to the product label for instructions on preparation and administration precautions on 
combination chemotherapy agents included in the trial: paclitaxel; doxorubicin and 
cyclophosphamide. 
 Clinical Procedures/Assessments 
 Adverse Event Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently, if clinically indicated. 
Adverse events will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 5.0. Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
 12-Lead Electrocardiogram  
A 12-lead electrocardiogram (ECG) will be performed according to the study calendar.  
 
 Echocardiography or Multigated Acquisition Scan 
An ECHO or MUGA scan will be required at screening for subjects with locally advanced 
TNBC to determine study eligibility. The assessment method will be at the investigator’s 
discretion and per the local standard of care. Additional assessments will be performed 
according to the study calendar and as clinically necessary. 
 Physical Examination 
7.1.2.4.1 Full Physical Examination 
The investigator or qualified clinical designee will perform a complete physical examination 
during the screening period. Clinically significant abnormal findings should be recorded as 
medical history. Post randomization, physical examinations should be performed at the 
discretion of the physician according to the subject’s signs and symptoms. 
7.1.2.4.2 Directed Physical Examination 
The investigator or qualified clinical designee will perform directed physical examinations to 
assess subject’s TNBC status according to the time points as specified in the study calendar. 
New clinically significant abnormal findings should be recorded as AEs. 

Product:  MK-3475 / IRX-2  
71 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Vital Signs 
The Investigator or qualified clinical designee will take vital signs according to the study 
calendar. Height will be measured at screening only. Vital signs should be taken prior to 
treatment administration. 
 Eastern Cooperative Oncology Group Performance Status 
The investigator or qualified clinical designee will assess ECOG performance according to the 
study calendar.   
 Tumor Tissue Biopsy and Sample Collection 
In accordance with the study inclusion criteria, subjects with locally advanced TNBC are 
required to have a core needle biopsy consisting of at least 1 tumor cores, utilizing multiple 
passes (fine needle aspirate not adequate) performed during or preceding the Screening Period 
for research. Diagnostic biopsy FFPE material is sufficient if at least 1 core (or at least 15 
slides if not possible) is available to be submitted. Tumor tissue samples will also be collected 
for both Control Arm and Arm A (IRX) patients during induction phase prior to initiation of 
Treatment 1 as per Arm specific Flow Chart calendar. Ideally at least 3 cores will be collected 
during study biopsies. Tumor tissue samples will also be collected from definitive surgery 
tissue for subjects who have not achieved a pCR. Detailed instructions for tissue collection, 
processing and shipment are provided in the Laboratory Manual. 
 Imaging Disease Assessment 
Subjects must have evidence of M0 disease based on the assessments from their initial 
diagnosis. In the event of suspected regional or distant metastasis during Screening, subjects 
should be thoroughly evaluated as clinically indicated; and those with metastatic disease 
should be excluded. Imaging (e.g., CT, MRI, Bone Scan) will be performed at the discretion 
of the investigator, as per the local institution’s standard of care.  
 Definitive Surgery 
Approximately 3-6 weeks following completion of the Neoadjuvant Treatment Phase or Early 
Discontinuation, subjects will undergo definitive surgery per local standard of care. Details 
regarding date of surgery, type of surgery, tumor resectability etc. will be recorded. 
Pathological staging per the current AJCC 8th edition staging criteria and assessment of 
surgical margins will be performed by the local pathologist on all the tissues removed during 
the surgery. For subjects who did not achieve a pCR, tumor tissue samples should be collected 
and submitted for translational research.  
In cases were there is evidence of clinical or radiographic residual disease at the completion of 
study therapy: if the investigating provider wishes to provide additional neoadjuvant therapy, 
the subject may undergo clinical biopsy to confirm non-pCR, and this may serve as a 
reasonable substitute to definitive surgery for ascertaining the primary endpoint. In this case, 
tissue from both the biopsy, and ultimately the resection specimen, should be obtained for 
research analysis.  

Product:  MK-3475 / IRX-2  
72 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Table 7.1.3-1 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human Chorionic 
Gonadotropin (β-hCG)a 
Hemoglobin 
Alkaline Phosphatase 
Glucose 
PT (INR)b 
Platelet Count 
Alanine Aminotransferase 
(ALT) 
Protein 
aPTT/PTTb 
White Blood Cell - 
WBC (total and 
differential) 
Aspartate Aminotransferase 
(AST) 
Specific Gravity  
Total Triiodothyronine (T3)c 
Red Blood Cell 
Count 
Carbon Dioxide (CO2 or 
Bicarbonate)d 
Microscopic exam, if 
abnormal results are 
noted  
Free Thyroxine (FT4) 
Absolute 
Neutrophil Count 
Calcium 
Urine Pregnancy Testa Thyroid Stimulating 
Hormone (TSH) 
Absolute 
Lymphocyte 
Count 
Chloride 
 
