Neoadjuvant Phase II Study of Pembrolizumab And Carboplatin Plus Docetaxel in Triple Negative Breast Cancer
Phase: PHASE2
Conditions: Triple-negative Breast Cancer
Sponsor: University of Kansas Medical Center

IIT-2017-NeoPACT    
 
Neoadjuvant Phase II Study of Pembrolizumab And Carboplatin Plus Docetaxel in 
Triple Negative Breast Cancer
NCT03639948
Document date: 13 January 2023

CONFIDENTIAL 
This material is the property of the University of Kansas Cancer Center.  
Do not disclose or use except as authorized in writing by the study sponsor-investigator. 
This confidential information about an investigational product is provided for the exclusive use of investigators of this product and is 
subject to recall at any time.  The information in this document may not be disclosed unless federal or state law or regulations require 
such disclosure.  Subject to the foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information. 
Investigator Initiated Trial 
Neoadjuvant Phase II Study of Pembrolizumab And Carboplatin plus Docetaxel in Triple Negative 
Breast Cancer (NeoPACT) 
SPONSOR - INVESTIGATOR 
Priyanka Sharma, MD 
Associate Professor of Medicine 
University of Kansas Medical Center 
2330 Shawnee Mission Parkway, Suite 210, MS 5003 
Westwood, KS 66205 
Phone: 
Fax: 
Email: 
Protocol Number: 
IIT-2017-NeoPACT 
Study Drug(s): 
Pembrolizumab 
Carboplatin 
Docetaxel 
IND / IDE Number: 
Exempt 
IND / IDE Holder Name: 
N/A 
Initial Version: 
Original Protocol Version 1.1 dated 10 July 2018 
Amendments 
Version 2.0 dated 27 February 2019 
Version 3.0 dated 05 April 2019 
Version 4.0 dated 09 November 2020 
Version 5.0 dated 13 January 2023  

 
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LIST OF COLLABORATORS 
 
Priyanka Sharma, M.D. (Principal Investigator) 
 
 
 
 
 
 
 
 
  
 
 
 
 

 
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1 
TABLE OF CONTENTS 
LIST OF COLLABORATORS .................................................................................................................................... 2 
1 
TABLE OF CONTENTS ..................................................................................... Error! Bookmark not defined. 
2 
LIST OF ABBREVIATIONS .............................................................................................................................. 7 
3 
SCHEMATIC OF STUDY DESIGN.................................................................................................................. 9 
4 
PROTOCOL SUMMARY ................................................................................................................................. 10 
5 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .......................... 11 
5.1 
Background Information .......................................................................................................................11 
5.1.1 
Triple Negative Breast Cancer ................................................................................................ 11 
5.1.2 
Neoadjuvant Chemotherapy .................................................................................................... 11 
5.1.3 
DNA Damaging Therapy in Triple Negative Breast Cancer ................................................ 12 
5.1.4 
Neoadjuvant Carboplatin plus Docetaxel ............................................................................... 12 
5.1.5 
PD-1 Immune Checkpoint Targeting ...................................................................................... 13 
5.1.6 
Surgery after Neoadjuvant Treatment .................................................................................... 14 
5.2 
Study Agent(s) / Treatment(s) .............................................................................................................14 
5.2.1 
Carboplatin (Paraplatin) ............................................................................................................ 14 
5.2.2 
Docetaxel (Taxotere) ................................................................................................................ 14 
5.2.3 
Pembrolizumab (Keytruda) ...................................................................................................... 15 
5.2.3.1 
Preclinical efficacy in breast cancer ............................................................................ 15 
5.2.3.2 
Pharmacodynamics ....................................................................................................... 15 
5.2.3.3 
Nonclinical pharmacokinetics and metabolism .......................................................... 15 
5.2.3.4 
Clinical pharmacology ................................................................................................... 16 
5.2.3.5 
Clinical efficacy ............................................................................................................... 17 
5.2.3.6 
Clinical safety .................................................................................................................. 17 
5.3 
Rationale for the Study .........................................................................................................................19 
5.3.1 
Justification for dose ................................................................................................................. 20 
5.4 
Study Risk / Benefit Ratio ....................................................................................................................20 
5.4.1 
Study Known Potential Risks ................................................................................................... 20 
5.4.2 
Study Known Potential Benefits .............................................................................................. 20 
6 
INVESTIGATIONAL NEW DRUG (IND) ....................................................................................................... 20 
7 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................... 20 
7.1 
OBJECTIVE(S) ......................................................................................................................................20 
7.1.1 
Primary Objective ...................................................................................................................... 20 
7.1.2 
Secondary Objective(s) ............................................................................................................ 21 
7.1.3 
Exploratory Objective(s) ........................................................................................................... 21 
7.2 
ENDPOINTS AND MEASURE(S) ......................................................................................................21 
7.2.1 
Primary Endpoint ....................................................................................................................... 21 
7.2.2 
Secondary Endpoint(s) ............................................................................................................. 21 
7.2.3 
Exploratory Endpoint(s) ............................................................................................................ 22 
8 
STUDY ENROLLMENT AND WITHDRAWAL ............................................................................................. 22 
8.1 
Participant Inclusion Criteria ................................................................................................................22 
8.2 
Participant Exclusion Criteria ..............................................................................................................24 
8.3 
Participant Withdrawal Or Termination ..............................................................................................26 
8.3.1 
Reasons For Withdrawal Or Termination............................................................................... 26 
8.3.2 
Participant Replacement .......................................................................................................... 26 
9 
MEASUREMENT OF EFFECT ...................................................................................................................... 26 

 
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9.1 
Solid Tumor26 
9.1.1 
Antitumor Effect ......................................................................................................................... 27 
10 STUDY AGENT ................................................................................................................................................ 27 
10.1 
Study Agent(s) / Therapy / Device And “Control” Description ........................................................27 
10.1.1 
Acquisition / How Supplied....................................................................................................... 27 
10.1.2 
Formulation, Appearance, and Packaging............................................................................. 28 
10.1.2.1 
Carboplatin ...................................................................................................................... 28 
10.1.2.2 
Docetaxel ........................................................................................................................ 28 
10.1.2.3 
Pembrolizumab............................................................................................................... 29 
10.1.3 
Agent Known Potential Side Effects ....................................................................................... 30 
10.1.3.1 
Carboplatin ...................................................................................................................... 30 
10.1.3.2 
Docetaxel ........................................................................................................................ 30 
10.1.3.3 
Pembrolizumab............................................................................................................... 30 
10.1.4 
Concomitant, Precautionary, Prohibited Medications, Foods And Treatments ................ 31 
10.1.4.1 
Acceptable concomitant medications .......................................................................... 31 
10.1.4.2 
Prohibited concomitant medications and treatments ................................................ 32 
10.1.4.3 
Rescue medications and supportive care .................................................................. 32 
10.1.5 
Return And Retention Of Study Agent ................................................................................... 33 
11 TREATMENT PLAN ......................................................................................................................................... 33 
11.1 
Dosing And Administration ..................................................................................................................34 
11.1.1 
Administration ............................................................................................................................ 34 
11.1.2 
Duration Of Therapy .................................................................................................................. 35 
11.1.3 
Study Agent Accountability Procedures / Participant Compliance ..................................... 36 
11.1.4 
Dose Adjustments/Modifications/Delays ................................................................................ 36 
11.1.4.1 
CARBOPLATIN AND DOCETAXEL ........................................................................... 36 
11.1.4.1.1 Hematologic toxicities ................................................................................. 36 
11.1.4.1.2 Non-hematologic toxicities ......................................................................... 37 
11.1.4.1.3 Hypersensitivity reactions: ......................................................................... 38 
11.1.4.1.4 Management of edema/fluid retention related to docetaxel: ................. 39 
11.1.4.1.5 Hepatic dysfunction ..................................................................................... 39 
11.1.4.2 
PEMBROLIZUMAB ........................................................................................................ 40 
11.1.4.2.1 Immune-related toxicities management and dose modification ........... 40 
11.1.4.2.2 Infusion reactions: toxicity management and dose modification .......... 42 
11.1.4.2.3 Other allowed dose interruptions .............................................................. 43 
11.1.5 
Concomitant, Precautionary, Prohibited Medications, Foods And Treatments ................ 43 
12 STUDY PROCEDURES AND SCHEDULE .................................................................................................. 43 
12.1 
DESCRIPTIVE SCHEDULE OF EVENTS ........................................................................................43 
12.1.1 
Screening/Enrollment/Baseline ............................................................................................... 44 
12.1.2 
Procedures During Treatment ................................................................................................. 46 
12.1.3 
Post-Treatment Follow-Up Visit(s) .......................................................................................... 47 
12.2 
SCHEDULE OF EVENTS TABLE ......................................................................................................48 
13 CORRELATIVE STUDIES .............................................................................................................................. 52 
13.1 
Sample Collection Instructions ............................................................................................................52 
13.2 
Sample Preparation, Handling, And Storage ....................................................................................52 
13.3 
Assay Methodology ..............................................................................................................................53 
13.4 
Sample Banking ....................................................................................................................................53 
14 STATISTICAL CONSIDERATIONS .............................................................................................................. 54 
14.1 
Statistical Hypotheses ..........................................................................................................................55 
14.2 
Sample Size Justification .....................................................................................................................56 

 
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14.3 
Accrual Method .....................................................................................................................................56 
14.4 
Description Of Statistical Methods .....................................................................................................57 
14.4.1 
General Approach ..................................................................................................................... 57 
14.4.2 
Analysis Of Primary Objective ................................................................................................. 57 
14.4.3 
Analysis Of Secondary Objective(s) ....................................................................................... 57 
14.4.4 
Safety Analyses ......................................................................................................................... 57 
14.4.5 
Planned Interim Analysis .......................................................................................................... 57 
14.4.6 
Exploratory Analysis .................................................................................................................. 57 
15 PARTICIPANT REGISTRATION PROCEDURES ...................................................................................... 58 
16 ASSESSMENT OF SAFETY .......................................................................................................................... 58 
16.1 
Specification Of Safety Parameters ...................................................................................................59 
16.1.1 
Definition Of Adverse Events (AEs) ........................................................................................ 59 
16.1.2 
Relationship To Study Agent ................................................................................................... 60 
16.2 
Reporting Procedures ..........................................................................................................................61 
16.2.1 
Adverse Event Reporting ......................................................................................................... 61 
16.2.2 
Recording Adverse Events And Documentation In CRIS .................................................... 62 
16.2.3 
Serious Adverse Event Reporting ........................................................................................... 62 
16.2.4 
Reporting To Merck ................................................................................................................... 62 
16.2.4.1 
Serious Adverse Events ................................................................................................ 62 
16.2.4.2 
Definition Of Overdose And Reporting Of Overdose ................................................ 63 
16.2.4.3 
Events Of Clinical Interest ............................................................................................ 64 
16.2.5 
Reporting Of Pregnancy and Lactation .................................................................................. 64 
16.2.6 
Summary Of Expedited Serious Adverse Event Reporting ................................................. 65 
16.2.7 
Voluntary Reporting of Unexpected, Related SAE/AESIs For Concomitant Medications
 
65 
17 DATA AND SAFETY MONITORING ............................................................................................................. 65 
17.1 
DSMC Oversight And Monitoring Plan ..............................................................................................65 
17.2 
Safety Review And Oversight Requirements ....................................................................................66 
17.2.1 
Serious Adverse Event ............................................................................................................. 66 
17.2.2 
Review Of Adverse Event Rates ............................................................................................. 66 
17.2.3 
Study Safety And Progress ...................................................................................................... 66 
17.3 
Unblinding Rules ...................................................................................................................................67 
18 REGULATORY CONSIDERATIONS ............................................................................................................ 67 
18.1 
Protocol Review And Amendments ....................................................................................................67 
19 ETHICS/PROTECTION OF HUMAN SUBJECTS ....................................................................................... 67 
19.1 
Ethical Standard ....................................................................................................................................67 
19.2 
Informed Consent Process ..................................................................................................................68 
20 DATA HANDLING AND RECORD KEEPING .............................................................................................. 68 
20.1 
Data Collection And Management Responsibilities .........................................................................68 
20.2 
Study Records Retention .....................................................................................................................68 
20.3 
Protocol Deviations ...............................................................................................................................68 
21 LITERATURE REFERENCES ....................................................................................................................... 69 
22 APPENDICES ................................................................................................................................................... 73 
Appendix A: Performance Status ......................................................................................................................73 
Appendix B: Contraceptive Guidance and Pregnancy Testing ....................................................................74 
Woman of Childbearing Potential (WOCBP) ........................................................................................... 74 
Contraception Requirements ..................................................................................................................... 74 

 
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Pregnancy Testing ....................................................................................................................................... 75 
Appendix C: Suggested Chemotherapy Pre-medication and Antiemetics .................................................76 
Appendix D: Specimen Collection, Processing, and Shipping .....................................................................77 
Appendix E: For Non-KU Sub-Sites Only – Specimen Packing List ...........................................................78 
Appendix F: Serious Adverse Event Fax Reporting Form ............................................................................79 
 
 
 

 
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2 
LIST OF ABBREVIATIONS 
 
A 
Anthracycline 
AC 
Doxorubicin plus cyclophosphamide regimen 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
 