FSH (+/-) Estradiol if 
clinically indicated to 
establish menopausal statuse 
 
Creatinine or Creatinine 
clearance (CrCl) 
 
 
 
Glucose 
 
 
 
Lactate Dehydrogenase (LDH) i  
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Total Bilirubin  
 
 
 
Direct Bilirubin, if Total 
Bilirubin is elevated above the 
upper limit of normali 
 
 
 
Total Protein 
 
 
 
Blood Urea Nitrogen or Ureag 
 
 
 
Uric Acidi 
 
 
 
Cortisolh 
 
 
 
Troponini 
 
 
a. 
Perform on women of childbearing potential only. Urine pregnancy test is preferred. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. The serum or urine pregnancy test should 
be performed within 72 hours prior to first dose of trial treatment 
b. 
Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the screening procedures and at the time 
points specified in the Trial Flow Chart. Additional testing to be conducted as clinically indicated for subjects taking 
anticoagulant therapy. 
c. 
Total T3 is preferred; if not available free T3 may be tested. 
d. 
 If considered standard of care in your region. If these tests are not done as part of standard of care in your region 
then these tests do not need to be performed. 
e. 
Blood for menopausal status is only required for some subjects 
g. 
Blood urea nitrogen is preferred; if not available urea may be tested. 
h. 
Cortisol is to be determined in the morning at screening. 
i. 
Troponin, LDH, Uric acid, direct bilirubin (if total bilirubin above ULN) measured at screening and then as clinically 
indicated. 

Product:  MK-3475 / IRX-2  
73 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Menopausal Status 
The menopausal status (pre- or post-menopausal) for women with locally advanced TNBC 
must be documented. Laboratory studies to assess menopausal status should be obtained per 
local standard of care when indicated.   
 
 Blood Collections Samples for Exploratory Biomarker Analyses 
Detailed instructions for sample collection, processing and shipment are provided in the 
Laboratory Manual. The following specimens are to be retained as part of Future Biomedical 
Research: leftover DNA for future research, leftover tumor tissue, leftover RNA, leftover 
plasma and serum from exploratory biomarker studies 
 Other Procedures 
 Withdrawal/Discontinuation 
Subjects who discontinue treatment prior to completion of the treatment regimen should be 
encouraged to continue to be followed for all remaining study visits. When a subject 
discontinues/withdraws from participation in the trial, all applicable activities scheduled for 
the Early Discontinuation visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed. 
Subjects may withdraw consent at any time by contacting the principal investigator for the 
main trial.   
 Visit Requirements 
 Screening 
Approximately 28 days prior to treatment allocation/randomization, potential subjects will be 
evaluated to determine that they fulfill the entry requirements. Results of a test performed prior 
to the subject signing consent as part of routine clinical management are acceptable in lieu of 
a screening test if performed within the specified time frame.  
Screening procedures are to be completed within 28 days prior to treatment 
allocation/randomization except for the following: 
• Laboratory tests and ECOG performance status are to be performed within 14 days 
prior to treatment allocation/randomization. 
• For women of reproductive potential, a urine and/or serum pregnancy test will be 
performed within 72 hours prior to receiving the first dose of study medication.  
 Treatment Cycles 
Visit timing requirements during the treatment period are delineated in section 6 study 
calendar.   

Product:  MK-3475 / IRX-2  
74 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Definitive Surgery 
Definitive surgery is to be conducted per standard of care. 
 Post-Treatment Visits 
7.1.5.4.1 Early Discontinuation Visit 
The Early Discontinuation Visit should be conducted if subject discontinues all protocol-
specified treatment after Treatment 1 Cycle 1 through the end of treatment.  If the 
Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time of the 
mandatory Safety Follow-Up Visit, procedures listed in the Early Discontinuation should be 
performed. 
7.1.5.4.2 Safety Follow-up Visits 
Mandatory Safety Follow-up Visits should be conducted according to the above treatment 
calendar.   
7.1.5.4.3 Unscheduled Visit 
Subjects who experience a toxicity that requires discontinuation of all components (i.e., 
pembrolizumab + paclitaxel) should be observed for recovery prior to initiation of the next 
treatment phase (i.e. treatment 1, reinduction, or treatment 2). Results from assessments 
performed during the Unscheduled Visit are acceptable in lieu of repeating assessments during 
the next treatment phase if performed within 3 days prior.  
7.1.5.4.4 Long Term Follow-up 
Subjects will be followed per standard-of-care periodically in routine clinical visits by their 
treating physician. During these visits, and via telephone calls if necessary, subjects will be 
assessed for disease status/recurrence every three months for 3 years, then every six months 
for 5 years from definitive surgery.   
 