Area under the curve 
BA/BE 
Bioavailability/Bioequivalence 
BCS 
Breast conservation surgery 
BID 
Twice daily 
BRCF 
Biospecimen Repository Core Facility 
BUN 
Blood urea nitrogen 
C 
 
Cyclophosphamide 
CAP 
College of American Pathologists 
Cb 
Carboplatin 
CBC 
Complete blood count 
CbD 
Carboplatin plus Docetaxel regimen 
CMP 
Comprehensive metabolic panel 
CRF 
Case report form 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CVAP 
Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone regimen 
DCIS 
Ductal carcinoma in situ 
ddAC 
Dose dense Doxorubicin + Cyclophosphamide 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiography 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
DSMC 
Data and Safety Monitoring Committee 
ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin-embedded 
FNA 
Fine needle aspiration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HER2 
Human epidermal growth factor receptor 2 
HR 
Homologous recombination 
IgG 
Immunoglobulin G 
IND 
Investigational new drug 
IRB 
Institutional review board 
IULN 
Institutional Upper Limit of Normal 
IV 
Intravenous 
LFT 
Liver function tests 
LVEF 
Left ventricular ejection fraction 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 

 
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MUGA 
Multi gated acquisition scan 
N+ 
Lymph node positive 
NCI 
National Cancer Institute 
pCR 
Pathological complete response 
PD-1 
Programmed cell death protein-1 
PD-L1 
Programmed cell death protein ligand 1 
PI 
Principal Investigator 
PO 
Per os/by mouth/orally 
PR 
Progesterone receptor 
RBC 
Red blood cells 
RCB 
Residual cancer burden 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SGOT 
Serum glutamic oxaloacetic transaminase 
SPGT 
Serum glutamic pyruvic transaminase 
T 
Tumor size 
Ta 
Taxanes 
TNBC 
Triple-negative breast cancer 
US 
Ultrasound 
USP 
United States Pharmacopeia 
 
 

 
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4 
PROTOCOL SUMMARY 
 
Title 
Neoadjuvant Phase II Study of Pembrolizumab And Carboplatin plus 
Docetaxel in Triple Negative Breast Cancer (NeoPACT) 
Protocol Number 
IIT-2017-NeoPACT 
Phase 
Phase II 
Methodology 
Single arm 
Study Duration 
66 months 
Study Center(s) 
 
 
 
 
 
Objectives 
Primary Objective: To determine pathological complete response rate 
with neoadjuvant chemotherapy regimen of CbD plus Pembrolizumab in 
patients with stage I-III TNBC. 
Hypothesis: Addition of Pembrolizumab to CbD will lead to 
improvement in pCR rates compared to historical control in patients 
with stage I-III TNBC. 
Number of Participants 
120 patients, accrued over 30 months. 
Diagnosis and Main 
Inclusion Criteria 
Newly diagnosed stage I (T>1cm or N+), II or III TNBC who have not 
undergone definitive breast surgery and have not received any systemic 
chemotherapy. 
Study Product(s), Dose, 
Route, Regimen 
Carboplatin (AUC 6, IV) and Docetaxel (75 mg/m2, IV) plus 
Pembrolizumab (200 mg, IV) every 21 days x 6 cycles.  
Pegfilgrastim or its biosimilar equivalent  (6 mg) SC Day 2 of each cycle.  
Duration of 
Administration 
18 weeks 
Reference Therapy 
Carboplatin (AUC 6, IV) and Docetaxel (75mg/m2, IV) every 21 days x 6 
cycles. 
Interim Monitoring 
None 
Statistical Methodology 
For Primary Endpoint 
The pCR rate will be estimated and 95% exact binomial confidence 
bounds will be calculated.  
Correlative Studies 
OR SAMPLE BANKING FOR 
FUTURE RESEARCH  
Yes 
Stopping Rules 
No 
 
 
 

 
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5 
 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
5.1 
Background Information 
 
5.1.1 Triple Negative Breast Cancer 
Breast cancer is the most commonly diagnosed malignancy and second leading cause of cancer mortality 
in American women. The lifetime risk of developing breast cancer is 12.2%, and the lifetime risk of 
breast cancer death is 3.3% 1. Triple negative breast cancer (TNBC) is defined by the lack of expression of 
estrogen receptor (ER) and progesterone receptor (PR), and absence of ERBB2 (HER2) overexpression 
and/or gene amplification. TNBC accounts for 15% of all breast cancer and is associated with poor long-
term outcomes compared to other breast cancer subtypes 2-4. Systemic neoadjuvant chemotherapy is 
recommended for all TNBC patients with stage I (T>1cm)-III disease 5. Due to the lack of specific 
therapeutic targets, chemotherapy remains the mainstay of systemic treatment in the adjuvant setting. 
However, despite receiving standard anthracycline-based adjuvant chemotherapy, a significant 
proportion (approximately 30-40%) of patients with early stage TNBC develop metastatic disease and 
succumb to the cancer 6-8. To improve outcomes for this subtype, we not only need novel targeted 
agents, but also need to identify predictors of response/resistance to standard chemotherapy. 
5.1.2 Neoadjuvant Chemotherapy 
Neoadjuvant (primary) chemotherapy refers to induction chemotherapy given before local treatment, 
such as surgery or radiation 9. The biologic rationale for the use of neoadjuvant therapy in breast cancer 
is based on several key observations. Animal models have demonstrated that the removal of a primary 
tumor may increase the rate of growth of micrometastases. Fisher suggested that this accelerated 
growth which is controlled by serum growth factors, could be prevented by systemic chemotherapy 
before tumor resection 10. Goldie and Coldman have proposed that the number of tumor cells is 
proportional to the number of chemoresistant clones, and therefore, neoadjuvant chemotherapy would 
be effective in maximizing future drug response 11. 
Clinically, neoadjuvant chemotherapy has a number of potential advantages. Decreasing the size of the 
primary tumor may effectively downstage a mass to make breast preservation more likely, and may 
improve local control 9. Chemotherapy may also decrease the intensity and morbidity of irradiation 
required to treat the breast or chest wall. Additionally, it allows for immediate objective assessment of 
chemotherapy response which offers prognostic information, as well as guides alterations in therapy. 
Finally and most importantly, neoadjuvant chemotherapy allows for rapid early assessment of new 
treatment approaches and to study the relationship of biologic markers and treatment response. 
In the landmark phase III randomized study (National Surgical and Adjuvant Breast Project [NSABP] B-
18), it was demonstrated that in patients with stage I and II disease, neoadjuvant chemotherapy was 
equivalent to adjuvant chemotherapy in terms of disease free survival, distant disease free survival and 
overall survival, however, a higher percentage of breast conservation surgeries (67% vs. 59%) was 
possible with neoadjuvant chemotherapy 12. For breast cancer, neoadjuvant chemotherapy was initially 
used in patients only with locally advanced or inoperable disease, but now is considered for patients 
who are candidates for adjuvant chemotherapy. 
It has been demonstrated that degree of tumor response and extent of residual disease after 
neoadjuvant chemotherapy are associated with relapse and long-term survival 13,14. Prospective trials 
have demonstrated that patients who achieve a pathological complete response (pCR) of the primary 

 
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tumor with neoadjuvant chemotherapy have significantly improved disease free and overall survival 
when compared with patients who do not have a pCR 13-18. Due to its value as a surrogate for survival, 
response to neoadjuvant chemotherapy is being used as a primary endpoint in studies that examine the 
efficacy of new drugs and novel drug combinations 19. 
5.1.3 DNA Damaging Therapy in Triple Negative Breast Cancer 
Sporadic and germline BRCA mutation-associated triple negative breast cancers (TNBC) share several 
pathological and molecular similarities. These similarities have led to the exploration of DNA damaging 
agents like platinum compounds in the general population of patients with TNBC. Growing evidence 
suggests that platinum compounds may be active in a significantly larger number of TNBC patients 
beyond germline BRCA mutation carriers 20,21. Currently, anthracyclines (A), cyclophosphamide (C) and 
taxanes (Ta) form the backbone of systemic chemotherapy for stage I-III TNBC (www.nccn.org). Recent 
studies demonstrate that addition of neoadjuvant carboplatin (Cb) to A/C/Ta-based chemotherapy 
improves pCR in patients with stage I-III TNBC (pCR improvement from 41% to 54% with addition of Cb) 
22-24. However, this improvement in pCR rate comes at the cost of increase in toxicity (dose 
reductions/omissions needed in 40-50% of patients) and also increases the financial cost of 
chemotherapy 23,24. Furthermore, anthracyclines and cyclophosphamide, although very active for 
treatment of breast cancer, have well-known small but serious long term risks (secondary leukemia and 
myelodysplastic syndrome, cardiomyopathy, premature menopause), and development of effective 
chemotherapy regimens that are devoid of long term side effects is desirable.  
Furthermore, although anthracycline agents induce double-strand breaks, repair of these lesions 
appears to require non-homologous end joining, an error-prone double strand break repair pathway 
that does not require BRCA1, and preclinical data suggests that anthracyclines do not exhibit selective 
toxicity in BRCA1-deficient cells 25-27. Conversely, repair of platinum-induced interstrand crosslinks 
invokes BRCA1-mediated homologous recombination, and there is abundant clinical and in vitro 
evidence that BRCA1-deficient cells are hypersensitive to platinum agents 25,27-29. 
5.1.4 Neoadjuvant Carboplatin plus Docetaxel 
Taxanes are an integral part of chemotherapy regimens for breast cancer treatment and appear to 
contribute particularly among patients with early stage TNBC 30,31. Several in vitro studies have 
demonstrated synergy between platinum compounds and taxanes in TNBC cell lines 32. Efficacy of 
anthracycline-devoid neoadjuvant platinum/taxane chemotherapy combination in sporadic and BRCA-
associated TNBC has not been well studied. We recently reported encouraging pCR rates with a non-
anthracycline carboplatin plus docetaxel (CbD) neoadjuvant chemotherapy regimen in 190 stage I-III 
TNBC patients 33. This CbD regimen yielded an overall pCR rate of 55% in unselected TNBC, with pCR 
rates of 59% and 56% for BRCA-associated and wild type TNBCs, respectively, indicating response among 
TNBC regardless of germline BRCA status (Table 1). 
Table 1:  Response rates among TNBC patients treated with neoadjuvant carboplatin and docetaxel 

 
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All patients (n=190) 
BRCA1/2 wild type 
(n=133) 
BRCA1/2 mutation 
carriers (n=27)  
Pathological Complete 
Response; n (%) 
100 (55%) 
75 (56%) 
16 (59%) 
 
                                                                                                     p=0.83 
Residual Cancer Burden 0/1; 
n (%) 
125 (68%) 
92 (69%) 
19 (70%) 
 
                                                                                                     p=1.0 
The chemotherapy regimen of carboplatin/docetaxel is well tolerated, and is routinely used for HER2 
positive and metastatic breast cancer, with well-known safety profile 5,34. In our neoadjuvant experience, 
most common Grade 3/4 toxicities with carboplatin/docetaxel were neutropenia (4%), anemia (6%), 
thrombocytopenia (6%), and diarrhea (6%). Thus, we have recently demonstrated in an observational 
cohort that the pCR achieved with carboplatin/docetaxel chemotherapy is comparable to the pCR noted 
with addition of carboplatin to AC/paclitaxel chemotherapy, with a more favorable profile, supporting 
further studies built on the CbD backbone. 
5.1.5 PD-1 Immune Checkpoint Targeting 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades 35. Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes and favorable prognosis in various malignancies 36,37. 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 is an 
immunoglobulin (Ig) superfamily member that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 38,39.  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2, leading to the 
dephosphorylation of effector molecules which are involved in the CD3 T-cell signaling cascade 39-42. 
Thus PD-1 activation by its ligands results in inhibited T-cell activation. Although PD-L1 is absent from 
normal breast tissue, it is expressed in approximately half of breast cancers, where it activates PD-1 and 
allows tumor cells to evade detection by the immune system 43. Furthermore, PD-L1 expression is found 
at higher rates in TNBC than in non-TNBC. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in TNBC. 
Preliminary data in breast cancer show encouraging efficacy of PD-1 inhibitors in both metastatic and 
early stage TNBC. The PD-L1 inhibitor avelumab has been investigated in breast cancer unselected for 
PD-L1 status and subtype, in the phase Ib solid tumor JAVELIN study. The overall response rate in this 
study was 4.8% (with 1 complete response and 7 partial responses), and an overall response rate of 
8.6% in TNBC patients (n=58) 44. Atezolizumab, an anti-PD-L1 monoclonal antibody, was evaluated in a 
phase I study that included 54 patients with metastatic TNBC. In this study, the overall response rate 
was 19% (including 2 complete responses and 2 partial responses) 45. Data on 112 metastatic TNBC 
patients treated with single-agent atezolizumab were recently presented at the 2017 American 
Association for Cancer Research Annual Meeting 46. This study reported an overall response rate of 10%, 
which was influenced by extent of prior treatment for metastatic disease (overall response rate was 26% 
among patients with no prior line of therapy). The median duration of response in all response-
evaluable patients was encouraging, at 21.1 months. Pembrolizumab, a monoclonal anti-PD-L1 antibody, 
was also evaluated in KEYNOTE-012, which enrolled multiple tumor types, including 32 patients with 
metastatic TNBC and tumor PD-L1 positivity. The overall response rate was 18.5%, including 1 complete 

 
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response and 4 partial responses 47. Additionally, the 6-month PFS rate was 24.4%, and at the time of 
publication, the median duration of response had not been reached. In the ongoing KEYNOTE-086 trial, 
patients with PD-L1-positive metastatic disease who had not received prior systemic treatment for 
metastatic disease had an overall response rate of 23.1% (4% complete response) with Pembrolizumab 
monotherapy 48. Several ongoing clinical trials are evaluating PD-1 and PD-L1 inhibitors in combination 
with cytotoxic chemotherapy for metastatic TNBC (NCT02425891, NCT02393794, NCT02628132, 
NCT02648477, NCT02499367). PD-1/PD-L1 inhibitors are also being evaluated in early stage TNBC in the 
neoadjuvant setting. In the I-SPY 2 trial, addition of Pembrolizumab to standard neoadjuvant therapy 
increased the rate of pathologic complete response (pCR) rate in TNBC approximately threefold 49.  
Based on these encouraging findings, several ongoing clinical trials are evaluating PD-1/PD-L1 antibodies 
in combination with various schedules of neoadjuvant chemotherapy in TNBC (NCT03036488, 
NCT02620280, NCT03281954, NCT03197935, NCT02883062). 
5.1.6 Surgery after Neoadjuvant Treatment 
Approximately one-third of patients thought to be in complete remission on clinical grounds after 
neoadjuvant chemotherapy still have residual disease at the time of pathologic examination. Therefore, 
pathologic examination following surgical excision of the suspected area of involvement is the best 
indicator of response 12. Appropriate selection of patients for breast conserving surgery (BCS) following 
neoadjuvant chemotherapy is important. Absolute contraindications for BCS include extensive, residual, 
or multifocal tumor, or positive resection margins, while a relative contraindication is predicted poor 
cosmetic outcome 50. 
 