TRIAL GOVERNANCE AND OVERSIGHT 
 Monitoring/Oversight Plan  
Oversight of patient safety will include review of adverse events as well as study progress and 
outcomes.  Patient updates, outcomes, and recruitment and retention of patients will be 
reviewed on a regular basis by the PI, research nurse, and data coordinator.  Deviations will be 
reviewed during oversight meetings and/or through internal reporting procedures.  Aggregate 
protocol deviations are monitored for trends to be reviewed by the Providence Cancer Institute 
Clinic and Research Quality Committee. In addition, a “first patient review” is conducted and 
documented for all clinical trials.  This review includes treatment administration, deviations, 
and SAEs to ensure any compliance and/or safety issues are addressed prior to the enrollment 
of additional patients. 
 

Product:  MK-3475 / IRX-2  
75 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Study monitoring activities (Quality Control Reviews) are performed by clinical research staff 
members who have completed specialized training in study monitoring procedures and human 
subjects’ protections.  Individuals who perform study monitoring activities do not report to 
Principal Investigators or research scientists and may not monitor studies for which they have 
direct responsibility.  Results of study monitoring activities will be reported to applicable study 
personnel, Clinical Trials Management and Quality Assurance.  Study monitoring activities 
are conducted regularly and include (but are not limited to) review and verification of the 
following:  
• Eligibility 
• Informed Consent process 
• Adherence to protocol treatment plan 
• Case Report Forms (CRFs) 
• Source Documentation 
• Adverse Events 
• Regulatory  
Quality Assurance  
Quality Assurance (QA) personnel will perform monitoring activities on a routine basis 
following the monitoring plan. If necessary, QA will determine follow-up actions to resolve 
significant findings. QA has the authority to request immediate corrective action if significant 
patient safety issues are identified.  QA will track and trend results from routine monitoring 
activities as well as associated corrective and preventive actions. If necessary, a QA summary 
report will be provided to the IRB at the time of continuing review. QA personnel do not have 
a direct reporting relationship to the principal investigator and are not responsible for 
enrollment or coordination of care for study participants. 
 
8.0 STATISTICAL ANALYSIS PLAN 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).  
 
 
Statistical Analysis Plan Summary 
This is a signal-seeking, phase II trial to evaluate multiple novel immunotherapy agents in 
combination with pembrolizumab and chemotherapy in a neo-adjuvant setting. Patients will 
be randomized to either a concurrent control arm (pembro and chemotherapy) or an 
experimental arm (a novel immunotherapy agent in combination with pembro and 
chemotherapy). Each novel immunotherapeutic agent will be evaluated sequentially. A 
concurrent control arm will be used to compare exploratory molecular endpoints. A table 
below shows the number of patients in each arm and concurrent control arm.  
 
Table 8.1-1: Sample Sizes 

Product:  MK-3475 / IRX-2  
76 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Control Arm 
(Pembro + Chemo) 
Arm A 
(IRX2 + Control) 
Subsequent arms (pending protocol amendment) 
 
15 
15 
 
5 
 
15 
 
A rationale of the study design is to allow a rapid identification of a novel neo-adjuvant 
immunotherapy with a promising signal. Upon the identification, such an arm can be expanded 
within the same protocol (via protocol amendment) or designed as a separate, larger phase II 
trial. Immunotherapy agents in subsequent arms will be determined and added to the protocol 
in the future as a new agent becomes available for the trial. Because experimental arms use a 
novel combination, we will implement a continual toxicity monitoring and conduct real-time 
toxicity monitoring to allow suspension of the trial in the presence of unacceptable toxicity. 
Primary and Secondary Endpoints: The primary endpoint is pathologic complete response 
(pCR) by AJCC 8th edition definition (ypT0/is ypN0) in each arm. The secondary endpoints 
are safety and tolerability profile, residual cancer burden (RCB) score, and increase in tumor 
infiltrating lymphocyte by H&E. Exploratory endpoints are TIL quantity, phenotype and 
activation status at baseline and following neo-adjuvant treatment by multispectral 
immunofluorescence and deep sequencing (TCRseq and RNAseq), and dynamic 
tumoral/immune cell PD-L1 expression.  
 Sample Size and Accrual: The merit of the experimental regimen will be based upon a 
combined assessment of clinical activity, tolerability, and biomarkers activity. Therefore, 
sample sizes are not determined based upon a formalized power calculation. A sample size of 
n=15 for each experimental arm would allow a meaningful biomarkers comparative 
assessment, as well as a meaningful preliminary estimation of pCR rate, according to the below 
table: 
Table 8.1-2: exact pCR confidence intervals at various response levels 
Observed pCR rate 
90% CI 
With 80% certainty, the pCR rate is at least: 
n=15/15 (100%) 
81.8-100% 
89.8% 
n=14/15 (93.3%) 
72.1-99.7% 
81.3% 
n=13/15 (86.6%) 
63.7-97.6% 
73.6% 
n=12/15 (80%) 
56.0-94.3% 
66.3% 
n=11/15 (73.3%) 
48.9-90.3% 
59.2% 
n=10/15 (66.6%) 
42.3-85.8% 
52.4% 
 