5.2 
Study Agent(s) / Treatment(s) 
 
5.2.1 Carboplatin (Paraplatin) 
Please refer to carboplatin package insert for full prescribing information. 
Carboplatin is a platinum analog that covalently binds to DNA, producing crosslinks leading to inhibition 
of DNA synthesis. It is a cell cycle non-specific chemotherapeutic agent. Single agent carboplatin is active 
in patients with previously untreated metastatic breast cancer, producing response rates of 20-35% 51-55. 
Combination regimens of carboplatin with other chemotherapy agents (taxanes, gemcitabine) are also 
active for treatment of advanced breast cancer 56-58. Platinum compounds are considered to be 
especially active for TNBC. Recent studies demonstrate that addition of neoadjuvant carboplatin to 
A/C/Ta-based chemotherapy improves pCR in patients with stage I-III TNBC 24,59. 
 
5.2.2 Docetaxel (Taxotere) 
Please refer to docetaxel package insert for full prescribing information. 
Docetaxel is an anti-microtubule taxane agent. Randomized phase III trials have confirmed the anti-
tumor activity of docetaxel in breast cancer in neoadjuvant, adjuvant and metastatic settings 60-69. 
Addition of docetaxel to anthracycline-based chemotherapy in the neoadjuvant setting has universally 
been associated with improved outcome in all studies (superior complete clinical and pathologic 
response rate in all, and improved survival in the Aberdeen study). One of the largest neoadjuvant 
studies, NSABP B-27, investigated neoadjuvant doxorubicin/cyclophosphamide +/- docetaxel in patients 
with early breast cancer (T>3 cm or lymph node positive). Addition of neoadjuvant docetaxel to 
doxorubicin and cyclophosphamide was associated with superior clinical response rate and pCR (pCR of 

 
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27% vs. 13%). The Aberdeen Breast Study investigated the use of neoadjuvant docetaxel in large or 
locally advanced breast cancer after treatment with induction cyclophosphamide, doxorubicin, 
vincristine, prednisolone (CVAP) 64. Patients who were responsive to induction CVAP and subsequently 
treated with sequential docetaxel achieved a 94% clinical and 34% pathologic response rate versus a 
66% clinical and 16% pathologic response rate in patients who received four additional cycles of CVAP 
therapy. Overall survival at 5 years was also superior in the docetaxel arm. 
 
5.2.3 Pembrolizumab (Keytruda) 
Please refer to the Pembrolizumab package insert for full prescribing information. 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on 
preclinical in vitro data, Pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an 
intravenous (IV) immunotherapy for advanced malignancies. Keytruda® (Pembrolizumab) is indicated for 
the treatment of patients across a number of indications because of its mechanism of action to bind the 
PD-1 receptor on the T cell. For more details on specific indications refer to the Investigator brochure.  
5.2.3.1 Preclinical efficacy in breast cancer 
Several preclinical studies have demonstrated activity of monoclonal antibodies targeting PD-1 or PD-L1 
in breast cancer cell lines, including TNBC lines 70,71. In xenograft models, anti-PD-1 antibodies 
demonstrated activity when combined with other agents targeting cytotoxic T-cells 71. Preclinical studies 
in mouse models show that antibody-mediated blockage of PD-1/PD-L1 interaction enhances infiltration 
of tumor-specific T-cells and leads ultimately to tumor rejection, either as a monotherapy or in 
combination with other treatment modalities 72. 
5.2.3.2 Pharmacodynamics 
 
 
 
(Merck, internal data). 
 
 
 
 
 
 (Merck, internal data). 
5.2.3.3 Nonclinical pharmacokinetics and metabolism 
 
(Merck, internal 
data). 

 
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 (Merck, internal data). 
 
 
 
 
 
 
 
 
 
 
 
 
 (Merck, internal data). 
5.2.3.4 Clinical pharmacology 
 
 
 
 
 
 
 
(Merck, internal data).  
 
 
 
 
 
 
 

 
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(Merck, internal data). 
 
 
 
 
 
 
 
 (Merck, internal data). 
 
 
 (Merck, internal data). 
5.2.3.5 Clinical efficacy 
Clinical efficacy in TNBC 
Preliminary data in breast cancer show encouraging efficacy of Pembrolizumab in TNBC. The phase Ib 
clinical trial KEYNOTE-012 included 32 patients with metastatic PD-L1 positive TNBC. The ORR among 
these patients was 18.5%, including one complete response and four partial responses 47. Additionally, 
the 6-month PFS was 24.4%, and the median duration of response had not been reached at time of 
publication. A phase II, two-part, multi-site, open-label trial (KEYNOTE-086) is evaluating Pembrolizumab 
200 mg IV every 3 weeks in metastatic TNBC. Part 1 of this study includes two cohorts (A and B), results 
of which were recently reported. In Cohort A, metastatic TNBC patients who had received at least 1 line 
of systemic treatment for metastatic disease (including an anthracycline and a taxane in neo/adjuvant or 
metastatic setting), an ORR of 5% (irrespective of PD-L1 expression) was noted with Pembrolizumab 
monotherapy 73. In Cohort B, subjects with PD-L1-positive mTNBC who had not received any prior 
systemic treatment for metastatic disease, ORR was 23.1% (4% had complete response), and the 
estimated 6-month PFS was 29% 48. Recently presented data from I-SPY 2 demonstrated that addition of 
Pembrolizumab to neoadjuvant paclitaxel plus doxorubicin and cyclophosphamide increased the 
estimated pCR rate in patients with TNBC from 20% to 60% 49.  
5.2.3.6 Clinical safety 
As of March 2017, over 14,000 patients with hematologic malignancies and solid tumors have received 
Pembrolizumab monotherapy or combination therapy in clinical trials. Pembrolizumab has been granted 
approval in a number of markets and indications (melanoma, NSCLC, HNSCC, cHL, UC, gastric and 
gastroesophageal junction adenocarcinoma, and MSI-H tumors) and has an established safety profile as 
outlined in the Company Core Data Sheet. Pembrolizumab has a positive benefit-risk profile and is well 
tolerated in the approved indications, 
 
 
 Furthermore, the frequency of immune-related reactions is low, and these events are readily 
managed in the clinical setting. 
Merck’s Reference Safety Dataset consisted of 
 
 
 

 
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 (Merck, 
internal data). 
Table 2: Merck’s Reference Safety Dataset, percentage of subjects with adverse events of special interest, by 
maximum toxicity grade 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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plus paclitaxel combination in TNBC. Pembrolizumab can be safely combined with docetaxel at 75 
mg/m2 every three weeks (NCT02331251). Ongoing phase II studies in solid tumors are combining 
Pembrolizumab 200 mg flat-dose every 21 days with docetaxel at a dose of 75 mg/m2 75. Thus, a phase II 
study of the combination of Pembrolizumab with carboplatin plus docetaxel at the proposed doses is 
feasible.  
5.3.1 Justification for dose 
Use of Pembrolizumab at a fixed dose of 200 mg every 21 days is supported by clinical trials in various 
solid tumors, which demonstrated near-maximal efficacy and an acceptable safety profile at this dose 
76,77. Phase I/II clinical trials in breast cancer have employed 200 mg Pembrolizumab both as 
monotherapy and in combination with cytotoxic chemotherapy. Based on the totality of data generated 
in the pembrolizumab development program, 200 mg every 3 weeks is the appropriate dose of 
Pembrolizumab for adults across all indications and regardless of tumor type (Merck, internal data). This 
dose level is FDA-approved in combination with chemotherapy for lung cancer (KEYNOTE-021 study). 
 
5.4 
Study Risk / Benefit Ratio 
 
The potential benefit of this study is judged to outweigh risk; therefore, the risk/benefit ratio is in favor 
of benefit. 
 
5.4.1 Study Known Potential Risks  
 
The research in this study poses greater than minimal risk with some potential prospect for direct 
benefit to the participant . The study is likely to yield generalizable knowledge about the treatment of 
triple negative breast cancer. 
 
5.4.2 Study Known Potential Benefits  
 
Potential benefits include the possibility of increased pathological response rates (compared to 
historical standard-of-care chemotherapy) for participants enrolling in this study. In addition, the study 
will yield information that may benefit future subjects by advancing knowledge regarding treatment of 
TNBC. 
 
 
6 
INVESTIGATIONAL NEW DRUG (IND)  
 
This study treatment meets the requirements for IND exemption; FDA confirmation has been obtained 
and is on file for this study. 
 
7 
STUDY OBJECTIVES AND ENDPOINTS 
 
7.1 
OBJECTIVE(S) 
 
7.1.1 Primary Objective 

 
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To determine the pathological complete response (pCR) rates with a neoadjuvant chemotherapy regimen 
of carboplatin and docetaxel (CbD) plus Pembrolizumab in patients with stage I-III TNBC. 
 
 
 
7.1.2 Secondary Objective(s) 
1. To evaluate minimal residual disease (MRD) rate (residual cancer burden score of 0/1) with a 
neoadjuvant chemotherapy regimen of CbD plus Pembrolizumab in patients with stage I-III 
TNBC. 
2. To determine 3-year recurrence-free survival with a neoadjuvant chemotherapy regimen of CbD 
plus Pembrolizumab in patients with stage I-III TNBC. 
3. To determine 3-year event-free survival with a neoadjuvant chemotherapy regimen of CbD plus 
Pembrolizumab in patients with stage I-III TNBC. 
4. To evaluate toxicity of neoadjuvant chemotherapy regimen of CbD plus Pembrolizumab in 
patients with stage I-III TNBC. 
 
7.1.3 Exploratory Objective(s) 
1. To evaluate markers of DNA repair deficiency and/or tumor genomic instability as biomarkers of 
response to treatment. 
2. To evaluate immune therapy response biomarkers (e.g. PD-L1 expression, gene expression 
signatures). 
3.  To evaluate overall survival with a neoadjuvant chemotherapy regimen of CbD plus 
Pembrolizumab in patients with stage I-III TNBC. 
 
7.2 
ENDPOINTS AND MEASURE(S) 
 
7.2.1 Primary Endpoint 
 
Rate  of pathological complete response (pCR) in breast and axilla after neoadjuvant CbD plus 
Pembrolizumab. 
Primary Endpoint Timeframe 
Time of definitive breast surgery. 
Primary Endpoint Measure(s):  
Percentage of participants with pathological response in breast and axilla, as evidenced by absence of 
invasive disease in breast and axillary lymph nodes (ypT0/Tis ypN0) determined by histopathological 
examination. 
 
7.2.2 Secondary Endpoint(s) 
1. Rates of minimal residual disease (MRD) after neoadjuvant CbD plus Pembrolizumab. 
Secondary Endpoint Timeframe(s): 
Time of definitive surgery. 

 
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Secondary Endpoint Measure(s):  
Residual cancer burden (RCB) score of 0/1. Residual cancer burden score for each patient is 
calculated using surgical pathology parameters using an online tool 
(http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3). 
 
2. 3-year recurrence-free survival (RFS)  
Secondary Endpoint Timeframe(s): 
Recurrence-free survival (RFS) is defined as the time from diagnosis to first recurrence (invasive 
ipsilateral breast, invasive local/regional, or distant), or to death as a result of any cause 78. 
Secondary Endpoint Measure(s):  
Recurrence-free survival (RFS) as defined above. 
 
3. 3-year event-free survival (EFS) 
Secondary Endpoint Timeframe(s): 
Event-free survival (EFS) is defined as the time from diagnosis to first recurrence (invasive 
ipsilateral breast, invasive local/regional, or distant), to second non-breast primary malignancy 
of any type, or to death from breast cancer or death from study treatment-related toxicity. 
Secondary Endpoint Measure(s): 
Event-free survival (EFS) as defined above. 
 
4. Toxicity 
Secondary Endpoint Timeframe(s): 
Start of study treatment (cycle 1 day 1) until 30 days after last dose of study treatment. 
Secondary Endpoint Measure(s): 
Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events 
(CTCAE), version 4.03. 
 
 
7.2.3 Exploratory Endpoint(s) 
 
1. To evaluate markers of DNA repair deficiency and/or tumor genomic instability as biomarkers of 
pathological response to treatment . 
2. To evaluate immune therapy response markers (e.g. PD-L1 expression, gene expression 
signatures) as biomarkers of pathological response to treatment. 
3.    To evaluate overall survival (defined as time from diagnosis to death as a result of any cause) 
with a neoadjuvant chemotherapy regimen of CbD plus Pembrolizumab in patients with stage I-
III TNBC. 
 
8 
STUDY ENROLLMENT AND WITHDRAWAL 
 
8.1 
Participant Inclusion Criteria 
Participants must meet all of the inclusion criteria listed below to participate in this study. 
 

 
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1. Ability of participant to understand this study, and participant willingness to sign a written 
informed consent for this trial. 
2. Female subjects age 18-70 years. 
3. Histologically confirmed stage I (T>1cm or cN+), II or III TNBC. 
a. The invasive tumor must be hormone receptor-poor, defined as both estrogen receptor 
(ER) and progesterone receptor (PR) staining present in ≤10% of invasive cancer cells by 
IHC. 
b. HER2 negativity will be based on current ASCO-CAP guidelines for HER2 testing 79. 
4. No previous definitive ipsilateral breast surgery for the current breast cancer. 
5. No previous chemotherapy, endocrine therapy, or radiation therapy with therapeutic intent 
for this cancer. 
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 
A) 80. Evaluation of performance status is to be performed within 10 days prior to the start of 
study treatment. 
7. Have adequate organ function as defined below: 
a. Hematological: 
i. Absolute neutrophil count ≥ 1,500/uL 
ii. Platelets ≥ 100,000/uL 
iii. Leukocytes ≥ 3,000/uL 
iv. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (criteria must be met without 
erythropoietin dependency and without packed red blood cell transfusion 
within last 2 weeks) 
b. Renal: 
i. Creatinine ≤ 1.5 mg/dL and/or creatinine clearance ≥ 60 mL/min 
c. Hepatic: 
i. Total bilirubin ≤ 1.5x IULN, OR direct bilirubin ≤ IULN for participants with total 
bilirubin levels > 1.5x IULN 
ii. AST(SGOT) and ALT(SPGT) ≤ 2x IULN 
d. Coagulation: 
i. International normalized ratio (INR) of coagulation OR prothrombin time (PT) 
OR activated partial thromboplastin time (aPTT) ≤ 1.5x IULN, unless patient is 
receiving anticoagulant therapy. If patient is receiving anticoagulant therapy, PT 
or aPTT is within therapeutic range of intended use of anticoagulants. 
e. Serum albumin ≥ 3.0 g/dL 
8. Pretreatment lab values must be performed within 10 days of treatment initiation, and other 
baseline studies performed within 30 days prior to registration. 
9. Subjects should have breast and axillary imaging with breast MRI (preferred) or breast and 
axillary ultrasound within 30 days prior to treatment initiation. 
10. Subjects with clinically/radiologically abnormal axillary lymph nodes should have pathological 
confirmation of the disease with image-guided biopsy/fine needle aspiration. 
11. Subjects must already be enrolled in P.R.O.G.E.C.T. observational registry (HSC #12614). This 
inclusion criteria is only applicable to patients enrolling at University of Kansas Cancer Center 
and its affiliates. 

 
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12. Have provided archival breast tumor tissue sample, which should include a formalin-fixed 
paraffin-embedded (FFPE) block or 12 unstained slides (ten 5-micron uncharged slides and 
two 5-micron charged slides) from primary breast tumor and/or axillary lymph node. If 
adequate archival breast tumor specimen is not available, a newly obtained core biopsy of 
breast tumor should be performed for submission of tumor specimen (details are provided in 
section 12.1).  
13. Staging to rule out metastatic disease is suggested for subjects with clinical stage III disease. 
14. Subjects with bilateral disease are eligible if they meet other eligibility criteria. 
15. Neuropathy: no baseline neuropathy grade >2. 
16. Cardiac function: 
a. Subjects should have LVEF ≥ 50% by echocardiogram or MUGA scan performed within 
30 days prior to treatment initiation. 
b. Subjects with congestive heart failure are not eligible, nor are subjects with myocardial 
infarction, unstable angina pectoris, an arterial thrombotic event, stroke or transient 
ischemia attack within the past 12 months, uncontrolled hypertension (systolic BP > 160 
or diastolic BP > 90), uncontrolled or symptomatic arrhythmia, or grade 2 or greater 
peripheral vascular disease. 
17. A female participant is eligible to participate if she is not pregnant (see Appendix B, 
Contraceptive Guidance and Pregnancy Testing), not breastfeeding, and at least one of the 
following conditions applies: 
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix B, OR 
b. A WOCBP who agrees to follow the contraceptive guidelines in Appendix B during the 
treatment period and for at least 120 days after the last dose of study treatment. Should 
a woman become pregnant or suspect she is pregnant while participating in this study, 
she should inform her treated physician immediately (see section 16.2.5, Reporting of 
Pregnancy and Lactation). 
 
8.2 
Participant Exclusion Criteria 
 
Participants meeting any of the exclusion criteria listed below at screening will be excluded from study 
participation. 
 
1. Current or anticipated use of other investigational agents while participating in this study. 
2. Subject has received chemotherapy, radiotherapy, or surgery for the treatment of breast cancer. 
3. Subject has metastatic disease. 
4. Subject has inflammatory breast cancer. 
5. Subjects with concomitant or previous malignancies within the last 5 years are excluded from 
the study.  
a. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (e.g. ductal carcinoma in situ (DCIS), carcinoma in situ of the 
cervix) that have undergone potential curative therapy are not excluded. 
6. History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to carboplatin, docetaxel, or other agents used in this study. 

 
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7. Has severe hypersensitivity (≥ grade 3) to Pembrolizumab or any of its excipients. 
8. Subject has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, 
CD137). 
9. If participant received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting study treatment. 
10. Subject has received a live vaccine within 30 days prior to the first dose of study drug. Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and 
are not allowed. 
11. Subject is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study treatment. 
12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of Pembrolizumab. 
13. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy 
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
14. Has a history of (non-infectious) pneumonitis that required steroids, or has current pneumonitis. 
15. Has an active infection requiring systemic therapy. 
16. Has a known history of Human Immunodeficiency Virus (HIV). 
17. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or 
known active Hepatitis C virus (defined as detectable HCV RNA) infection. Note: no testing for 
Hepatitis B and Hepatitis C is required unless mandated by local health authority. 
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the full 
duration of the study, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.  
19. Subject has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
20. Subject is pregnant or breast feeding, or expecting to conceive within the projected duration of 
the study, starting with the screening visit through 120 days after the last dose of trial 
treatment. There is a potential for congenital abnormalities and for this regimen to harm 
breastfeeding infants (if applicable). 
21. Subject is a WOCBP who has had a positive urine pregnancy test within 24 hours prior to 
initiation of study treatment (see Appendix B, Contraceptive Guidance and Pregnancy Testing, 
for definition of WOCBP). If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 

 
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a. Note: In the event that 24 hours have elapsed between the screening pregnancy test 
and the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for subject to start receiving study medication. 
22. Ejection fraction < 50% on ECHO or MUGA. 
 
 
8.3 
 Participant Withdrawal Or Termination 
 
8.3.1 Reasons For Withdrawal Or Termination 
 
Participants may discontinue study treatment at any time for any reason or be dropped from the study 
treatment at the discretion of the investigator should any untoward effect occur. In addition, a 
participant may be discontinued from study treatment by the investigator or the Sponsor if study 
treatment is inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
A participant must be discontinued from study treatment but continue to be monitored in the study for 
any of the following reasons: 
• 
Participant or participant’s legally acceptable representative requests to discontinue 
study treatment;  
• 
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment; 
• 
Unacceptable adverse experiences; 
• 
Medical condition or personal circumstance which, in the opinion of the investigator 
and/or sponsor, places the participant at unnecessary risk from continued 
administration of study treatment; 
• 
Confirmed positive serum pregnancy test (pregnancy to be reported along the same 
timelines as a serious adverse event; see Section 16.2.5, Reporting of Pregnancy); 
• 
Recurrent grade 2 pneumonitis 
• 
Noncompliance with study treatment or procedure requirements; 
• 
Treating physician judges continuation on the study would not be in the participant’s 
best interest; 
• 
Administrative reasons; 
• 
Lost to follow-up 
 
A participant must be discontinued from study treatment and further monitoring in the study for the 
following reason (no further data collection will be done): 
• 
Participant withdraws consent. 
 
 
8.3.2 Participant Replacement 
Participants who do not complete the study treatment due to toxicity or other reasons will not be 
replaced. 
 
9 
MEASUREMENT OF EFFECT  
 
9.1 
Solid Tumor 
 

 
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9.1.1 Antitumor Effect 
 
Definitions 
Evaluable for toxicity: Any eligible participant who receives treatment on this protocol will be evaluable 
for toxicity. Each subject will be assessed for the development of toxicity according to the Schedule of 
Events table (Table 6). Toxicity will be assessed according to the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE), version 4.03 81. Dose modifications for chemotherapy in event of toxicity (see 
Section 11.1.4, Dose Adjustments/Modifications/Delays) are applicable only if the toxicity is deemed 
“treatment-related.” This is in accordance with standard clinical practice. Dose adjustments should be 
made according to the system showing the greatest degree of toxicity. 
 
Response Criteria 
Pathological complete response (pCR): Absence of invasive disease in breast and axillary lymph nodes at 
the time of pathology review, with the exception of ductal carcinoma in situ (DCIS) in breast (ypT0/Tis 
ypN0). 
Residual cancer burden (RCB) 0/1: Residual cancer burden (RCB) score is used to determine minimal 
residual disease (MRD). RCB will be calculated by study personnel utilizing surgical pathology 
parameters using a free online tool (http://www3.mdanderson.org/app/medcalc/index.cfm?pagename 
=jsconvert3) 
 
Recurrence-Free Survival 
Recurrence-free survival (RFS), is defined as the time from diagnosis to first recurrence (invasive 
ipsilateral breast, invasive local, /regional, or distant), or to death as a result of any cause 78. Recurrence 
will be determined by the treating physician using clinical, radiological, and/or pathological methods. 
Participants who are lost to follow-up will be censored on the date they were last known to be alive and 
without recurrence. Patients who withdraw consent will be censored on the date of consent withdrawal. 
 
Event-Free Survival 
Event-free survival (EFS) is defined as the time from diagnosis to first recurrence (invasive ipsilateral 
breast, invasive local/regional, or distant), to second non-breast primary malignancy, or to death from 
breast cancer or death from study treatment-related toxicity. Recurrence will be determined by the 
treating physician using clinical, radiological, and/or pathological methods. Participants who are lost to 
follow-up will be censored on the date they were last known to be alive and without recurrence or 
second primary malignancy. Patients who withdraw consent will be censored on the date of consent 
withdrawal. 
 
10 STUDY AGENT  
10.1 Study Agent(s) / Therapy / Device And “Control” Description 
 
10.1.1 Acquisition / How Supplied 
 
Carboplatin, docetaxel, and pegfilgrastim (or its biosimilar equivalent) are commercially available.  
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
 

 
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The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
 
 
 
 
 
 
 
 
 
10.1.2 Formulation, Appearance, and Packaging 
10.1.2.1 Carboplatin 
 
Other names for the drug(s): Paraplatin 
 
Classification - type of agent: Alkylating agent/platinum coordination compound 
 
Mode of action: Covalently binds to DNA, producing cross-links which lead to inhibition of DNA 
synthesis. 
 
Preparation: Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin. Carboplatin 
injection, 10 mg/mL, can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in 
Water or 0.9% Sodium Chloride Injection (NS), USP.  
 
Storage and Stability: Unopened vials of carboplatin injection, 10 mg/mL, are stable to the date indicated 
on the package when stored at 25°C (77°F), excursions permitted from 15°C-30°C (59°F - 86°F) [see USP 
Controlled Room Temperature]. Protect from light. When prepared as directed, carboplatin aqueous 
solutions are stable for 8 hours at room temperature (25°C). Since no antibacterial preservative is 
contained in the formulation, it is recommended that carboplatin aqueous solutions be discarded 8 
hours after dilution. 
 
Nursing implications: Incompatible with amphotericin B cholesteryl sulfate complex. Use appropriate 
precautions for handling and disposal (hazardous). 
10.1.2.2 Docetaxel 
 
Other names for the drug(s): Taxotere 
 
Classification - type of agent: Anti-microtubule agent 
 
Mode of action: Induces apoptosis via bcl-2 phosphorylation, binds to tubulin and inhibits microtubule 
depolymerization, has antiangiogenic properties. 
 
Preparation: Docetaxel for injection concentrate is diluted to 10 mg/mL in 13% ethanol in water for 
injection. The initial diluted solution may be used immediately or stored either in the refrigerator or at 
room temperature for a maximum of 8 hours. This initial dilution (10 mg/mL) is further diluted into 250 
mL of 0.9% sodium chloride or 5% dextrose solution to produce a final concentration of 0.3 to 0.74 

 
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mg/mL. If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion 
vehicle so that a concentration of 0.74 mg/mL is not exceeded. 
 