The observed clinical activity of the experimental regimen will be estimated as above and 
interpreted in the context of historical control data from the ISPY2 trial (60% predicted pCR) 
and a contemporary randomized trial (Merck KEYNOTE-522) which is evaluating 
pembrolizumab plus neoadjuvant carboplatin-containing chemotherapy for the same patient 
population. For example, a sample size of 15 would provide 83% power to discriminate a pCR 

Product:  MK-3475 / IRX-2  
77 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
rate of 60% (the expected pCR rate in the control arm from the I-SPY2 trial) vs. 85% based on 
a one-sample binomial test with a one-sided exact significance level of 9%. 
Because this is a small, signal-seeking study, regimens that achieve pCR rates numerically 
higher than the historical control, even if not statistically significant based upon this threshold, 
may still be considered meritorious for further study if robust pharmacodynamic changes are 
observed in comparison with the control arm. 
Assuming an annual accrual rate of 20 patients each year, each experimental arm will take 1-
1.5 years to complete the accrual. 
Randomization: A randomization list will be generated prior to the start of the trial using a 
permuted block randomization with a block size of 3 per Arm (6). 
Analysis Populations: An intent to treat analysis set includes all patients who consent to enroll 
in a trial and are randomized to either a control or experimental arm, regardless of actual 
exposure to the neo-adjuvant treatment. An intent to treat analysis set is used to report accruals 
and demographic characteristics of trial participants. A safety analysis set includes patients 
who are exposed to at least one dose of the experimental treatment. Safety endpoints will be 
evaluated using the safety analysis set. An evaluable analysis set includes those with a specific 
endpoint available, e.g., pCR evaluable patients includes all patients with pCR outcome is 
available. An analysis set used for each endpoint will be defined and stated clearly in the results 
reporting. 
Statistical Analysis: Because each arm is sequentially tested, the analysis will be conducted 
each arm separately as soon as the data for each arm become available. A control arm may be 
analyzed multiple times during the trial depending on the needs for the concurrent control data. 
For the primary endpoint, a point and 90% exact binomial confidence interval of pCR will be 
provided for each arm. For safety and tolerability, all serious adverse events (SAE) will be 
summarized according to major organ categories of the NCI CTCAE v5.0. The incidence and 
rate of SAE will be presented for each arm. For residual cancer burden (RCB) score and 
increase in tumor infiltrating lymphocyte by H&E, descriptive statistics (mean, median, range, 
and standard deviation) will be provided for each arm.  Wherever possible, data visualization 
techniques (e.g., histogram, box plot and waterfall plot) will be used to display the data for 
exploratory data analyses. 
Continuous Toxicity Monitoring: A dose-limiting toxicity (DLT) is defined as any Grade 3 
or higher toxicity defined by NCI CTCAE v5.0. We derived sequential boundaries based on 
the method proposed by Ivanova et al.33, which has 90% probability of stopping when the 
underlying DLT probability is 33%. Specifically, the trial will be suspended for further safety 
review if the number of patients experiencing DLT is bn or greater among n patients.  
 
 
Table 8.1-3 Continuous Toxicity Monitoring  
Number of Patients, n 3 6 9 12 15 
Boundary, bn 
1 2 3 4 
5 
 

Product:  MK-3475 / IRX-2  
78 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Missing Values: Data will be analyzed using all available data, and missing values will not be 
imputed. A sensitivity analysis may be performed to evaluate robustness of the results in cases 
where there are substantial amount of missing data. Every efforts will be made to minimize 
missing data, especially for the primary and secondary endpoints. 
 