Storage and Stability: The initial diluted solution (10 mg/mL) may be stored either in the refrigerator or at 
room temperature for a maximum of 8 hours. Final infusion solution, if stored between 2° and 25°C (36°F 
- 77°F) is stable for 4 hours; fully prepared infusion solution (in either 0.9% sodium chloride solution or 5% 
dextrose solution) should be used within 4 hours (including the 1 hour IV administration).  
 
Nursing implications: Incompatible with amphotericin B, doxorubicin liposome, methylprednisolone 
sodium succinate, nalbuphine; compatibility with ceftriaxone is variable (consult detailed reference). 
Administer anti-emetics, advise regarding alopecia, monitor for hypersensitivity reactions, evaluate LFTs, 
evaluate for sites of infiltration, peripheral neuropathy, and monitor for fluid retention. 
10.1.2.3 Pembrolizumab 
 
Other names for the drug(s): 
Keytruda 
 
Classification - type of agent: PD-1 humanized monoclonal antibody 
 
Mode of action: Blocks PD-1 activation to reverse checkpoint inhibition of endogenous immune reaction 
 
Formulation: 
 
 
 
 
 
 
 
 
 
 
Appearance and Packaging: T
 
 
 
 
 
Preparation: 
 
 
 
 
 
 
 
Storage and Stability: 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
Nursing implications: 
 
 
 
 
10.1.3 Agent Known Potential Side Effects 
10.1.3.1 Carboplatin 
• 
Alopecia 
• 
Hypomagnesemia, hypokalemia, hyponatremia, hypocalcemia 
• 
Nausea, vomiting, stomatitis 
• 
Myelosuppression (dose-related and dose-limiting); thrombocytopenia (37% to 80%); 
leukopenia (27% to 38%) 
• 
Increase in alkaline phosphatase and AST (usually mild and reversible) 
• 
Hearing loss at high tones 
• 
BUN and/or creatinine increase 
• 
Peripheral neuropathy 
10.1.3.2 Docetaxel 
• 
Neutropenia is the dose-limiting hematologic toxicity 
• 
During organogenesis, docetaxel is embryotoxic and fetotoxic 
• 
Fluid retention, possibly severe; requires appropriate steroid pre-medication 
• 
Hypersensitivity reactions can occur within minutes following administration and subjects should 
be appropriately pre-medicated 
• 
Neurotoxicity (paresthesias, dysethesias, pain) 
• 
Alopecia 
• 
Nausea/vomiting/diarrhea 
• 
Transaminase or bilirubin elevation 
10.1.3.3 Pembrolizumab 
• 
Fatigue, headache, dizziness 
• 
Cough, dyspnea 
• 
Diarrhea, abdominal pain 
• 
Pruritis, rash, vitiligo, skin peeling 
• 
Arthralgia, myalgia, back pain 
• 
Hypothyroidism, hyperthyroidism 
• 
Pyrexia 
• 
Pneumonitis 
• 
Infusion reactions 
• 
Gastrointestinal inflammation/colitis 

 
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• 
Neuritis, neuropathy 
• 
Myositis 
• 
Pancreatitis 
• 
Uveitis 
• 
Hepatitis 
• 
Hypophysitis 
• 
Renitis 
• 
Endocarditis 
• 
Thyroiditis 
• 
Adrenal insufficiency 
• 
Type 1 diabetes mellitus 
• 
Granulomatosis 
• 
Graft versus host disease 
• 
Hyponatremia 
• 
Arthritis 
 
10.1.4 Concomitant, Precautionary, Prohibited Medications, Foods And Treatments 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial. If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy may be required. The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the participant’s 
primary physician. 
Patients should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea, or vomiting. 
10.1.4.1 Acceptable concomitant medications 
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. 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 days 
after the last dose of trial treatment should be recorded. Concomitant medications administered after 
30 days after the last dose of trial treatment should be recorded for SAEs and ECIs. 
All treatments that the investigator considers necessary for a participant’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  
 
Antiemetics 
Use of antiemetics is allowed. 
 
Fertility preservation 
Use of goserelin for fertility preservation is allowed. 
 
Anticoagulants 
Anticoagulants or other anti-aggregation agents may be administered at the discretion of the 
investigator. Subjects on anticoagulation with warfarin should be carefully monitored and have PT/INR 
checked every week. 

 
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Contraceptives 
Highly effective contraception should be maintained throughout the study and for 120 days after study 
drug discontinuation. Hormone contraceptives are not allowed for this study. Allowed contraceptive 
methods are described in Appendix B, Contraceptive Guidance and Pregnancy Testing. 
10.1.4.2 Prohibited concomitant medications and treatments 
Participants are prohibited from receiving the following therapies during the Screening and Treatment 
phase of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol 
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than Pembrolizumab 
• 
Radiation therapy 
• 
Live vaccines within 30 days prior to the first dose of study treatment and while participating in the 
study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.  
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology or for use as a pre-medication for 
chemotherapeutic agents. 
Note: Inhaled steroids are allowed for management of asthma. 
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to IV contrast dye) is 
permitted. 
Additionally, use of erythropoietin-stimulating agents is not allowed. 
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. All treatments that the 
Investigator considers necessary for a participant’s welfare may be administered at the discretion of the 
Investigator in keeping with the community standards of medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study.  If there is a clinical indication for any medication or vaccination specifically prohibited 
during the study, discontinuation from study therapy or vaccination may be required. The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the participant's primary 
physician.  However, the decision to continue the participant on study treatment requires the mutual 
agreement of the investigator, the Sponsor and the participant. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
10.1.4.3 Rescue medications and supportive care 
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined along with the dose modification guidelines in Section 11.1.4.3.1, 
[Table 4]. Where appropriate, these guidelines include the use of oral or IV treatment with 

 
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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 11.1.4, Dose 
Adjustments/Modifications/Delays 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.  
 
10.1.5 Return And Retention Of Study Agent 
 
Study drug will be obtained from commercial supply and handled according to institutional drug 
handling procedures. Upon completion or termination of the study, all unused and/or partially used 
Pembrolizumab will be destroyed at the site per institutional policy. 
 
11 TREATMENT PLAN 
Neoadjuvant chemotherapy  
Neoadjuvant chemotherapy will consist of carboplatin, docetaxel, Pembrolizumab, and supporting 
medications, and will be given for 6 cycles of 21 days each. Following neoadjuvant chemotherapy, 
participants will undergo definitive breast surgery. Adjuvant chemotherapy and radiation therapy will be 
administered at the discretion of the treating physician.  
In general chemotherapy pre-medications and at-home supportive medications to prevent anticipated 
side effects are to follow institutional guidelines. Appendix D describes the suggested pre-medication 
use during treatment.  
Table 3: Study drug treatment summary 
Agent 
Dose 
Route 
Schedule Cycle Length  
Carboplatina 
AUC 6 
IV over 30 min  
Day 1 
21 daysb x 6 
 
Docetaxel 
75 mg/m2  
IV over 60 min 
Day 1 
Pembrolizumab 
200 mg 
IV over 30 min 
Day 1 
Pegfilgrastim (or 
its 
biosimilar 
equivalent) 
6 mg 
SC 
Day 2 
a The SWOG (Southwest Oncology Group) guidelines must be followed for carboplatin dose calculation: 1) Use of 
Modified Cockcroft-Gault formula for calculating renal function, 2) Calculating Modified Cockcroft-Gault with 
serum creatinine set to 0.8 mg/dL if actual serum creatinine < 0.8 mg/dL, 3) Maximum GFR is 125 mL/min, 4) 
Limiting weight to 140% of ideal body weight for calculation of creatinine clearance, 5) Maximum carboplatin 
dose to be given is 900 mg. 
b +/- one day 

 
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Growth factor support: Erythropoietin growth factor support for fatigue/anemia is not allowed. Packed 
RBC transfusion is allowed at the discretion of the treating physician. Pegfilgrastim (or its biosimilar 
equivalent) growth factor support as described above is included in the treatment plan. 
Surgery 
After completion of neoadjuvant therapy, subjects will proceed with definitive surgery (appropriate 
surgery type to be determined by surgeon). Surgery should take place between 3-10 weeks after the last 
chemotherapy cycle.  
All subjects with pretreatment lymph node positive disease and positive sentinel lymph node will 
undergo complete axillary lymph node dissection and/or axillary radiation. Histopathological 
examination of the surgical specimen will be done to determine the extent of residual disease.  
Pathological complete response (pCR) will be defined as no evidence of disease in the breast and axilla 
at the time of pathology review, except for DCIS. 
Adjuvant therapy 
Adjuvant chemotherapy: as per recommendations of treating physician. 
Adjuvant radiation therapy: As per recommendations of the treating physician. In general adjuvant 
radiation is recommended for patients who undergo breast-conserving surgery, have tumors > 5 cm, 
have skin or chest wall involvement, or have pathologically positive lymph node(s) after neoadjuvant 
chemotherapy. 
Duration of follow-up  
After completion of all local and systemic treatment for breast cancer (surgery, chemotherapy, or 
radiation, whichever comes last), all subjects will be followed approximately every 6 months until 3 
years post-diagnosis. Information to be collected includes but is not limited to new anti-cancer therapy, 
disease progression, and death. 
11.1 Dosing And Administration 
 
11.1.1 Administration 
Trial treatment will be administered on the given cycle day(s) after all procedures/assessments have 
been completed as detailed on the Trial Flow Chart (Table 6). All trial treatments will be administered on 
outpatient basis. 
 
Carboplatin 
Carboplatin AUC 6 will be given on day 1 of each cycle of 21 days (±1 day), for 6 cycles. The SWOG 
(Southwest Oncology Group) guidelines must be followed for carboplatin dose calculation, below. 
Dosing calculations should be based on actual body weight, with the exception of point #4 below. 
1) Use of Modified Cockcroft-Gault formula for calculating renal function 
2) Calculating Modified Cockcroft-Gault with serum creatinine set to 0.8 mg/dL if actual serum 
creatinine < 0.8 mg/dL  
3) Maximum GFR is 125 mL/min 
4) Limiting weight to 140% of ideal body weight for calculation of creatinine clearance 
5) Maximum carboplatin dose to be given is 900 mg.  

 
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Carboplatin will be administered as a 30-minute (± 5 minutes) IV infusion, using a volumetric pump with 
a 0.2-1.2 um in-line filter at the protocol-specified dose. It is not to be administered as an IV push or 
bolus injection. At the end of the infusion, flush the line with a sufficient quantity of normal saline. 
Other considerations: Dose rounding per institutional guidelines. Pre-medications per institutional 
guidelines. 
 
Docetaxel 
Docetaxel 75 mg/m2 will be given on day 1 of each cycle of 21 days (±1 day), for 6 cycles. Dosing 
calculations should be based on actual body weight. If the participant’s body weight differs more than 
10% from the weight used to calculate the dose of docetaxel, the dose will be recalculated using current 
body weight. 
Docetaxel will be administered as a 60-minute (± 10 minutes) IV infusion, using a volumetric pump with 
a 0.2-1.2 um in-line filter at the protocol-specified dose. It is not to be administered as an IV push or 
bolus injection. At the end of the infusion, flush the line with a sufficient quantity of normal saline. 
Other considerations: Dose rounding per institutional guidelines. Pre-medications per institutional 
guidelines. 
 
Pembrolizumab 
Pembrolizumab 200 mg will be given on day 1 of each cycle of 21 days (±1 day), for 6 cycles.  
Pembrolizumab will be administered as a 30-minute IV infusion, using a volumetric pump with a 0.2-1.2 
um in-line filter at the protocol-specified dose. Every effort will be made to target infusion timing to be 
as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a 
window a -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). It 
is not to be administered as an IV push or bolus injection. At the end of the infusion, flush the line with a 
sufficient quantity of normal saline. 
 
Pegfilgrastim (or its biosimilar equivalent) 
Pegfilgrastim (or its biosimilar equivalent) 6 mg will be given on day 2 of each cycle of 21 days, for 6 
cycles.  
Pegfilgrastim (or its biosimilar equivalent)will be administered subcutaneously at the protocol-specified 
dose.  
 
11.1.2 Duration Of Therapy 
 
In the absence of treatment delays due to adverse events, all subjects will receive 6 cycles of 
neoadjuvant chemotherapy with carboplatin, docetaxel, and Pembrolizumab given every 21 days. The 
total duration of this treatment should not exceed 22 weeks.  
 
Treatment may be stopped at any time during the schedule if any of the following occur: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Death 
• 
Subject’s decision to withdraw from the study 
• 
General or specific changes in the subject’s condition which render the subject unacceptable for 
further treatment in the judgment of the investigator. 

 
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ANCa < 1000/uL (day 1 of cycle) 
Delay docetaxel and carboplatin until ANC 
≥1,000/uL. If counts recover to ≥ 1,000/uL in ≤ 1 
week, resume at current dose. 
 
If docetaxel and carboplatin are delayed for 2 
consecutive weeks for ANC < 1000/uL, reduce 
docetaxel and carboplatin by one dose level for 
all subsequent cycles.  
 
If docetaxel and carboplatin are delayed for 3 
consecutive weeks for ANC < 1000/uL, 
discontinue docetaxel and carboplatin. 
ANC < 100/uL or febrile neutropeniaa 
(at any time) 
Reduce docetaxel and carboplatin by one dose 
level for all subsequent cycles. 
Platelets < 50,000/uL (day 1 of cycle) 
Hold docetaxel and carboplatin until platelets ≥ 
75,000/uL, then resume docetaxel and 
carboplatin with one dose level reduction for 
both drugs for all subsequent doses. 
 
If docetaxel and carboplatin are held for 3 
consecutive weeks for platelets < 75,000/uL, 
discontinue treatment.   
Platelets ≥ 50,000/uL and < 75,000/uL 
(day 1 of cycle) 
Hold both docetaxel and carboplatin until 
platelets ≥ 75,000/uL and resume docetaxel at 
previous dose and carboplatin with one dose 
level reduction for all subsequent doses.  
 
If docetaxel and carboplatin are held for 3 
consecutive weeks for platelets < 75,000/uL, 
discontinue treatment.   
a There will be no dose modifications for grade 1-4 anemia. If the ANC is < 1,000/uL or platelet count is 
< 50,000/uL when drawn more than 24 h prior to the scheduled treatment, CBC should be re-checked 
on the day of treatment to see if the blood counts have recovered sufficiently to allow the schedule 
treatment to be given. 
b Febrile neutropenia: a single temperature ≥ 38.3°C or a sustained temperature of ≥ 38°C for more than 
an hour in presence of ANC < 1,000/uL. 
If carboplatin and docetaxel are delayed for > 4 weeks for any reason, discontinue study 
treatment.  
 
11.1.4.1.2 Non-hematologic toxicities 

 
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Peripheral neuropathy 
Grade 1: Continue treatment  
Grade 2: Decrease the dose of docetaxel by one dose 
level for all subsequent doses. The dose of carboplatin is 
not reduced. 
Grade 3: Hold docetaxel and carboplatin. When 
neuropathy improves to ≤ grade 2, resume treatment 
with one dose level reduction of both docetaxel and 
carboplatin. 
If grade 3 peripheral neuropathy does not improve within 
3 weeks, discontinue docetaxel and carboplatin. 
For grade 3 neuropathy that has recurred after recovery 
to ≤ grade 2, discontinue docetaxel and carboplatin. 
Grade 4: Discontinue docetaxel and carboplatin  
Hypersensitivity reactions 
See below for management. 
Fluid retention 
There are no dose reductions for fluid retention (see 
below for management). 
Hepatic dysfunction  
(day 1 LFTs) 
See below for dose reductions chart. Patients with total 
bilirubin > 1.5x IULN should not receive docetaxel.  
Patients with AST and/or ALT > 1.5x IULN concomitant 
with alkaline phosphatase > 2.5x IULN should not receive 
docetaxel. 
Other non-hematologic 
toxicities 
For any other grade 3 or 4 toxicity (with the exception of 
fatigue, nausea or vomiting), delay docetaxel and 
carboplatin until toxicity improves to ≤ grade 2. When 
treatment is resumed, reduce the doses of docetaxel and 
carboplatin by one dose level.  
If toxicity does not improve to ≤ grade 2 within 3 weeks, 
discontinue docetaxel and carboplatin and proceed to 
surgery when feasible. 
If carboplatin and docetaxel are delayed for > 4 weeks for any reason, discontinue study 
treatment. 
11.1.4.1.3 Hypersensitivity reactions: 
During docetaxel infusion 
Grade 1: Continue docetaxel infusion. Consider decreasing the rate of infusion. Consider more intensive 
pre-medication prior to subsequent doses. 
Grade 2: Interrupt docetaxel infusion. Manage reaction according to institutional procedures. Resume 
docetaxel when reaction has completely resolved. Consider more intensive pre-medication 
prior to subsequent doses. 
Grade 3: Stop docetaxel infusion. Manage reaction according to institutional procedures. Do not resume 
docetaxel infusion that day and delay carboplatin dose that was to be administered that day. It 
is up to the treating physician to decide whether to attempt re-treatment with docetaxel the 
following cycle with more intensive pre-medication or to discontinue docetaxel. 

 
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Grade 4: Stop docetaxel infusion. Manage reaction according to institutional procedures. Discontinue 
docetaxel. Carboplatin and Pembrolizumab can be continued per the discretion of the treating 
physician.   
 
During carboplatin infusion  
Grade 1 or 2: Stop carboplatin infusion. Manage reaction according to institutional procedures. Do not 
resume carboplatin infusion that day. It is up to the treating physician to decide whether to 
re-attempt carboplatin infusion with next cycle (with or without desensitization) or to 
discontinue carboplatin and continue treatment with docetaxel only. 
Grade 3 or 4: Stop carboplatin infusion. Manage reaction according to institutional procedures. 
Discontinue carboplatin. Docetaxel and Pembrolizumab can be continued per the 
discretion of the treating physician. 
 
11.1.4.1.4 Management of edema/fluid retention related to docetaxel: 
No dose reduction is required. Subjects developing new onset edema, progression of existing edema, or 
another sign of fluid retention (e.g. pound weight gain) can be treated with oral diuretics. Regimens 
found to be effective in the management of fluid retention due to docetaxel are listed below: 
• 
Hydrochlorothiazide/Triamterene one capsule 25/37.5 mg PO up to three times per day per the 
discretion of the treating physician   
• 
Furosemide 40 mg PO daily if edema progresses despite hydrochlorothiazide/triamterene therapy. 
Potassium supplementation should be given as needed. 
• 
If after a two week trial, furosemide 40 mg PO daily is ineffective, the patient may be treated with 
furosemide 20 mg PO daily plus metolazone 2.5 mg PO daily, with potassium supplementation as 
needed. 
Further therapy should be customized depending upon the clinical situation. The clinical tolerance of the 
subject, the overall tumor response, and the medical judgment of the investigator will determine if it is 
in the subject’s best interest to continue or discontinue treatment. 
11.1.4.1.5 Hepatic dysfunction 
Dose modifications are based on day 1 liver function tests: 
Liver Function Tests 
Dose Modification 
Total bilirubin > 1.5x IULN concomitant with 
alkaline phosphatase > 2.5x IULN 
Do NOT administer docetaxel.  If not 
resolved in one week, subject should be 
removed from protocol treatment. 
AST/ALT >2.5x IULN but ≤ 5x IULN 
AND 
Alkaline phosphatase > IULN but ≤ 2.5x IULN 
Docetaxel dose reduced by 20%. 
AST/ALT >1.5x IULN and ≤ 5x IULN 
AND 
Alkaline phosphatase > 2.5x IULN but ≤5x IULN 
Docetaxel dose reduced by 20%. 

 
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11.1.5 Concomitant, Precautionary, Prohibited Medications, Foods And Treatments 
 
See Section 10.1.4, “Concomitant, Precautionary, Prohibited Medications, Foods And Treatments” for a 
list and discussion of acceptable and unpermitted medications. 
Patients should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea, or vomiting. 
 
12 STUDY PROCEDURES AND SCHEDULE 
 
12.1 DESCRIPTIVE SCHEDULE OF EVENTS 

 
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12.1.1 Screening/Enrollment/Baseline 
 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. If the tests required at screening were performed as part of standard of 
care prior to signing consent for this study, the results from those tests are allowed in this study if the 
tests were completed within the timeframe listed below. 
 
All screening procedures must be performed within 30 days prior to registration unless otherwise 
stated.  
 
SCREENING  
 
Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’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 will be given to 
the participant before participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the participant must receive the IRB’s approval/favorable opinion in 
advance of use.  The participant or his/her legally acceptable representative will be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the trial.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures the 
participant’s dated signature or by the participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and Sponsor 
requirements. 
Medical history 
Complete medical, surgical and oncology history, as well as history of infections, are obtained at 
screening. Medical history will include all active conditions, and any conditions diagnosed within the 
prior 10 years that are considered to be clinically significant by the investigator. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and not listed as 
medical history. Any changes from Screening (e.g. worsening severity or abnormal findings) are 
considered to be adverse events (AEs). 
Disease details and treatments 
Prior and current details regarding disease status will be collected.  
Demographics 
Demographic profile will include date of birth, gender, race, ethnicity, and zip code. 
Review participant eligibility criteria 
Review of eligibility criteria to ensure participant qualification for study entry. 
Previous and concomitant medications (performed within 10 days prior to start of study treatment) 
All prior medications taken by the participant within 4 weeks before starting the study are to be 
recorded. Treatment for the disease for which the participant has enrolled in this study will be recorded 
separately and not listed as a prior medication. 

 
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If changes occur during the trial period, documentation of drug dosage, frequency, route, and date may 
also be included on the CRF. Concomitant medications (including prescription, over-the-counter (OTC), 
herbal supplements, and IV medications and fluids) taken by the participant during the study are to be 
recorded up until 30-days after last study dose. If a reportable adverse event (see section with title 
Adverse Events) occurs within 30-days after last study dose, recording of concomitant medications 
should continue until resolution of the adverse event. 
Physical exam (performed within 10 days prior to start of study treatment) 
Exam will include vital signs, height (to be measured at screening/baseline only), and assessment of all 
major body systems. 
Note: Vital signs include temperature, pulse, respiration rate, blood pressure, and weight. 
Performance status (evaluated within 10 days prior to start of study treatment) 
Performance status based on ECOG criteria (Zubrod scale) will be evaluated prior to study entry. Specific 
criteria for assessing performance status can be found in Appendix A. 
Hematology (collected within 10 days prior to start of study treatment) 
Hematology testing will include hemoglobin, hematocrit, platelets, red blood cells, leukocyte total and 
differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils), absolute neutrophil count, 
and absolute lymphocyte count. 
Serum chemistries (collected within 10 days prior to start of study treatment) 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, 
lactate dehydrogenase (LDH), BUN, uric acid, creatinine or GFR (creatinine clearance to be evaluated if 
creatinine >1.5x IULN), electrolytes (sodium, potassium, phosphorus, magnesium, calcium, chloride, 
bicarbonate), glucose, total bilirubin (direct bilirubin to be evaluated if total bilirubin is elevated > 1.5x 
IULN), and total protein. 
Additional laboratory tests (collected within 30 days prior to start of study treatment) 
International normalized ratio (INR) of coagulation OR prothrombin time (PT) OR activated partial 
thromboplastin time (aPTT), total thriiodothyronine (T3), free tyroxine (T4), thyroid stimulating hormone 
(TSH), ACTH, and AM cortisol. 
Pregnancy test for WOCBP (performed within 24 h prior to start of study treatment) 
Urine pregnancy test to be performed for all participants who qualify as WOCBP (see Appendix B). If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test (β-human chorionic 
gonadotropin, β-hCG) will be required. 
Note: In the event that 24 hours have elapsed between the screening pregnancy test and the 
first dose of study treatment, another pregnancy test (urine or serum) must be performed and 
must be negative in order for subject to start receiving study medication. 
Tumor assessment 
All patients must have breast and axillary ultrasound or breast MRI (preferred unless MRI is 
contraindicated, e.g. presence of metal hardware in body, or if unable to be performed) within 30 days 
prior to treatment initiation, for accurate assessment of breast and axillary disease. Subjects with 
clinically or radiologically abnormal axillary lymph node(s) should have pathological documentation of 
the nodal involvement (fine needle aspiration or core needle biopsy). 
Cardiac function evaluation 
MUGA or echocardiogram will be performed for all patients within 30 days prior to treatment initiation. 
Primary tumor tissue submission 

 
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Formalin-fixed paraffin-embedded (FFPE) block or 12 unstained slides (ten 5-micron uncharged slides 
and two 5-micron charged slides) from primary breast tumor and/or axillary lymph node will be 
collected for all patients prior to start of study treatment.   
 
If adequate archival breast tumor specimen is not available, a newly obtained image-guided core biopsy 
of breast tumor should be performed for submission of tumor specimen. The use of imaging to facilitate 
biopsies will be decided by members of the radiology team and may include ultrasound or MRI.  
Sites are requested to follow the below standard instructions for preparation of FFPE block: 
o Obtain four 16-gauge or 14-gauge core needle biopsy specimens. 
o Place the fresh tissue in formalin. Do not exceed 24 hours fixation time. 
o Fixed tissue must be paraffin embedded within 24 hours. 
o Cut one H&E (hematoxylin and Eosin) stained section from the representative paraffin-
embedded tissue block.  
o Fixed tissue block and the H&E slide should be sent for storage to BRCF (see section 13.4) 
 
12.1.2 Procedures During Treatment 
 
PRIOR TO EACH TREATMENT CYCLE #2-6: 
Concomitant medications (collected within 48 hours prior to each treatment cycle) 
Any new medications, discontinued medications, or dose alterations will be reviewed. 
History and physical exam (collected within 48 hours prior to each treatment cycle) 
History and physical exam will be performed as clinically indicated. Vital signs to be collected are 
temperature, pulse, respiratory rate, weight, and blood pressure. Toxicity evaluation will be included. 
Performance status (collected within 48 hours prior to cycle treatment) 
ECOG performance status will be evaluated prior to each treatment cycle. Specific criteria for assessing 
performance status can be found in Appendix A. 
Hematology (collected within 48 hours prior to each treatment cycle) 
Hematology testing will include hemoglobin, hematocrit, platelets, red blood cells, leukocyte total and 
differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils), absolute neutrophil count, 
and absolute lymphocyte count. 
Serum chemistries (collected within 48 hours prior to each treatment cycle) 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, 
lactate dehydrogenase, carbon dioxide, BUN, uric acid, creatinine or GFR (creatinine clearance to be 
evaluated if creatinine >1.5x IULN), electrolytes (sodium, potassium, phosphorus, magnesium, calcium, 
chloride, bicarbonate), glucose, total bilirubin (direct bilirubin to be evaluated if total bilirubin is 
elevated > 1.5x IULN), and total protein. 
Pregnancy test for WOCBP (performed within 24 h prior to cycle treatment) 
Urine pregnancy test to be performed for all participants who qualify as WOCBP (see Appendix B). If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test (β-human chorionic 
gonadotropin, β-hCG) will be required. 
Note: In the event that 24 hours have elapsed between the screening pregnancy test and the 
first dose of study treatment, another pregnancy test (urine or serum) must be performed and 
must be negative in order for subject to start receiving study medication. 
 