 
 Analysis Endpoints 
Efficacy and safety endpoints that will be evaluated are listed below. 
 Efficacy Endpoints 
Primary 
Pathological Complete Response (pCR) Rate (ypT0/Tis ypN0) 
pCR rate (ypT0/Tis ypN0) 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 per the 
current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery.   
Subjects who don’t receive any study medication will be replaced. Subjects who are 
discontinued from the study treatment and continue with other neoadjuvant treatment not 
specified by the study prior to definitive surgery will be classified as not having a pCR (non-
responders) in the efficacy analyses, regardless of the results obtained from the surgery.   
Subjects who are discontinued from study treatment due to the reasons that preclude surgery 
are considered non-responders. 
Subjects without pCR data due to any reason will be counted as non-responders. 
Secondary  
The secondary endpoints are safety and tolerability profile (point estimates and 90% 
confidence intervals of toxicity incidence, assessed by CTCAE v5.0, residual cancer burden 
(RCB) score, and increase in tumor infiltrating lymphocyte by H&E (comparing diagnostic 
biopsy to post-induction biopsy. Tumor infiltrating lymphocytes will be assessed by the San 
Antonio stromal TIL criteria1. The rationale for this endpoint is that therapy-associated tumor 
lymphocyte infiltration may be a surrogate of immune activation/stimulation. The stromal TIL 
criteria is validated to be both predictive and prognostic in breast cancer, with reasonable intra-
observer reproducibility. Scores will be reported as an average of two blinded pathologist 
reads.    
 
 Other Exploratory Endpoints 
Immune-based biomarkers, owing to their exploratory nature, will be primarily reported 
descriptively. If data permit, it may be possible to formally test whether each of the 
experimental interventions is associated with a change in a specific biomarker relative to the 
control arm using testing methods appropriate for the nature of the data type for each 
biomarker. Such statistical testing will be reserved for biomarkers that have significant 

Product:  MK-3475 / IRX-2  
79 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
rationale founded upon published pre-clinical and preceding clinical data. To account for 
multiple-testing bias, such tests will be adjusted for multiple comparisons using a method such 
as the Bonferroni correction. 
9.0 REGULATORY AND REPORTING REQUIREMENTS 
 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) active 
version (v5.0).  The CTCAE active version can be accessed from the CTEP home page 
(http://ctep.cancer.gov). 
 
Definitions 
Adverse event: 
Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable, or definite).  Medical conditions or diseases present 
before starting the investigational drug will be considered as treatment-related AEs if they 
worsen after starting study treatment. 
 
Serious adverse event: 
Any adverse drug experience occurring at any dose that results in any of the following 
outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  For this trial, SAEs will be captured from the start of study treatment until 
completion of adjuvant treatment. 
  
Unexpected adverse event:  
Any adverse drug experience, the specificity or severity of which is not consistent with the 
current investigator brochure; or, if an investigator brochure is not required or available, the 
specificity or severity of which is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as amended. 
  
Disability: 
A substantial disruption of a person's ability to conduct normal life functions. 
 

Product:  MK-3475 / IRX-2  
80 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Life-threatening adverse drug experience: 
Any adverse drug experience that places the patient or subject, in the view of the investigator, 
at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction 
that, had it occurred in a more severe form, might have caused death. 
 
Unanticipated Problem: 
An unanticipated problem is an adverse event that is (i) unexpected; (ii) serious; and (iii) felt 
by the investigator to be possibly, probably, or definitely related to the research intervention. 
Only adverse events that meet this definition need be reported to the IRB. 
 
For more information on the definition of an unanticipated problem and reporting requirement, 
consult 
current 
PH&S 
AE 
Guidelines 
on 
the 
IRB 
website 
(http://phsnet.phsor.org/institutional_review_board). 
 
 
Adverse Event Reporting 
Adverse events will be reported from the time of the first dose through 90 days following 
cessation of treatment, or the initiation of new anti-cancer therapy, whichever is earlier. 
 
Any serious adverse event, or follow up to a serious adverse event, that occurs to any subject 
from the time of the first dose through 90 days following cessation of treatment, or 
the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to 
Merck/Brooklyn Immunotherapeutic product, must be reported within 24 hours to the Sponsor 
(via email at OREACRISAEreporting@providence.org) and within 2 working days to Merck 
Global Safety (Attn: Worldwide Product Safety; FAX 215-661-6229) and Brooklyn ITX (via 
email SAE@linical.accelovance.com, and safety@brooklynitx.com) via the MedWatch 3500 
reporting form. 
 
IRB:  
An unanticipated event that is serious and definitely or probably caused by the study treatment 
(drugs or device) will be reported to the IRB of record in accordance with their guidelines and 
within their timelines. 
 