 
EACH TREATMENT CYCLE (every 21 ± 1 days) 

 
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Chemotherapy and growth factor support 
Carboplatin, docetaxel and Pembrolizumab on day 1 of each cycle. 
Pegfilgrastim (or its biosimilar equivalent) on day 2 (+ 2 days) of each cycle. 
 
 
CYCLE #4, DAY 1 
Additional laboratory tests 
Total thriiodothyronine (T3), free tyroxine (T4), and thyroid stimulating hormone (TSH) will be evaluated 
on Day 1 of cycle #4. 
 
 
PRIOR TO CYCLE #5: 
Tumor re-assessment (performed +/- 14 days prior to start of cycle #5) 
All patients must have a repeat breast and axillary ultrasound or breast MRI (preferred unless MRI is 
contraindicated, e.g. presence of metal hardware in body, or unable to be performed) prior to study 
treatment cycle #5, for preliminary assessment of response.  
 
 
AFTER CYCLE #6: 
Correlative blood specimen (collected 21 ±7 days after cycle #6) 
A blood specimen for correlative studies (see Section 13, Correlative Studies) will be drawn after the last 
cycle of chemotherapy and before surgery. Collection of this specimen is required for all participants 
who received at least one dose of study treatment. These blood draws do not need to be duplicated if 
already done under P.R.O.G.E.C.T. protocol. 
 
Safety follow-up visit (30 +21/-7 days after day 1 of cycle #6) 
Adverse events and concomitant medications will be reviewed at the mandatory safety follow-up visit. 
The safety follow-up visit should be conducted approximately 30 days after the last dose of 
Pembrolizumab or before the initiation of a new anti-cancer treatment, whichever comes first. All AEs 
that occur prior to the safety follow-up visit should be recorded. Participants with an AE of grade >1 will 
be followed until the resolution of the AE to grade 0-1 or until the beginning of a new anti-cancer 
therapy, whichever occurs first. SAEs that occur within 90 days of the end of Pembrolizumab treatment 
or before initiation of a new anti-cancer treatment should also be followed and recorded. 
Thyroid function laboratory tests (at safety follow-up visit, 30 +21/-7 days after day 1 of cycle #6) 
Total thriiodothyronine (T3), free tyroxine (T4), and thyroid stimulating hormone (TSH) will be evaluated 
at the safety follow-up visit. 
Pregnancy test for WOCBP (approximately 120 days after day 1 of cycle #6) 
Urine pregnancy test to be performed approximately 120 days after the last dose of Pembrolizumab for 
all participants who qualify as WOCBP (see Appendix B). If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test (β-human chorionic gonadotropin, β-hCG) will be 
required. 
Surgery (between 3 and 10 weeks after cycle #6) 
After completion of study treatment cycle #6, subjects will proceed to either mastectomy or 
lumpectomy. 
 
12.1.3 Post-Treatment Follow-Up Visit(s) 

 
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After completion of all local and systemic treatment for breast cancer (surgery, chemotherapy, or 
radiation, whichever comes last), all subjects will be followed approximately every 6 months until 3 
years post-diagnosis. Information to be collected includes but is not limited to new anti-cancer therapy, 
disease progression, and death. 
12.2 SCHEDULE OF EVENTS TABLE 
The Schedule of Events table below summarizes the trial procedures to be performed at each visit. 
Individual trial procedures are described in detail in Section 12.1.2, Procedures During Treatment. It may 
be necessary to perform these procedures at unscheduled time points if deemed clinically necessary by 
the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or Merck for 
reasons related to participant 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 participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations. 
Each treatment cycle is 21 days (+/- 1 day).

 
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g INR/PT/aPTT should be tested at baseline and monitored closely for subjects on anticoagulation therapy.  
h For WOCBP only. Serum β-hCG required if urine test is positive or cannot be confirmed as negative. 
i Performed within 24 h prior to day 1 of the cycle. 
j Performed approximately 120 days after last dose of Pembrolizumab. 
k Drawn 21 ± 7 days after day 1 of cycle #6, prior to breast surgery. 
l After completion of all local and systemic treatment for breast cancer (surgery, chemotherapy, or radiation, whichever comes last), to be 
performed approximately every 6 months until 3 years post-diagnosis. 
m These blood draws do not need to be duplicated if already done under P.R.O.G.E.C.T. protocol. 
n At the end of all definitive curative breast cancer treatment (14-180 days after surgery, radiation, and chemotherapy, whichever treatment 
comes last). 

 
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13 CORRELATIVE STUDIES 
 
Correlative blood specimen collection is to be performed day 1 cyle 1 and 21 ± 7 days after the last 
chemotherapy cycle, and prior to surgery. Specimen will be collected from all patients who undergo at 
least one dose of study treatment. 
 
 
 
  
 
13.1 Sample Collection Instructions 
 
 
 
 
 
 
  
 
 
   
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
13.2 Sample Preparation, Handling, And Storage 
 
 
 
 

 
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Endpoints 
Primary endpoint is pathologic complete response (pCR) in breast and axilla, which is defined as no 
evidence of disease in the breast and axillary lymph nodes at the time of pathology review, except for 
DCIS in the breast and isolated tumor cells in the axillary lymph nodes. 
Secondary endpoints: 
Assessment of minimal residual disease (MRD), which is defined as residual cancer burden (RCB) score 
of 0/1. Residual cancer burden score will be calculated utilizing surgical pathology parameters by a study 
personnel by using a free online tool (http://www3.mdanderson.org/app/medcalc/index.cfm? 
pagename=jsconvert3) 
 
Recurrence-free survival (RFS), is defined as the time from diagnosis to first recurrence (invasive 
ipsilateral breast, invasive local/regional, or distant), or to death as a result of any cause 78. 
 
14.1 Statistical Hypotheses 
Primary study objective: To determine the pathological complete response (pCR) rates with a neoadjuvant 
chemotherapy regimen of carboplatin and docetaxel (CbD) plus Pembrolizumab in patients with stage I-
III TNBC. 
 
Hypothesis: Addition of Pembrolizumab to CbD will lead to improvement in pCR rates over known 
historical control (improvement from 50% → 65%). 
 
Secondary study objectives:  
1. To evaluate minimal residual disease (MRD) rate (residual cancer burden score of 0/1) with a 
neoadjuvant chemotherapy regimen of CbD plus Pembrolizumab in patients with stage I-III TNBC. 
Hypothesis: Addition of Pembrolizumab to CbD will lead to improvement in MRD rates over known 
historical control (improvement from 65% → 78%). 
 
2. To determine 3-year recurrence-free survival with a neoadjuvant chemotherapy regimen of CbD 
plus Pembrolizumab in patients with stage I-III TNBC. 
Hypothesis: Addition of Pembrolizumab to CbD will lead to improvement in 3-year recurrence-free 
survival over known historical control (improvement from 75% → 86%). 
 
3. To determine 3-year event-free survival with a neoadjuvant chemotherapy regimen of CbD plus 
Pembrolizumab in patients with stage I-III TNBC. 
Hypothesis: Addition of Pembrolizumab to CbD will lead to improvement in 3-year event-free 
survival over known historical control (improvement from 75% → 86%). 
 
4. To estimate pathological complete response (pCR) rates in subgroup of patients with node positive 
and/or T3-T4 disease  
Hypothesis: Addition of Pembrolizumab to CbD will lead to improvement in pCR rates over known 
historical control (improvement from 40% →60%). 

 
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5. To evaluate toxicity of with a neoadjuvant chemotherapy regimen of CbD plus Pembrolizumab in 
patients with stage I-III TNBC. 
 
 
14.2 Sample Size Justification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.3 Accrual Method 
 
 
 
 
 
 
 
   
Intent-to-treat (ITT) population will include all enrolled and eligible patients and serve as the population 
for primary and secondary analyses.  
Patients with disease progression during protocol therapy will be classified as not having pathological 
complete response. Patients with death due to disease progression during protocol therapy will also be 
classified as not having a pathological complete response. 
 
 

 
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15 PARTICIPANT REGISTRATION PROCEDURES 
 
General Guidelines 
Institutions will register eligible participants through the KUCC Clinical Research Office central 
registration process. Registration must occur prior to the initiation of therapy, with treatment 
assignment (for both randomized and non-randomized studies) provided by KUCC. Any participant not 
registered to the protocol before treatment begins will be considered ineligible and registration will be 
denied.  
 
The completed source documentation provided for eligibility verification and registration must be kept 
in the participant binder for monitoring purposes and documentation of participant eligibility. 
 
Issues that would cause treatment delays should be discussed with the Sponsor - Investigator. If a 
participant does not receive protocol therapy following registration, notify the KU Cancer Center Project 
Director or designee so that the participant’s status can be changed in the CRIS system. 
 
Registration Process for KUCC and Other Participating Centers 
The Coordinating Center (KUCC), specifically the Project Director or designee is accessible for 
registration Monday through Friday from 8:00 AM to 5:00 PM Central Time.  
 
The registration procedures are as follows: 
1. Obtain written informed consent from the participant prior to the performance of any study 
related procedures or assessments. NOTE – if tests required at screening were performed as 
part of standard of care prior to signing consent for this study, the results from those tests are 
allowed in this study IF those tests were performed within the timeframe listed in the section of 
this protocol. 
 
2. Complete the appropriate baseline demographic information in CRIS and any required 
registration forms using the eligibility assessment documented in the participant’s 
medical/research record.  To be eligible for registration to the study, the participant must meet 
each inclusion and none of the exclusion criteria listed in this protocol. 
 
3. Send via e-mail the eligibility checklist (checklist to be created from each version of this protocol 
and maintained by the KU Clinical Project Director and clinical team), supporting eligibility 
documentation, and all pages of the consent form to the appropriate KU Clinical Project 
Director.  
 
4. The KU Clinical Project Director or designee will a) validate eligibility and b) register the 
participant on the study. 
 
5. The KU Project Director or designee will send an email confirmation of the registration to the 
person initiating the registration within 24 h of validating eligibility. 
 
 
16 ASSESSMENT OF SAFETY 

 
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16.1 Specification Of Safety Parameters 
 
Analyses will be performed for all eligible participants having received at least one dose of study drug.  
The study will use the CTCAE version 4.03 81. The document may be viewed on the Cancer Therapy 
Evaluation Program (CTEP) website at this URL: 
 
  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
The investigators in this study will use this document for assessing and reporting of adverse events.  
 
16.1.1 Definition Of Adverse Events (AEs) 
 
Text below in italics is verbatim from “Guidance for Industry and Investigators. Safety Reporting 
Requirements for INDs and BA/BE Studies,” issued December 2012 by U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, and Center 
for Biologics Evaluation and Research. The guidance may be retrieved from:  
 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227
351.pdf?source=govdelivery  
 
Adverse Event [21 CFR 312.32(a)]  
An adverse event means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, and does not imply any judgment about causality.  An adverse event can arise with any use of the 
drug (e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose. 
 
Suspected Adverse Reaction [21 CFR 312.32(a)] 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of safety reporting, ‘reasonable possibility’ means there 
is evidence to suggest a causal relationship between the drug and the adverse event. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug.  
 
Suspected adverse reactions are the subset of all adverse events for which there is a reasonable 
possibility that the drug caused the event. Inherent in this definition, and in the requirement to report 
suspected adverse reactions, is the need for the sponsor to evaluate the available evidence and make a 
judgment about the likelihood that the drug actually caused the adverse event.  
 
Unexpected [21 CFR 312.32(a)] 
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; or, if an 
investigator brochure is not required or available, is not consistent with the risk information described in 

 
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the general investigational plan or elsewhere in the current application… “Unexpected,” as used in this 
definition, also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the Particular drug under 
investigation. 
 
This definition relies entirely on a listing of the adverse events or suspected adverse reactions in the 
investigator brochure…as the basis for determining whether newly acquired information generated from 
clinical trials or reported from other sources is unexpected. This means that events not listed for the 
Particular drug under investigation in the investigator brochure are considered “unexpected” and those 
listed are considered “expected.”  When new adverse event information is received, it is the sponsor’s 
responsibility to determine whether the event is “unexpected” for safety reporting purposes. 
 