FDA Reporting: 
The Principal Investigator is responsible for determining whether or not the suspected adverse 
reaction meets the criteria for expedited reporting in accordance with Federal Regulations (21 
CFR §312.32).  A suspected adverse reaction must be both serious and unexpected in order to 
meet the reporting requirements.   
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; 

Product:  MK-3475 / IRX-2  
81 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application, as amended. 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator, it results in any of the following outcomes: Death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA 
no later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report 
will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
 
Continuing Review and Final Reports 
An annual progress report (continuing review) will be submitted to the IRB for the duration of 
the study. A final report to the IRB will be submitted at the summation of the study. Safety and 
efficacy reports will be submitted to Merck and Brooklyn Immunotherapeutics regularly once 
enrollment commences. 
 
Protocol Amendments 
Once the protocol has been approved by the IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be approved by IRB prior to 
implementation.  If it becomes necessary to alter the protocol to eliminate an immediate hazard 
to patients, an amendment may be implemented prior to IRB approval.  In this circumstance, 
however, the Investigator must then notify the IRB in writing within five (5) working days 
after implementation from the IRB will be forwarded to the FDA. 
 
Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends. 

Product:  MK-3475 / IRX-2  
82 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the 
study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring 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. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which 
it is being investigated; or, if no application is to be filed or if the application is not approved 
for such indication, until 2 years after the investigation is discontinued and FDA is notified. 
 
Data Management 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into Velos eResearch via eCRFs.  
The Clinical Research Associate (CRA) will complete the CRFs as soon as possible upon 
completion of the study visit; the Investigator will review and approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s electronic medical records.  All 
printed source documentation should be kept in separate research folders for each patient. 
 
 
 
 
 
 
 
 

Product:  MK-3475 / IRX-2  
83 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
10.0 LIST OF REFERENCES 
1. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes 
(TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann 
Oncol 2015;26:259-71. 
2. Siegel RL, KMiller KD, Jemal A. Cancer Statistics, 2018. Ca Cancer J Clin 2018;6:7-30. 
3. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and 
patterns of recurrence. Clin Cancer Res 2007;13:4429-34. 
4. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen 
receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive 
breast cancer, the so-called triple-negative phenotype: a population-based study from the 
California cancer Registry. Cancer 2007;109:1721-8. 
5. Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO International Consensus Guidelines 
for Advanced Breast Cancer (ABC 4). Ann Oncol 2018. 
6. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor 
chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13:2329-34. 
7. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical 
benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164-72. 
8. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after 
Preoperative Chemotherapy. N Engl J Med 2017;376:2147-59. 
9. von Minckwitz G, Rezai M, Loibl S, et al. Capecitabine in addition to anthracycline- and 
taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III 
GeparQuattro study. J Clin Oncol 2010;28:2015-23. 
10. von Minckwitz G, Kummel S, Vogel P, et al. Intensified neoadjuvant chemotherapy in 
early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst 
2008;100:552-62. 
11. Martin M, Ruiz Simon A, Ruiz Borrego M, et al. Epirubicin Plus Cyclophosphamide 
Followed by Docetaxel Versus Epirubicin Plus Docetaxel Followed by Capecitabine As 
Adjuvant Therapy for Node-Positive Early Breast Cancer: Results From the GEICAM/2003-
10 Study. J Clin Oncol 2015;33:3788-95. 
12. von Minckwitz G, Untch M, Nuesch E, et al. Impact of treatment characteristics on 
response of different breast cancer phenotypes: pooled analysis of the German neo-adjuvant 
chemotherapy trials. Breast Cancer Res Treat 2011;125:145-56. 
13. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev 
Immunol 2004;22:329-60. 
14. Stanton SE, Disis ML. Clinical significance of tumor-infiltrating lymphocytes in breast 
cancer. Journal for immunotherapy of cancer 2016;4:59. 
15. Finak G, Bertos N, Pepin F, et al. Stromal gene expression predicts clinical outcome in 
breast cancer. Nat Med 2008;14:518-27. 
16. Ghebeh H, Mohammed S, Al-Omair A, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory 
molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation 
with important high-risk prognostic factors. Neoplasia 2006;8:190-8. 
17. Kuk M, Voorwerk L, Horlings H, et al. Adaptive phase II randomized trial of nivolumab 
after induction treatment in triple negative breast cancer (TONIC trial): Final response data 
stage I and first translational data.  ASCO Annual Meeting; 2018 June 4, 2018; Chicago, IL. 