Serious [21 CFR 312.32(a)] 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, 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 patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 
 
Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the investigator or sponsor, its occurrence places the patient or patient at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death 
 
16.1.2 Relationship To Study Agent 
 
Factors to be considered in assessing the relationship of the adverse event to study drug include: 
 
• 
The temporal sequence from study drug administration: The event should occur after the study 
drug is given. The length of time from study drug exposure to event should be evaluated in the 
clinical context of the event. 
• 
Recovery on discontinuation (de-challenge), recurrence on reintroduction (re-challenge): 
participant’s response after drug discontinuation (de-challenge) or participants response after 
study drug re-introduction (re-challenge) should be considered in the view of the usual clinical 
course of the event in question. 
• 
Underlying, concomitant, intercurrent diseases: Each report should be evaluated in the context 
of the natural history and course of the disease being treated and any other disease the 
participant may have. 
• 
Concomitant medication or treatment: The other drugs the participant is taking or the 
treatment the participant receives should be examined to determine whether any of them may 
be suspected to cause the event in question. 

 
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• 
The pharmacology and pharmacokinetics of the study drug: The pharmacokinetic properties 
(absorption, distribution, metabolism and excretion) of the test drug(s), coupled with the 
individual participant’s pharmacodynamics should be considered. 
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. 
 
Attribution will be assigned as follows: 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Possible – The AE may be related to the study treatment.  
Probable – The AE is likely related to the study treatment. 
Definite – The AE is clearly related to the study treatment. 
 
 
16.2 Reporting Procedures 
 
16.2.1 Adverse Event Reporting 
 
Information for adverse events, whether reported by the participant, directly observed, or detected by 
physical examination, laboratory test or other means, will be collected, recorded, followed and reported 
in the study Case Report Form (CRF) as described in the following sections.  
 
ALL adverse events experienced by participants will be collected and reported after signing consent form 
as follows: 
 
• 
Adverse events will be reported from Day 1 of study treatment and/or procedure, throughout the 
study, and up to and including day 30 after the last dose of study drug and/or last study procedure. 
 
• 
SERIOUS adverse events that meet the definition(s) of a serious adverse event will be reported from 
date of screening (if related to the screening procedure(s)), then from Day 1 of study treatment 
and/or procedure, and up to and including day 30 after the last dose of study drug and/or last study 
procedure. 
 
Participants who experience an ongoing adverse event related to a study procedure and/or study 
medication beyond 30 days will continue to be contacted by a member of the study team until the event 
is resolved, stabilized, or determined to be irreversible by the Sponsor-investigator. 
 
Study participants should also be instructed to report any new serious post-study event(s) that might 
reasonably be related to participation in this study. 
 
Medical conditions/diseases, or cancer related symptoms present before starting study treatment are 
considered adverse events only if they worsen after initiation of study drug.   
 

 
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Abnormal laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms, or require therapy.  In this case they will be recorded on the Adverse Events CRF, along with 
the associated signs, symptoms or diagnosis. 
 
16.2.2 Recording Adverse Events And Documentation In CRIS 
 
All expected and unexpected adverse events and serious adverse events occurring after the participant 
has initiated study treatment will be reported as described previously in this document, and must be 
fully recorded in the participant’s case record form. 
 
All AEs and SAEs regardless of causality must be entered in the 
 
 Unexpected and expected adverse 
events must be entered within 5 days and include: new unexpected adverse events; worsening baseline 
conditions; clinically significant laboratory findings; disease-related signs and symptoms that were not 
present at baseline, and any event of findings that the Investigator feels is clinically significant. 
 
Documentation must be supported by an entry in the participant’s file. A laboratory test abnormality 
considered clinically significant (e.g., causing the participant to withdraw from the study, requiring 
treatment or causing apparent clinical manifestations, or judged relevant by the investigator, should be 
reported as an adverse event). Each event should be described in detail along with start and stop dates, 
severity, relationship to investigational product, action taken and outcome. 
 
 
16.2.3 Serious Adverse Event Reporting  
 
For serious adverse events, the clinical research site will follow local IRB policies and procedures. 
 
All SAEs, regardless of causality, must be entered into CRIS within 24 hours. Entering the event into CRIS 
will send an automatic email to the KUCC Regulatory team and the KUCC DSMC.   
 
Follow-up source documentation is required within 5 days.  
 
Send all supporting documents with a cover sheet to: 
 
KUCC DSMC 
 
 
 
16.2.4 Reporting To Merck  
16.2.4.1 Serious Adverse Events 
 
 
 
 
 
 
 
 
 

 
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The multidisciplinary KUCC Data and Safety Monitoring Committee (DSMC) is charged with overseeing 
the monitoring of participant safety, conduct and scientific progress of research protocols, and the 
validity and integrity of the data for clinical trials. The KUCC DSMC has the authority to require 
amendments, suspend, or terminate any research activities that fall within its jurisdiction, and can 
institute other appropriate actions as needed to protect subject safety. 
 
The study will be monitored at appropriate intervals, no less than those assigned by the KUCC Protocol 
Review and Monitoring Committee, to assure compliance to GCP and to assess the data quality and 
study integrity. The frequency of monitoring may vary depending on enrollment rate and the quality of 
data collected. 
 
The investigator and staff are expected to cooperate and provide all relevant study documentation in 
detail at each site visit on request for review. The study monitor will have direct access to source data 
for data verification. Data verification will be conducted by comparing the data entered into the CRFs 
with source data 
 
17.2 Safety Review And Oversight Requirements 
 
17.2.1  Serious Adverse Event  
 
Serious adverse events that require expedited reporting will be reviewed by the DSMC Chair or designee 
who will determine if immediate action is required. If determined to be necessary by the DSMC, all 
participating sites will be notified of the event and any resulting action within one working day of this 
determination.  
 
17.2.2 Review Of Adverse Event Rates 
 
Once per month, adverse event rates will be monitored by the DSMC Coordinator. If any study site has 
had 2 or more of the same SAE reported within one month, or more than 6 of the same SAE in 6 months, 
the DSMC will review summaries of SAEs, and discuss events in detail with the PI. The DSMC chair or 
designee determines whether further action is required. The DSMC Coordinator ensures that 
collaborating investigators and IRBs for all participating sites are notified of any resulting action. 
 
17.2.3 Study Safety And Progress 
 
An overall assessment of toxicities as described in the protocol is reviewed at DSMC meetings. This 
review enables DSMC committee members to assess whether significant risks are occurring that would 
warrant study suspension/closure or protocol amendment. 
 
The DSMC is an autonomous committee. However, its actions are communicated to other committees 
engaged in oversight of clinical research at KUCC. The PI is responsible for forwarding all DSMC letters, 
including those recommending continuation of the study, to the IRB and PRMC. DSMC 
recommendations for modifications to the trial are forwarded to the Deputy Director of KUCC. The PI is 
notified of this recommendation, and is expected to alert all collaborating investigators about the DSMC 
action. At this time the PI may appeal the Committee’s decision to the Deputy Director of KUCC or their 
designee. The Deputy Director of the KUCC or their designee will notify the PI if he/she concurs with the 
DSMC’s recommendation, including suspension or closure. 

 
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17.3 Unblinding Rules 
 
None. 
 
18 REGULATORY CONSIDERATIONS 
 
18.1 Protocol Review And Amendments 
 
This protocol, the proposed informed consent and all forms of participant information related to the 
study (e.g., advertisements used to recruit participants) and any other necessary documents must be 
submitted, reviewed and approved by a properly constituted IRB. 
 
Any changes made to the protocol must be submitted as amendments and must be approved by the IRB 
prior to implementation. Any changes in study conduct must be reported to the IRB. The sponsor- 
Investigator will disseminate protocol amendment information to all study team members.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
19 ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
19.1 Ethical Standard  
 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good and 
sound research practice: 
 
1. State laws 
 
2. ICH Consolidated Good Clinical Practice: Guidelines (E6)    
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM073122.pdf 
 
3. US Code of Federal Regulations (CFR) governing clinical study conduct and ethical principles that 
have their origin in the Declaration of Helsinki 
 
4. http://www.ecfr.gov/cgi-bin/ECFR?page=browse 
 
With attention to the following specific regulations: 
 
a. Title 21 Part 50 – Protection of Human Subjects 
b. Title 21 Part 56 – Institutional Review Boards  
c. Title 21 Part 312 – Investigational New Drug Application Responsibilities of Sponsors and 
Investigators  
 
5. Institutional research policies and procedures: 

 
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http://policy.ku.edu/research/human-subjects  
 
AND 
 
http://www.kumc.edu/human-research-protection-program/institutional-review-
board/policies-and-regulations.html  
 
19.2 Informed Consent Process  
 
Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. The 
formal consent of a participant, using the IRB approved consent form, must be obtained before the 
participant is involved in any study-related procedure. The consent form must be signed and dated by 
the participant or the participant’s legally authorized representative, and by the person obtaining the 
consent. The participant must be given a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research file. 
 
20 DATA HANDLING AND RECORD KEEPING  
 
20.1 Data Collection And Management Responsibilities 
 
Case report forms (CRFs) will be completed for each subject enrolled. All CRFs will be customized to this 
study, in order to emphasize completeness and accuracy. The medical chart and any other clinical 
worksheets, procedural reports, etc. will be the source documentation of data captured into the study 
database. Data entry for each subject (enrolled or screen failure) will be entered in a timely manner. 
Data entry timelines will be reviewed regularly with notification sent to site if found outstanding. 
 
20.2 Study Records Retention 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information 
enables the study to be fully documented and the study data to be subsequently verified. Original 
source documents supporting entries in the case report forms include but are not limited to hospital 
records and clinic charts, laboratory and pharmacy records, ECG, signed ICFs, participant diaries and 
pathology reports. All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
20.3 Protocol Deviations 
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. All deviations must be entered into CRIS and 
reported to the DSMC. All deviations must be reported to the IRB according to the local reporting policy.  
 
 

 
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21 LITERATURE REFERENCES  
1. 
Harris J, Morrow M, Norton L. Malignant tumors of the breast. In: DeVita VJ, Hellman S, Rosenberg S, eds. 
Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven; 1997:1557-1602. 
2. 
Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of 
recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429-4434. 
3. 
Liedtke C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients 
with triple-negative breast cancer. J Clin Oncol. 2008;26(8):1275-1281. 
4. 
Osborne C, Kannan L, Xie X, Ashfaq R, Bian A, Baylor T. Neoadjuvant chemotherapy for basal-like breast 
cancer cohort: clinical and pathological outcome [abstract]. Breast Cancer Res Treat. 2006;100:S53. 
5. 
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer. 
2017; 2.2017:https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 18, 2017. 
6. 
Haffty BG, Yang Q, Reiss M, et al. Locoregional relapse and distant metastasis in conservatively managed 
triple negative early-stage breast cancer. J Clin Oncol. 2006;24(36):5652-5657. 
7. 
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22 APPENDICES 
 
 
Appendix A: Performance Status 
 
Zubrod Performance Scale (Eastern Cooperative Oncology Group) 
 
POINT 
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 housework, office work. 
2 
Ambulatory and capable of self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of 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. 
 
 
 

 
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Appendix B: Contraceptive Guidance and Pregnancy Testing 
WOMAN OF CHILDBEARING POTENTIAL (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). Women must meet the criteria below to be considered non-WOCBP, 
regardless of sexual orientation, having undergone tubal ligation, or remaining celibate by choice. 
 
Women in the following categories are not considered WOCBP: 
• 
Premenarchal 
• 
Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• 
Postmenopausal female 
o 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
o 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION REQUIREMENTS 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception that has a low user dependency consistently and correctly as 
described in Table 8 during the protocol-defined time frame in Section 10.1.4.1. 
 
Table 8: Highly effective contraceptive methods that have low user dependency 
Highly effective methods that have low user dependency  
Failure rate of <1% per year when used consistently and correctly 
• 
Non-hormone-releasing intrauterine device (IUD) 
• 
Progestogen-only implant 
• 
Vasectomized partner  

 
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A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
• 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.  
Notes: Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies.  
PREGNANCY TESTING 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test and in 
accordance with local requirements. When applicable, this test should be repeated a maximum of 24 
hours before the first dose of study treatment. 
Following initiation of treatment, additional pregnancy testing will be performed within 24 hours prior 
to each treatment cycle (at a minimum of monthly) during the treatment period and at 120 days after 
the last dose of study treatment. Pregnancy testing will be performed whenever an expected menstrual 
cycle is missed or when pregnancy is otherwise suspected. 
 
 
 

 
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Appendix C: Suggested Chemotherapy Pre-medication and Antiemetics 
Carboplatin/Taxotere  
Day 1 of Treatment (cycles 1-6)  
LORazepam tablet 0.5-1 mg 
Dexamethasone 20 mg in sodium chloride 0.9% (NS) 50 mL IVPB 
Palonosetron injection 0.25 mg 
Take-Home Medication  
Decadron 4-8mg PO BID Day -1, 1, 2  
Ondansetron 4 mg PO TID PRN 
Prochlorperazine 10 mg PO TID PRN 
Ativan 0.5 mg PO TID PRN 
*For patients who have uncontrolled nausea after first cycle of carboplatin, consider adding Emend 
(fosaprepitant dimeglumine) 150 mg or Cinvanti (aprepirant, injectable emulsion) 130 mg to 
chemotherapy premedication for remaining carboplatin doses. If aprepirant is added, 50% dosage 
reduction of dexamethasone is recommended to account for a drug interaction with aprepirant. 
 
 
 
 
 
 

 
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Appendix D: Specimen Collection, Processing, and Shipping