Product:  MK-3475 / IRX-2  
84 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
18. Egan JE, Quadrini KJ, Santiago-Schwarz F, Hadden JW, Brandwein HJ, Signorelli KL. 
IRX-2, a novel in vivo immunotherapeutic, induces maturation and activation of human 
dendritic cells in vitro. J Immunother 2007;30:624-33. 
19. Schilling B, Halstead ES, Schuler P, Harasymczuk M, Egan JE, Whiteside TL. IRX-2, a 
novel immunotherapeutic, enhances and protects NK-cell functions in cancer patients. Cancer 
Immunol Immunother 2012;61:1395-405. 
20. Schilling B, Harasymczuk M, Schuler P, Egan JE, Whiteside TL. IRX-2, a novel biologic, 
favors the expansion of T effector over T regulatory cells in a human tumor microenvironment 
model. Journal of molecular medicine 2012;90:139-47. 
21. Czystowska M, Han J, Szczepanski MJ, et al. IRX-2, a novel immunotherapeutic, protects 
human T cells from tumor-induced cell death. Cell death and differentiation 2009;16:708-18. 
22. Czystowska M, Szczepanski MJ, Szajnik M, et al. Mechanisms of T-cell protection from 
death by IRX-2: a new immunotherapeutic. Cancer Immunol Immunother 2011;60:495-506. 
23. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. 
Oncogene 2008;27:5904-12. 
24. Naylor PH, Hernandez KE, Nixon AE, et al. IRX-2 increases the T cell-specific immune 
response to protein/peptide vaccines. Vaccine 2010;28:7054-62. 
25. McMasters KM, Wong SL, Martin RC, 2nd, et al. Dermal injection of radioactive colloid 
is superior to peritumoral injection for breast cancer sentinel lymph node biopsy: results of a 
multiinstitutional study. Ann Surg 2001;233:676-87. 
26. Page D, Pucilowska J, Berinstein NL, Egan JE. Tumor infiltrating lymphocyte recruitment 
in patients with early stage breast cancer after intramammary IRX-2 cytokine immunotherapy.  
ASCO-SITC Clinical Immuno-Oncology Symposium; 2018 January 25, 2019; San Francisco, 
CA. 
27. Emens LA, Jaffee EM. Leveraging the activity of tumor vaccines with cytotoxic 
chemotherapy. Cancer research 2005;65:8059-64. 
28. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-
L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563-7. 
29. Berinstein NL, Wolf GT, Naylor PH, et al. Increased lymphocyte infiltration in patients 
with head and neck cancer treated with the IRX-2 immunotherapy regimen. Cancer Immunol 
Immunother 2012;61:771-82. 
30. Wolf GT, Fee WE, Jr., Dolan RW, et al. Novel neoadjuvant immunotherapy regimen safety 
and survival in head and neck squamous cell cancer. Head Neck 2011;33:1666-74. 
31. Whiteside TL, Butterfield LH, Naylor PH, et al. A short course of neoadjuvant IRX-2 
induces changes in peripheral blood lymphocyte subsets of patients with head and neck 
squamous cell carcinoma. Cancer Immunol Immunother 2012;61:783-8. 
32. Nanda R, Liu M, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-
risk breast cancer (BC): Results from I-SPY 2.  ASCO Annual Meeting; 2017 June 5, 2017; 
Chicago, IL. 
33. Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics 2005;61:540-5. 
 

Product:  MK-3475 / IRX-2  
85 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
APPENDICES 
 ECOG Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
http://ecog-acrin.org/resources/ecog-performance-status  
 
 
 

Product:  MK-3475 / IRX-2  
86 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
 

Product:  MK-3475 / IRX-2  
87 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
 Abbreviations 
Abbreviation/ 
Term 
Definition 
AC 
Doxorubicin + Cyclophosphamide 
ACT 
Doxorubicin + Cyclophosphamide + Paclitaxel 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine Aminotransferase 
ASaT 
All Subjects as Treated 
ASCO 
American Society of Clinical Oncology  
AST 
Aspartate Aminotransferase 
aPTT 
Activated partial thromboplastin time 
AUC 
Area under the curve 
β-hCG 
β-human Chorionic Gonadotropin 
BCS 
Breast Conservation Surgery 
BRCA 
Breast Cancer 1 
CAP 
College of American Pathologists 
Cb 
Carboplatin 
CbK 
Carboplatin + Pembrolizumab 
CBC 
Complete Blood Count 
CD8+ 
Cluster of Differentiation 8 positive 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
cN+ 
Palpable and/or sonographically suspicious lymph nodes 
cN0 
Node-negative disease; 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCs 
Circulating Tumor Cells 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
circulating tumor DNA  
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen-4 
CTL 
Circulating T Lymphocytes 
DIC 
Disseminated intravascular coagulation 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
EC 
Epirubicin + cyclophosphamide 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
EOC 
Executive Oversight Committee 
EFS 
Event-free Survival 
EGFR 
Epidermal Growth Factor Receptor 
EORTC 
European Organisation for Research and Treatment of Cancer  
EORTC QLQ-
BR23 
European Organisation for Research and Treatment of Cancer 
Breast Cancer–Specific Quality of Life Questionnaire  

Product:  MK-3475 / IRX-2  
88 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Abbreviation/ 
Term 
Definition 
EORTC QLQ-
C30 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 
ePRO 
Electronic Patient Reported Outcomes  
EQ-5D™ 
EuroQol-5 Dimension Questionnaire  
ER 
Estrogen Receptor 
ERC 
Ethics Review Committee 
FA 
Final Analysis 
FBR 
Future Biomedical Research 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FFPE 
Formalin-fixed Paraffin Embedded 
FTV 
Functional Tumor Volume 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
HER2 
Human Epidermal Growth Factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and neck squamous cell cancer 
HR 
Hazard Ratio 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IgG 
Immunoglobulin 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
irAEs 
Immune-related Adverse Events 
IRB 
Institutional Review Board 
ITIM 
Immunoreceptor tyrosine-based inhibition motif 
ITSM 
Immunoreceptor tyrosine-based switch motif 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Integrated Web Response System 
K 
Pembrolizumab 
KAC 
Pembrolizumab + doxorubicin + cyclophosphamide 
KCb 
Pembrolizumab + carboplatin  
KEC 
Pembrolizumab + epirubicin + cyclophosphamide 
KN 
KEYNOTE 
KX 
Pembrolizumab + paclitaxel 
LMP 
Last Menstrual Period 
LVEF 
Left ventricular ejection fraction 
M0 
non-metastatic 
mAb 
Monoclonal antibody 
MAH 
Marketing Authorisation Holder  
miRNA 
microRNA  
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
mTNBC 
Metastatic Triple-negative Breast Cancer 
MUGA 
Multigated Acquisition 
N 
Node 
NACT 
Neoadjuvant chemotherapy 

Product:  MK-3475 / IRX-2  
89 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
Abbreviation/ 
Term 
Definition 
NCI 
National Cancer Institute 
NKC 
Natural Killer Cell 
NMR 
Nuclear Magnetic Resonance 
NSCLC 
Non-Small Cell Lung Cancer 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
OS 
Overall Survival 
OTC 
Over-the-counter 
pCR 
Pathological Complete Response 
PD 
Progressive Disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed Death - Ligand 1 
PD-L2 
Programmed Death - Ligand 2 
PIN 
Personal Identification Number 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial thromboplastin time 
PTEN 
Phosphatase and Tensin Homolog 
Q2W 
Every 2 Weeks 
Q3W 
Every 3 Weeks 
QoL 
Quality of Life 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
SAC 
Scientific Advisory Committee 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SHP 
Src homology phosphatase 
SOP 
Standard Operating Procedures 
sSAP 
Supplemental statistical analysis plan 
SmPC 
Summary of Product Characteristics 
T 
Tumor 
T3 
Total triiodothyronine 
T4 
Free thyroxine  
TCR 
T Cell Receptor 
TILs 
Tumor-Infiltrating T Lymphocytes 
TNBC 
Triple-negative Breast Cancer 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
X 
Paclitaxel 
yCN0 
Node-negative disease after chemotherapy 
 

Product:  MK-3475 / IRX-2  
90 
PH&S IRB# 2019000486, Version 28-Jul-2021  
 
 
 
 
Confidential 
 
11.0 SIGNATURES 
I agree to conduct this clinical trial in accordance with the design outlined in this protocol and 
to abide by all provisions of this protocol (including other manuals and documents referenced 
from this protocol).  I agree to conduct the trial in accordance with generally accepted standards 
of Good Clinical Practice.  I also agree to report all information or data in accordance with the 
protocol and, in particular, I agree to report any serious adverse events as defined in Section 
7.0 – TRIAL PROCEDURES (Adverse Event Monitoring).  I also agree to handle all clinical 
supplies provided by the Sponsor and collect and handle all clinical specimens in accordance 
with the protocol.  I understand that information that identifies me will be used and disclosed 
as described in the protocol, and that such information may be transferred to countries that do 
not have laws protecting such information.  Since the information in this protocol and the 
referenced Investigator’s Brochure is confidential, I understand that its disclosure to any third 
parties, other than those involved in approval, supervision, or conduct of the trial is prohibited.  
I will ensure that the necessary precautions are taken to protect such information from loss, 
inadvertent disclosure or access by third parties. 
 
 Coordinating Site Lead Principal Investigator 
PRINTED  NAME 
David Page, MD 
TITLE 
Assistant Member,  Earle A. Chiles Research Institute, Providence 
Portland Medical Center 
SIGNATURE 
 
DATE SIGNED 
 
 
Participating Site Principal Investigator 
PRINTED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED