Clinical trial NCT03121352
Conditions: Metastatic Triple Negative Breast Cancer
Keywords: Carboplatin Nab-Paclitaxel Pembrolizumab
Sponsor: Case Comprehensive Cancer Center
Start date: 2017-05-19; Completion date: 2022-05-23
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see how effective the combination of the two chemotherapy drugs (carboplatin and nab-paclitaxel) are when added to a third drug, pembrolizumab.

Pembrolizumab is an investigational (experimental) drug that works by reinvigorating the immune system, allowing it to target and destroy cancer cells. Pembrolizumab is experimental because it is not approved by the Food and Drug Administration (FDA) for this type of breast cancer treatment.

Detailed description:
Primary Objective - Determine overall response rate (ORR) in patients treated with CNP

Secondary Objective(s)

* Determine progression-free survival (PFS), and disease control rate (DCR) in patients treated with CNP.
* Determine duration of response in patients treated with CNP.
* Determine safety/tolerability of CNP.

Correlative Endpoints

\- Identify pathologic and genomic correlates of response to CNP.

Study design including dose escalation / cohorts This is prospective pilot clinical trial of CNP in up to 30 patients with mTNBC

Arms: arm 1: Combination therapy of Carboplatin, Nab-paclitaxel, and Pembrolizumab
Interventions: intervention 1: Carboplatin intervention 2: Nab-paclitaxel intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: AUC 4.5 IV day 1 of 21-day cycle intervention 2: 75mg/m2 IV days 1, 8 and 15 of 21-day cycle intervention 3: 200 mg IV every 21 days

Protocol documents:
Prot_SAP_000.pdf: 
CASE xxxx 6115  
 
 
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STUDY NUMBER:  CASE 6115  
 
Clinicaltrials.gov #: 
NCT03121352 
 
Protocol Date: 04.04.2022 
 
STUDY TITLE:  Pilot Study of Carboplatin, Nab-Paclitaxel and Pembrolizumab 
for Metastatic Triple-Negative Breast Cancer 
 
 
 
 
 
PRINCIPAL INVESTIGATOR Joseph Baar, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Cleveland Medical Center 
 
 
 
 
Seidman Cancer Center 
11100 Euclid Avenue  
 
 
 
Cleveland, OH 44106 
 
 
 
 
 
 
CO-PI 
 
 
 
Jame Abraham, MD 
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic  
Taussig Cancer Center 
 
9500 Euclid Avenue  
 
 
 
Cleveland, OH 44195 
 
 
 
CO- INVESTIGATORS  
G. Thomas Budd, MD 
Taussig Cancer Center 
9500 Euclid Avenue 
Cleveland, OH 44195 
 
 
 
 
 


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Halle Moore, MD 
Taussig Cancer Center 
9500 Euclid Avenue 
Cleveland, OH 44195 
 
 
STATISTICIAN:  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
STUDY COORDINATOR: 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
 
SUPPORT/FUNDING: 
 
Merck 
 
SUPPLIED AGENT: 
 
Pembrolizumab 
 
IND #:  
 
 
 
  
 
 
 
 AGENT(S): 
 
Nab-paclitaxel, Carboplatin 


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SUMMARY OF CHANGES 
 
Protocol 
Date 
Section 
Change 
11/01/2016  
Initial IRB approval 
02/07/2017 6.2 
Revised to indicate that steroids are permitted as an anti-emetic during 
chemotherapy. 
 
 
11.2 
Revised to indicate the timing of the tests and procedures: the text was 
changed from Day 1 of cycle 1-3 to Day 1 of cycle 1-n1, Day 8 of cycle 1-
3 was changed to Day 8 of Cycle 1- n1 and Day 15 of cycle 1-3  was 
changed to Day 15 of cycle 1- n1 and End of Treatment was changed to 30 
Day Follow-up; in addition footnote #1 was added to clarify that patients 
may receive treatment for up to 24 months; a row was added to clarify 
that the thyroid hormone tests are being done at Screening and on Day 1 
of  each cycle and that this test is not included with the serum chemistries 
done weekly. 
 
02/22/2017 
8.1 
Revised to include the updated risk profile from Investigator Brochure 
v13 
 
10.4 
Updated with the contact information for the central laboratory that will 
be processing the biopsy samples for PDL-1 expression testing and to 
indicate that samples will be shipped in batches 
 
11.1 
Text was added to clarify that T4 testing is for Thyroxine 
 
11.2 
Revised to clarify that T4 testing is for Thyroxine and that Urinalysis is 
performed at screening 
10/16/2017 
Cover page 
Revised to add IND # and update institution name from University 
Hospitals Case Medical Center to University Hospitals Cleveland 
Medical Center, version date 
 
Treatment 
Schema 
Carboplatin changed to AUC 4.5 and nab-paclitaxel to 75 mg/m2. 
 
Protocol 
Synopsis-
Interventions 
Carboplatin changed to AUC 4.5 and nab-paclitaxel to 75 mg/m2. 
 
1.3 
NB: For the first 2 patients entered into this study at dosing levels of 
carboplatin AUC 6 and nab-paclitaxel 100 mg/m2, there were significant 
treatment delays with subsequent dose reductions because of prolonged 
thrombocytopenia and profound asthenia. Therefore, moving forward, it 
was decided to reduce the starting doses of carboplatin and nab-paclitaxel 
by 25% (i.e., carboplatin at AUC 4.5 and nab-paclitaxel at 75mg/m2). 
 
4.1.2 
Subjects must have received no more than 2 prior therapies for metastatic 
triple-negative breast cancer. 
 
6.1 
Patients will then receive 3 cycles of CNP. Carboplatin (C) will be 
administered intravenously (IV) on day 1 of a 21-day cycle at AUC 4.5. 
Nab-paclitaxel (N) will be administered at 75 mg/m2 IV on days 1, 8 and 
15 of a 21-day cycle. Pembrolizumab (P) will be administered at a dose 
of 200 mg IV on day 15 of each cycle, prior to any chemotherapy. 
 
6.1.1 
C, Carboplatin, AUC 4.5 IV day 1 of 21-day cycle 
N, Nab-paclitaxel, 75mg/m2 IV days 1, 8 and 15 of 21-day cycle 


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P, Pembrolizumab, 200 mg IV every 21 days  
  
NB: If there is a treatment delay on day 8 because of low blood counts 
(ANC or platelets), then day 8 nab-paclitaxel will be held. If blood counts 
have recovered on day 15, then nab-paclitaxel will be administered at 
75% dose from the day 1 dose in combination with the standard dose of 
pembrolizumab (200 mg IV). If blood counts have not recovered by day 
15, nab-paclitaxel will continue to be held but pembrolizumab will be 
administered as a single agent.  
 
 
6.1.2 
Carboplatin starting dose level: Dose level 0 at AUC 4.5 given IV every 3  
weeks. 
Carboplatin does reductions will occur for any ≥ grade 3 hematologic 
toxicity or a ≥ grade 2 non-hematologic toxicity. 
The carboplatin dose will be reduced by 25% (AUC 3.4) for all 
subsequent cycles of therapy. 
 
Nab-paclitaxel starting dose level: Dose level 0 at 75 mg/m2 given IV 
weekly. 
The first and subsequent doses of nab-paclitaxel will be delayed until 
ANC > 1000/μl and platelets > 100,000/μl and resolution of any grade ≥2 
non-hematologic toxicities except residual grade 2 neuropathy.  
In patients experiencing febrile neutropenia or delay of recovering of 
ANC to > 1000/μl beyond day 21 of the preceding cycle or the 
development of grade ≥3 non-hematologic toxicities, subsequent doses of 
nab-paclitaxel will be reduced by 25% to 56 mg/m2 for all subsequent 
cycles of therapy. For recurrence of these dose-limiting toxicities, 
protocol therapy will be discontinued. 
 
 
 
6.2.3 
       The carboplatin dose will be reduced by 25% (AUC 3.4). 
       In patients experiencing febrile neutropenia or delay of recovering of 
ANC to > 1000/μl beyond day 21 of the preceding cycle or the 
development of grade >3 non-hematologic toxicities, subsequent 
doses of nab-paclitaxel will be reduced by 25% to 56 mg/m2. For 
recurrence of these dose-limiting toxicities, protocol therapy will be 
discontinued. 
  
Dose 
level 
C 
N 
P 
-1  
Dose level 0 - 
25% (AUC 3.4) 
Dose level 0 - 25% 
(56mg/m2) 
200 mg IV 
0 
AUC 4.5 
75 mg/m2 
200 mg IV 
 
 
9.2.1 
Route of administration: AUC 4.5 IV on Day 1 of 21-day cycle. 
 
11.1.2 
 
C, Carboplatin, will be administered AUC 4.5 IV day 1 of 21-day cycle. 
N, Nab-paclitaxel, will be administered 75 mg/m2 IV days 1, 8 and 15 of 
21-day cycle. 
P, Pembrolizumab, will be administered 200 mg IV every 21 days . 
 


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12/04/17 
Cover page 
Revised version date 
 
7.0 
Dose Modification Table for the management of immune-related adverse 
events associated with Pembrolizumab updated to include new risks 
identified in Investigator Brochure v15  
 
8.1 
Revised to include the updated risk profile from Investigator Brochure 
v15 
01/18/18 
Cover page 
Revised version date 
 
10.0 
Corrections have been made to the biopsy collection and specimen 
processing paragraphs regarding the type of samples being obtained 
 
11.2 
Study Calendar has been revised to indicate that the post-treatment biopsy 
is taken after the completion of 3 cycles of treatment not at the 30 day 
follow-up time point 
06/28/18 
Cover page 
Revised version date 
 
6.1 
Revised to clarify the timing of radiologic restaging. 
 
6.1.1 
 Revised to clarify that missed doses of paclitaxel are not made up in 
order to maintain dosing of  pembrolizumab  every 3 weeks 
 
6.1.2 
Revised to clarify carboplatin dosing and criteria for removal from study 
due to treatment delay 
 
7.0  
Revised to clarify timing of dose delays/dose modifications 
 
10.0 
Revised to clarify that the biopsy can be obtained with a range of needle 
gauges per institutional practice 
 
11.1.1 
Revised to clarify that screening studies and evaluations can be 
completed within 28 days of study entry 
 
11.2 
Revised to specify the lab tests that can be done within the 3 day window 
09/17/18 
Cover page 
Revised version date 
 
3.4 
Revised to clarify duration of treatment for patients who respond 
 
6.1 
Text added to clarify that patients experiencing pseudo-progression will 
be able to continue to receive an additional 3 cycles of treatment  
 
6.1.2 
Revised to clarify criteria for dose reductions 
 
6.2 
Revised to clarify when the use of growth factor support is appropriate 
 
8.1 
The risks of pembrolizumab have updated to be consistent with the 
changes in the latest Investigator Brochure 
 
8.4.6 
The FDA reporting requirements for Serous Adverse Events have been 
added in this section. 
 
10.0 
Revised to have the needle gauge range consistent throughout 
 
11.2 
Footnotes have been added to the Study Calendar  to clarify the timing of 
the optional biopsy and Cycle 3 disease assessment scans 
11/12/18 
Cover page 
Revised version date 
 
6.1.2 
Revised to clarify the circumstances where patients can continue to receive 
treatment even though one or more of the medications needs to be 
discontinued: patients who have an allergic reaction to carboplatin can 
continue to be treated with nab-paclitaxel as a single agent on days 1 and 
8 and nab-paclitaxel with  pembrolizumab on day 15 for each subsequent 
cycle; patients who experience a grade >2 toxicity that persists resulting 
in a treatment delay of more than 4 weeks attributable to carboplatin 
and/or nab-paclitaxel but not pembrolizumab, may continue on single-
agent pembrolizumab given every 3 weeks intravenously as long as there 
is evidence for ongoing clinical benefit to the patient (i.e., regression or 
stability of metastatic disease);  however,  patients who have  a grade ≥2 


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toxicity that persists resulting in a treatment delay of more than 4 weeks 
where attribution to either carboplatin, nab-paclitaxel or pembrolizumab 
cannot be distinguished, then protocol treatment will be discontinued and 
the patient will be removed from the study. 
 
 
 
 
 
01/14/19 
Cover page 
Revised version date 
 
11.2 
Revised to clarify the timing of study visits and tests for patients who had 
discontinued chemotherapy due to toxicities experienced but who tolerate 
and continue to receive pembrolizumab 
 
Appendix II 
Title corrected 
08/16/19 
Cover page 
Revised version date; updated the contact information for the study 
coordinator 
 
8.1 
The risks of pembrolizumab were updated to be consistent with the 
changes in the latest Investigator Brochure 
 
11.2 
Revised to clarify that  the tests for the 30 day follow-up visit can be done 
within a 3 day window 
 
13.1 
Revised to indicate the use of the 21 CFR Part 11 compliant electronic data 
capture system, Forte EDC in addition to OnCore® 
10/02/19 
Cover page 
Revised version date 
 
6.1.2 
Revised to clarify that the protocol does not allow for dose delays for study 
medications; since the drug is held not delayed patients continue to be 
treated per the study schedule with no change for subsequent cycles. 
 
8.2 
The risks of Carboplatin were revised to correct the typographical error 
under LESS COMMON third bullet point. It should be cough instead of 
bough. 
05/31/21 
Cover page 
Revised version date; updated the study staff and the contact information 
for the study coordinator 
 
6.2 
Revised to clarify which influenza vaccines are permitted and the use of 
systemic coriticosteroids 
 
7.0 
Dose Modification Table for the management of immune-related adverse 
events associated with Pembrolizumab updated to include new risks 
identified in Investigator Brochure v20; revised to clarify timing of dose 
delays/dose modifications 
 
8.1 
The risks of pembrolizumab were updated to be consistent with the 
changes in the latest Investigator Brochure 
04/04/22 
Cover page 
Revised version date 
 
6.4 
The sponsor has decided to limit the follow-up period to at least 12 months 
after the post 30 day follow-up. 
 
11.1.4 
The sponsor has decided to limit the follow-up period to at least 12 months 
after the post 30 day follow-up. 
 


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TREATMENT SCHEMA 
 
Day 
1 
8 
15 
22 
29 
36 
43 
50 
 
57 
C 
X 
 
 
X 
 
 
X 
 
 
 
N 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P 
 
 
X 
 
 
X 
 
 
 
X 
C, Carboplatin, AUC 4.5 IV day 1 of 21-day cycle 
N, Nab-paclitaxel, 75mg/m2 IV days 1, 8 and 15 of 21-day cycle 
P, Pembrolizumab, 200 mg IV every 21 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Synopsis:  
 
Protocol Number/Title 
Case 6115: Pilot Study of Carboplatin, Nab-Paclitaxel and 
Pembrolizumab 
for Metastatic Triple-Negative Breast 
Cancer 
Study Phase 
Pilot  
Brief Background/Rationale 
 
 
 
Given the significant activity of single-agent 
pembrolizumab in a heavily pre-treated cohort of patients 
with mTNBC and the favorable cytotoxic and 
immunomodulatory properties of carboplatin and nab-
paclitaxel, there is a strong rationale to treat patients with 
mTNBC with the combination of carboplatin (C), nab-
paclitaxel (N) and pembrolizumab (P) (CNP). 
 
Primary Objective  
Primary Endpoint(s) 
Determine overall response rate (ORR) in patients treated 
with CNP. 
 
Secondary Objective(s) 
Determine progression-free survival (PFS) in patients 
treated with CNP. 
 
Determine disease control rate (DCR) in patients treated 
with CNP. 
 
Correlative Objective(s) 
 
Correlative Endpoint(s) 
Identify pathologic and genomic correlates of response to 
CNP. 
 
Determine safety/tolerability of CNP.  
 
Sample Size 
30 patients  
Disease sites/Conditions 
Metastatic Triple-Negative Breast Cancer 
Interventions 
C, Carboplatin, AUC 4.5 IV day 1 of 21-day cycle 
N, Nab-paclitaxel, 75mg/m2 IV days 1, 8 and 15 of 21-day 
cycle 
P, Pembrolizumab, 200 mg IV every 21 days 
 
 
 
 
 
 
 
 
 
 


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Abbreviations  
 
 
 
CCCC 
Case Comprehensive Cancer Center 
CRF 
Case Report Form 
DCRU 
Dahm’s Clinical Research Unit 
DSTC 
Data Safety Toxicity Committee 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRMC 
Protocol Review and Monitoring Committee 
SOC 
Standard of Care 
CCF 
Cleveland Clinic Foundation 
UH 
University Hospitals 
TNBC 
Triple Negative Breast Cancer 
mTNBC Metastatic Triple Negative Breast Cancer  
BC 
Breast Cancer 
EGFR 
Epidermal Growth Factor Receptor 
TIL 
Tumor-infiltrating lymphocytes  
Tregs 
Regulatory T-Cells  
MDSC 
Myeloid-derived Suppressor Cells 
C 
Carboplatin 
N 
Nab-paclitaxel 
P 
Pembrolizumab 
CNP 
Carboplatin, nab-paclitaxel, pembrolizumab 
 
 
 
 


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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background of Triple-Negative Breast Cancer  
1.2  
Name/description of Chemo-Immunotherapy  
1.3  
Rationale   
1.4 
Background and rationale of correlative studies 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
2.3 
Correlative Objective(s) 
 
3.0 
STUDY DESIGN 
3.1 
Study design, dose escalation, and cohorts 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview  
6.2 
General Concomitant Medications and Supportive Care Guidelines 
6.3 
Criteria for Removal from Study 
6.4 
Duration of Follow-Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
Agent Adverse events 
8.2 
Definitions 
8.3 
Serious Adverse Event Report Form 
8.4 
Reporting Procedures for Serious Adverse Event  
8.5 
Serious Adverse Events and OnCoreTM    
8.6 
Data Safety Toxicity Committee 
8.7 
Data and Safety Monitoring Plan 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Investigational Agent(s) 
 
9.2 
Commercial Agent(s) 


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10.0 
EXPLORATORY/CORRELATIVE  
10.1  Name of Exploratory or Correlative Study #1 
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT choose appropriate measurement of effect; i.e. 
RECIST (solid tumors) / hematologic diseases / other response measurement 
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
REFERENCES 
 
  
APPENDICES  
 
 
 
APPENDIX I  
 
ECOG PS Status  
 
 
 
 
APPENDIX II 
 
Immune-mediated Adverse Reactions 
 


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1.0 
Introduction  
 
1.1 
Background of Study Disease  
 
Triple-negative breast cancer (TNBC) constitutes 10-15% of newly-diagnosed breast 
cancer (BC) and is associated with an aggressive phenotype and a high risk of distant 
metastases with decreased survival [1-4]. Molecular profiling of TNBC has demonstrated 
that the majority of cases have a basal-like subtype with high expression of the epidermal 
growth factor receptor (EGFR), basal cytokeratins, and genes involved in proliferation [5, 
6]. Unlike ER+ and HER2+ BC, there are no targeted agents against TNBC and clinical 
trials of therapeutic agents against putative biological targets of metastatic TNBC, such 
as EGFR [7, 8] and poly-ADP-ribose polymerase [9], have been largely negative in terms 
of improved survival.  
 
TNBC is characterized by tumor-infiltrating lymphocytes (TIL) [10], which are 
composed of a variety of cells including natural killer cells, B lymphocytes and CD4+ 
and CD8+ T cells [11]. Of note, studies have demonstrated that BC associated with high 
levels of TIL has a better prognosis than BC associated with low or no TIL [12-14]. Also, 
the presence of TIL in the tumor microenvironment appears to be indicative of an 
immune recognition of tumor-associated antigens, particularly in highly proliferative 
tumors [11].  
 
However, potent immune suppressive signals exist within the tumor microenvironment 
which are mediated by infiltrating cells such as regulatory T cells (Tregs) and myeloid-
derived suppressor cells (MDSC)  [15-20] as well as by cell-surface ligand/receptor 
interactions such as those mediated, for example, by programmed death 1 (PD-1) with its 
ligand, PD-L1 [reviewed in 21]. TIL express high levels of PD-1 [22] which, when bound 
by its cognate receptor PD-L1 on tumor cells, causes apoptosis of the PD-1+ CD8+ 
cytotoxic T cell [21].  
 
It has been shown that PD-L1 is expressed in some TNBC and such PD-L1+ TNBC has a 
greater CD8 (+) T cell infiltrate than PD-L1 negative tumors [23]. Therefore, one 
approach to decrease immune suppression in the tumor microenvironment of TNBC is to 
interfere with the PD-1/PD-L1 signaling pathway. Thus, a recent phase Ib study of 
single-agent pembrolizumab in 32 patients with advanced TNBC [24] has demonstrated 
that 16.1% of patients had a partial response to therapy and 9.7% had stable disease. 
These findings attest to the effectiveness of single-agent pembrolizumab in a subset of 
heavily pre-treated patients with recurrent/metastatic TNBC. 
 
1.2 
Name and Description of Chemo-Immunotherapy  
 
Metastatic TNBC (mTNBC) is responsive to cytotoxic chemotherapy and the 
combination of carboplatin and nab-paclitaxel has been shown to be a particularly 
effective regimen with an excellent safety profile when combined with antibody-based 
therapy [25, 26]. In particular, a phase 2 clinical trial (25) of nab-paclitaxel given at 100 
mg/m2 weekly for 3/4 weeks, carboplatin given at AUC 2 weekly for 3/4 weeks and 


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bevacizumab given at 100 mg/m2 every 2 weeks demonstrated significant activity in 
patients with mTNBC with an overall response rate of 85% and a median progression-
free survival of 9.2 months. 
 
Studies have also demonstrated that immunotherapy of cancer is augmented by 
concomitant cytotoxic chemotherapy [reviewed in 27]. It appears that the 2 major 
immunomodulatory 
mechanisms 
mediated 
by 
chemotherapy 
involve, 
first, 
the 
downregulation of infiltrating immune suppressor cells such as Tregs and MDSC [28] 
and, second, an increase in local tumor antigen release and the subsequent uptake and 
processing of such antigens by dendritic cells, which in turn prime cytotoxic CD8+ T 
cells against the tumor targets [29, 30]. Of significant interest, carboplatin [31-33] has 
favorable immunomodulatory properties and is also an active agent against TNBC (14, 
34).  
 
1.3 
Rationale  
 
Given the significant activity of single-agent pembrolizumab in a heavily pre-treated 
cohort of patients with mTNBC and the favorable cytotoxic and immunomodulatory 
properties of carboplatin and nab-paclitaxel, there is a strong rationale to treat patients 
with mTNBC with the combination of carboplatin (C), nab-paclitaxel (N) and 
pembrolizumab (P) (CNP). 
 
NB: For the first 2 patients entered into this study at dosing levels of carboplatin AUC 6 
and nab-paclitaxel 100 mg/m2, there were significant treatment delays with subsequent 
dose reductions because of prolonged thrombocytopenia and profound asthenia. 
Therefore, moving forward, it was decided to reduce the starting doses of carboplatin and 
nab-paclitaxel by 25% (i.e., carboplatin at AUC 4.5 and nab-paclitaxel at 75mg/m2). 
 
1.4 
Background and rationale of correlative studies 
 
As stated above, TNBC expresses PD-L1 as well as a variety of other genomic markers 
and these will be assayed in this study. Tumor tissue from the primary and metastatic 
sites (biopsied pre and post therapy) from up to 30 patients will be used for analysis of 
PD-L1 expression by immunohistochemistry, TIL scoring (intratumoral and stromal per 
Loi et al) and genomic analysis.  RNA and DNA will be extracted from tumor cores 
using Qiagen AllPrep FFPE Kit. Affymetrix Human Transcriptome Array (HTA) 2.0 
will be used to generate whole genome gene expression data. After normalization and 
gene-level expression summarization, the Pietenpol molecular subytypes will be 
assessed TNBC using the online “TNBC type” tool (36).   
 
In addition, newer classifications of TNBC (37) that have identified Basal-Like Immune 
activated (BLIA) and Basal-like Immune Suppressed (BLIS) phenotypes, will be applied 
to the dataset. Furthermore, pathway analysis using NCI-PID will be performed to 
assess differential pathway expression between responders and non-responders. Finally, 
predefined immune signatures will be scored for each sample (38).  
 


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2.0  
Objectives 
 
2.1  
Primary Objective  
 Determine overall response rate (ORR) in patients treated with CNP   
 
 
2.2 
Secondary Objective(s) 
 Determine progression-free survival (PFS), and disease control rate (DCR) in 
patients treated with CNP. 
 Determine duration of response in patients treated with CNP. 
 Determine safety/tolerability of CNP.  
 
2.3 
Correlative Objective(s) 
 Identify pathologic and genomic correlates of response to CNP. 
 
3.0 
Study Design 
 
3.1  
Study design including dose escalation / cohorts  
 
This is prospective pilot clinical trial of CNP in up to 30 patients with mTNBC.  
 
3.2 
Number of Subjects 
 
Approximately 30 subjects will be enrolled in this trial.  
 
3.3 
Replacement of Subjects  
 
If a subject is not administered the first full cycle of study drug regimen, the subject will 
be replaced because he/she has not taken enough drug to confirm safety at that dose level.  
 
3.4  
Expected Duration of Treatment and Subject Participation 
 
Duration of treatment with P will be limited to 2 years in individual patients, with 
possibility for an additional year of treatment in patients who stop treatment in a state of 
response (stable disease or better) and progress. Patients with a confirmed CR will get 
one additional full course of carboplatin + nab-paclitaxel + pembrolizumab (i.e., 3 doses 
of pembrolizumab) and will then be restaged. If they continue to be in CR, then all 
treatment will be stopped and they will get repeat restaging scans every 3 months. If there 
is a post-CR relapse, then patients will be retreated once again with 3 full cycles of CNP 
and then restaged. A decision about additional treatment will be made on the basis of the 
restaging results. 


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4.0 
Subject Selection 
 
Each of the criteria in the sections that follow must be met in order for a subject to be 
considered eligible for this study. Use the eligibility criteria to confirm a subject’s 
eligibility.  
 
 
Subject’s Name 
_____________________________________________________________ 
 
Medical Record # 
___________________________________________________________ 
 
Research Nurse / Study Coordinator Signature: 
_________________________________________________ 
 
 
Date __________ 
 
Treating Physician [Print] 
____________________________________________________ 
 
Treating Physician Signature: 
_________________________________________________ 
 
 
Date __________ 
 
4.1 
Inclusion Criteria 
 
 

 
4.1.1 Subjects must have histologically or cytologically confirmed metastatic 
triple negative breast cancer.  
 

 
4.1.2 Subjects must have received no more than 2 prior therapies for metastatic 
triple-negative breast cancer. 
 

 
4.1.3 Age ≥ 18 years. Because no dosing or adverse event data are currently 
available on the use of the proposed investigational drug combination in subjects 
< 18 years of age, children are excluded from this study. 
 

 
4.1.4 ECOG Performance Status 0-1 [See Appendix I].  
 

 
4.1.5 Subjects must have normal organ and marrow function as defined below:   
 
 Hemoglobin ≥ 10.0 g/dl  
 Absolute neutrophil count ≥ 1,000/µL 
 Platelet count ≥ 100,000/µL 


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 Total bilirubin within normal institutional limits 
 AST (SGOT) ≤ 2.5 X institutional upper limit of normal 
 ALT (SGPT) ≤ 2.5 X institutional upper limit of normal 
 Serum creatinine ≤ 1.5 normal institutional limits 
 

 
4.1.6 Life expectancy of 12 weeks or more. 
 

 
4.1.7 Subjects must have the ability to understand and the willingness to sign a 
written informed consent document. 
 

 
4.1.8 Subjects must have measurable disease per RECIST v1.1  
 

 
4.1.9 Subjects must be willing to undergo a preliminary biopsy of a metastatic 
focus for research purposes. A second post-treatment biopsy will be offered but 
will not be mandated. 
 
4.2 
Exclusion Criteria 
 

 
4.2.1 Prior treatment toxicities have not resolved to ≤ Grade 1 according to NCI 
CTCAE Version 4.0 (except for alopecia and neuropathy). 
 

 
4.2.2 Subjects receiving any other investigational agents.  
 

 
4.2.3 Subjects with radiographically stable treated brain metastases are eligible 
but must not have been on steroid therapy for at least 4 weeks. 
 

 
4.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to nab-paclitaxel, carboplatin, pembrolizumab, or other agents used 
in this study. 
 

 
4.2.5 Subjects with uncontrolled intercurrent illness including, but not limited to 
ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements.  
 

 
4.2.6 Pregnant or breastfeeding women are excluded from this study because the 
study agents include the potential for teratogenic or abortifacient effects. Because there is 
an unknown, but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with the study agents, breastfeeding should be discontinued if the 
mother is treated with the study agents. These potential risks may also apply to other 
agents used in this study.  
 
Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 


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Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician 
immediately. 
 

 
4.2.7 Patients with conditions requiring immunosuppressive medications or 
chronic infections (including HIV infection, hepatitis B and C). 
 

 
4.2.8 Patients with chronic autoimmune disease.  
 

 
4.2.9 Patients with prior therapy with antibodies that modulate T-cell function 
(e.g., anti-PD-1, anti-PD-L1) 
 

 
 4.2.10 Patients with evidence of active, non-infectious pneumonia. 
 

 
4.2.11 Patients active infection requiring intravenous systemic therapy. 
 

 
4.2.12 Patients with known psychiatric or substance abuse disorders that would 
interfere with cooperation with requirements of the trial.  
 

 
4.2.13 Patients who have received a live vaccine within 30 days prior to the first 
dose of pembrolizumab.  
 

 
4.2.14 Patients with a known additional malignancy that is progressing or requires 
active treatment (within the last 5 years). Exceptions: basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin or in situ cervical cancer that has undergone 
potentially curative therapy. 
 

 
4.2.15 Patients who have received monoclonal anti-cancer antibody within 4 
weeks of first dose of study drugs.  
 

 
4.2.16 Patients who have received chemotherapy, small molecule targeted therapy 
or radiation within the 2 weeks of first dose of study drugs. 
 

 
4.2.17 Patients who have participated in MK-3475 Merck studies. 
 

 
4.2.18 Patients with carcinomatous meningitis.  
 
4.3 
Inclusion of Women and Minorities  
 
Women and members of all races and ethnic groups are eligible for this trial. 


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5.0 
Registration 
 
All subjects who have been consented are to be registered in the OnCore™ Database. For 
those subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded. 
 
All subjects will be registered through UHCMC and will be provided a study number by 
contacting the study coordinator listed on the cover page.  
 
6.0  
Treatment Plan 
 
6.1 
Treatment Regimen Overview 
 
Patients will initially undergo baseline blood work and radiological staging to determine 
eligibility for enrollment into the study. Patients must have biopsy-proven mTNBC, 
which will be obtained as a baseline prior to the start of therapy.  
 
Patients will then receive 3 cycles of CNP. Carboplatin (C) will be administered 
intravenously (IV) on day 1 of a 21-day cycle at AUC 4.5. Nab-paclitaxel (N) will be 
administered at 75 mg/m2 IV on days 1, 8 and 15 of a 21-day cycle. Pembrolizumab (P) 
will be administered at a dose of 200 mg IV on day 15 of each cycle, prior to any 
chemotherapy.  
 
Rationale for Pembrolizumab dosing: 
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication 
settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 


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mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on 
distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) 
the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
Rationale for carboplatin and nab-paclitaxel dosing: 
Since pembrolizumab will be administered every 3 weeks, this schedule needed to be 
adapted to a dosing schedule of carboplatin and abraxane that incorporates a 21-day 
treatment cycle, which is one that has been used in advanced lung cancer (39). It has 
therefore been adopted for this clinical trial. 
 
Rationale for CNP dosing schedule: 
The rationale for this approach is that, on days 1 and 8 of the first cycle, only CN will be 
administered to first down regulate immune suppressor cells such as Tregs and MDSC in 
the tumor microenvironment and, second, to increase local tumor antigen release and 
uptake by dendritic cells for the priming of antitumor cytotoxic CD8+ T cells. Then, on 
day 15, P will be administered to enhance newly-generated antitumor CD8+ T cell 
cytotoxicity. In subsequent cycles, P will be administered every 3 weeks, which is the 
favored dosing schedule for this compound (Merck, personal communication) and which, 
by default, will always correspond to concurrent administration with day 15 N.     
 
All trial treatments will be administered on an outpatient basis.  
 
Carboplatin 
administration 
may 
take 
approximately 
60 
minutes. 
Nab-paclitaxel 
administration may take approximately 30 minutes. Pembrolizumab administration may 
take approximately 30 minutes. 
 
After completing 3 cycles of CNP, patients will be radiologically restaged by CT chest, 
abdomen, pelvis and bone scan before starting the next 3 cycles of treatment  and clinical 
responses will be scored according to standard RECIST v1.1 criteria. In an exploratory 
fashion, responses will also be scored using immune response RECIST (irRECIST) 
criteria. Patients will then undergo a post-therapy biopsy. Patients with stable or 
regressing disease will be eligible for 3 additional cycles of CNP whereas patients with 
progressive disease will be removed from the study. Per the investigators’ discretion, 


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patients with pseudo-progression (as per post cycle 3 scans) according to irRECIST 
guidelines may receive an additional 3 cycles of treatment. 
 
NB: While we will be scoring screening TNBC biopsies for PD-L1 expression, we will 
not limit this study to PD-L1 (+) tumors. Our rationale is that chemotherapy may induce 
an 
inflammatory 
T-cell 
infiltration 
into 
an 
initially 
PD-L1-negative 
tumor 
microenvironment causing a subsequent upregulation of PD-L1 expression on tumor cells 
by a T cell-derived cytokine such as IFNγ (35). Thus, what was initially PD-L1 negative 
at the time of the screening biopsy subsequently becomes PD-L1 positive because of 
chemotherapy-induced inflammatory T cell infiltration and, as a result, benefits from 
anti-PD1-based therapy. 
 
No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the subject's malignancy. 
 
6.1.1 Treatment Administration 
 
Day 
1 
8 
15 
22 
29 
36 
43 
50 
 
57 
C 
X 
 
 
X 
 
 
X 
 
 
 
N 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P 
 
 
X 
 
 
X 
 
 
 
X 
 
C, Carboplatin, AUC 4.5 IV day 1 of 21-day cycle 
N, Nab-paclitaxel, 75mg/m2 IV days 1, 8 and 15 of 21-day cycle 
P, Pembrolizumab, 200 mg IV every 21 days  
 
6.1.2 Chemotherapy Dosing Adjustments 
 
A. Carboplatin 
 
 Carboplatin starting dose level: Dose level 0 at AUC 4.5 given IV every 3 weeks. 
Carboplatin dose capping should follow institutional or ASCO guidelines. 
 Carboplatin dose reductions will occur for any ≥ grade 3 hematologic toxicity or a ≥ 
grade 2 non-hematologic toxicity (see below in C.) 
 
B. Nab-Paclitaxel 
 
 Nab-paclitaxel starting dose level: Dose level 0 at 75 mg/m2 given IV weekly. 
 Nab-paclitaxel dose reductions (25% / 56 mg/m2) will occur for any ≥ grade 3 
hematologic toxicity or a ≥ grade 2 non-hematologic toxicity (see below in C.) 
 
 


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C.  Carboplatin and Nab-Paclitaxel 
 For ANC < 1000/μl and/or platelets < 100,000/μl, subsequent doses of carboplatin 
and nab-paclitaxel will be held until ANC ≥ 1000/μl and platelets ≥ 100,000/μl and 
there is resolution of any grade ≥ 2 non-hematologic toxicities (except residual grade 
2 neuropathy) with no dose modification of either drug in subsequent cycles if the 
hematologic toxicities recover by day 21.  
o If nab-paclitaxel is held  on day 8 or day 15 for two  cycles for either ANC < 
1000/μl and/or platelets < 100,000/μl, the subsequent doses of nab-paclitaxel 
and carboplatin will be dose reduced – these reductions will occur even if 
ANC ≥ 1000/μl and platelets ≥ 100,000/μl by day 21. 
 In patients experiencing febrile neutropenia or delay of recovering of ANC to ≥ 
1000/μl beyond day 21 of the preceding cycle or the development of grade  ≥ 3 non-
hematologic toxicities, subsequent doses of both nab-paclitaxel and carboplatin will 
be reduced by 25% to 56 mg/m2 (nab-paclitaxel) and to AUC 3.4 (carboplatin) for all 
subsequent cycles of therapy.  
 If a patient develops an allergic reaction to carboplatin, the patient may still continue 
with nab-paclitaxel as a single agent on days 1 and 8 and nab-paclitaxel with  
pembrolizumab on day 15 for each subsequent cycle. 
 If a grade ≥2 toxicity persists resulting in  treatment being held for more than 4 weeks 
attributable to carboplatin and/or nab-paclitaxel but not pembrolizumab, patients may 
continue on single-agent pembrolizumab given every 3 weeks intravenously as long 
as there is evidence for ongoing clinical benefit to the patient (i.e., regression or 
stability of metastatic disease)  
 If a grade ≥2 toxicity persists resulting in treatment being held for more than 4 weeks 
where attribution to either carboplatin, nab-paclitaxel or pembrolizumab cannot be 
distinguished, then protocol treatment will be discontinued. If this occurs, the patient 
will be removed from the study. 
 
D.  Pembrolizumab 
 
 Pembrolizumab will always be administered on day 15 of each cycle of therapy. 
 If the administration of nab-paclitaxel is held on day 15 because of non-resolution of 
toxicities (see above), then pembrolizumab will still be administered as a single agent 
without nab-paclitaxel.  
 
6.2 
General Concomitant Medications and Supportive Care Guidelines 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  


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o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine. 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.  The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.   
Subjects may receive other medications including white cell growth factor support that 
the treating physician deems to be medically necessary. These treatment decisions should 
be discussed with the principal investigator and handled on an individual patient basis. 
The exclusion criteria describe other medications which are prohibited in this trial. 
There are no prohibited therapies during the post-treatment follow-up phase. 
6.2.1 Supportive Care  
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  


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o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In 
hyperthyroidism, 
non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  


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o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
 Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
Table 6.2.1 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 6.2.1 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
No subsequent dosing 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
support indicated 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
6.3 
Criteria for Removal from Study 
 
In the absence of treatment delays due to adverse events, treatment may continue for 24 
months or until one of the following criteria applies: 
 
• Disease progression, 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• The investigator considers it, for safety reasons, to be in the best interest of the subject.  
 
• Unacceptable adverse event(s) such as:  
o Unacceptable treatment related toxicity, NCI CTC AE version 4.0 Grade 3 or 4 
that fails to recover to baseline or < Grade 3 in the absence of treatment within 4 
weeks. 
o Any toxicity or other issue that causes a delay of study drug administration by 
more than 4 weeks. 
 
• Subject decision to withdraw from treatment (partial consent) or from the study (full 
consent), 
• Pregnancy during the course of the study for a child-bearing participant 
 
• Death 
 
• Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. 
The date and reason for discontinuation must be documented. Every effort should be 
made to complete the appropriate assessments.  
 
6.4 
Duration of Follow Up 
 
The investigator will capture information after a patient withdraws from study (per 
patient agreement).  
 
Subjects will be followed for toxicity for 30 days after treatment has been discontinued or 
until death, whichever occurs first.  
 


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The clinical course of each event will be followed no more than 6 months until 
resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
Patients will be followed for survival every 3 months for at least 12 months after their 
post study 30-day follow-up. 
 
7.0  
Dose Delays/Dose Modifications 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology.  These adverse events may occur shortly after 
the first dose or several months after the last dose of treatment. Pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per Table 7.0 
below. See Section 6.4 for supportive care guidelines. 
 
Table 7.0 Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab  
 
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
Pneumonitis  
Grade 2 
Withhold  
 
Administer corticosteroids (initial dose of 
1-2 mg/kg prednisone or equivalent) 
followed by taper 
 
  Add prophylactic antibiotics for 
opportunistic infections 
 
Monitor 
participants for 
signs and 
symptoms of 
pneumonitis 
 
Evaluate 
participants 
with suspected 
pneumonitis 
with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment 
 
 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 


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Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 
Administer corticosteroids (initial dose of 
1-2 mg/kg prednisone or equivalent) 
followed by taper 
 
 
Monitor 
participants for 
signs and 
symptoms of 
enterocolitis 
(ie, diarrhea, 
abdominal 
pain, blood or 
mucus in stool 
with or without 
fever) and of 
bowel 
perforation 
(ie, peritoneal 
signs and 
ileus). 
 
Participants 
with ≥ Grade 2 
diarrhea 
suspecting 
colitis should 
consider GI 
consultation 
and performing 
endoscopy to 
rule out colitis.  
 
Participants 
with 
diarrhea/colitis 
should be 
advised to 
drink liberal 
quantities of 
clear fluids.  If 
sufficient oral 
fluid intake is 
not feasible, 
fluid and 
electrolytes 
should be 
substituted via 
IV infusion. 
Recurrent Grad3 or 
Grade 4 
Permanently 
discontinue 
AST / ALT elevation 
or Increased bilirubin 
Grade 2 
Withhold 
 
Administer corticosteroids (initial dose of 
0.5- 1 mg/kg prednisone or equivalent) 
followed by taper 
 
Monitor with 
liver function 
tests (consider 
weekly or 
more 
frequently until 
liver enzyme 
value returned 
to baseline or 
is stable 
Grade 3 or 4  
Permanently 
discontinue 
 
Administer corticosteroids (initial dose of 
1-2 mg/kg prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
Newly onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
 
Initiate insulin replacement therapy for 
participants with T1DM  
 
Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
 
Monitor 
participants for 
hyperglycemia 
or other signs 
and symptoms 
of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.   
 
 
Monitor for 
signs and 
symptoms of 
hypophysitis 
(including 
hypopituitaris
m and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  


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Hyperthyroidism  
Grade 2 
Continue  
 
Treat with non-selective beta-blockers (eg, 
propranolol) or thionamides as appropriate  
 
Monitor for 
signs and 
symptoms of 
thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 
Initiate thyroid replacement hormones (eg, 
levothyroxine or liothyroinine) per 
standard of care 
 
Monitor for 
signs and 
symptoms of 
thyroid 
disorders.  
 
Nephritis:  grading 
according to 
increased creatinine 
or acute kidney injury 
Grade 2 
Withhold  
 
Administer corticosteroids (prednisone 1-2 
mg/kg or equivalent) followed by taper. 
 
Monitor 
changes of 
renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold  
Grade 3 or 4  
Permanently discontinue 
 
Withhold  
Permanently discontinue 
 
 
Based on severity of AE administer 
corticosteroids 
 
Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes 
Myocarditis 
Grade 1 or 2 
Withhold 
 
Based on severity of AE administer 
corticosteroids 
 
Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes 
Grade 3 or 4 
Permanently 
discontinue 
 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, TEN,  
Or DRESS 
Confirmed SJS, TEN,  
Or DRESS 
 
Withhold 
Permanently discontinue 
 
 
Based on severity of AE administer 
corticosteriods 
 
Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes 
 
All other immune-
related AEs 
Persistent Grade 2 
Withhold 
 
Based on type and severity of AE 
administer corticosteroids  
 
Ensure 
adequate 
evaluation to 
confirm 
etiology and/or 
exclude other 
causes 
 
Grade 3 
Withhold or discontinue 
based on the type of 
event.  Events that 
require discontinuation 
include and not limited 
to:  Gullain-Barre 
Syndrome, encephalitis 
Grade 4 or recurrent 
Grade 3  
Permanently 
discontinue 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T 1DM).   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy 


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within 4 weeks of the scheduled interruption, unless otherwise discussed with the 
Sponsor. The reason for interruption should be documented in the patient's study record. 
 
8.0 
Adverse Events and Potential Risks  
 
8.1 
Pembrolizumab  
MK-3475 (pembrolizumab) is an agent involved in the blockage of “immune 
checkpoints”. This may result in severe and possibly fatal immune-mediated side effects 
probably due to stimulation and growth of immune cells (T-cells).  Immune-mediated 
side effects have been reported in patients receiving MK-3475 (pembrolizumab).  In 
clinical trials, most immune-mediated side effects went away when pembrolizumab was 
stopped for a short time, steroids were taken and other supportive care given. 
 
MK-3475 can cause the immune system to attack normal organs and tissues in many 
areas of your body and can affect the way they work. These problems can sometimes 
become serious or life-threatening. 
 
1. Lung problems (pneumonitis). Symptoms of pneumonitis may include: 
 
shortness of breath 
 
chest pain 
 
new or worse cough 
 
 
2. Intestinal problems (colitis) that can lead to tears or holes in the intestine. Signs and 
symptoms of colitis may include: 
 
diarrhea or more bowel movements than usual 
 
stools that are black, tarry, sticky, or have blood or mucus 
 
severe stomach-area (abdomen) pain or tenderness 
 
3.  Liver problems (hepatitis). Signs and symptoms of hepatitis may include: 
 
yellowing of the skin or the whites of your eyes 
 
dark urine 
 
nausea or vomiting 
 
feeling less hungry than usual 
 
pain on the right side of your stomach area (abdomen) 
 
bleeding or bruising more easily than normal 
 
4.  Hormone gland problems (especially the thyroid, pituitary, and adrenal glands). Signs 
and symptoms that hormone glands are not working properly may include: 
 
rapid heart beat 
 
weight loss 
 
increased sweating 
 
weight gain 
 
hair loss 
 
feeling cold 


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 
constipation 
 
voice gets deeper 
 
muscle aches 
 
dizziness or fainting 
 
headaches that will not go away or unusual headache 
 
5.  Kidney problems, including nephritis and kidney failure. Signs of kidney problems 
may include: 
 
change in the amount or color of urine. 
 
6. Inflammation of the skin  causing widespread peeling of the skin, itching, and skin 
redness. More severe skin reactions may involve the inside of the mouth, the surface of 
the eye and genital areas, and/or may cause the top layer of the skin to peel from all over 
the body which can cause severe infection.  Rarely these reactions lead to death. 
 
7. Inflammation of the middle layer of the heart wall (myocarditis) that may cause the 
heart to have difficulty pumping blood throughout the body, which can cause chest pain, 
shortness of breath and swelling of the legs.  It is possible to experience a fast or irregular 
heartbeat that may cause dizziness or fainting.  Sometimes this condition can lead to 
death 
 
8.  Problems in other organs. Signs of these problems may include: 
 
rash 
 
changes in eyesight 
 
severe or persistent muscle or joint pains 
 
severe muscle weakness 
 
VERY COMMON 
 
Out of 100 people who receive pembrolizumab, 20 or more people may have the following: 
 Itching of the skin 
 Loose or watery stools 
 Cough 
COMMON 
 
Out of 100 people who receive pembrolizumab at least 5 but less than 20 people may have: 
 
Joint pain 
 
Rash 
 
Fever 
 
Back pain 
 
Pain in the belly 
 
Loss of skin color 
 
Not enough thyroid hormone so subjects may feel tired, gain weight, feel cold, 
have infrequent or hard stools (hypothyroidism) 
 
Low levels of salt in the blood that may cause subjects to feel tired, confused, 
have a headache, muscle cramps and/or feel sick to their stomach (hyponatremia) 
 


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UNCOMMON 
 
Out of 100 people who receive pembrolizumab, at least 1 but less than 5 people may have the 
following: 
 
Too much thyroid hormone so subjects may feel anxious, angry, have trouble 
sleeping, feel weak, tremble, sweat, feel tired, have loose and watery stools 
(hyperthyroidism)  
 
Inflammation of the lungs so subjects may feel short of breath and cough. 
(pneumonitis)   
 
Infusion reaction, where subjects may feel dizzy or faint, flushed, get a rash, have 
a fever, feel  short of breath, experience a decrease in blood pressure at the time 
of receiving their infusion (IV) or just after, or have pain at the site of infusion 
 
Inflammation of the bowels/gut which may cause severe pain in the belly with 
loose or watery stools and black, tarry, sticky stools or stools with blood or 
mucus (colitis) 
 
Inflammation of the skin so subjects may have peeling of the skin, itchiness, 
and/or skin redness. The skin inflammation (i.e. peeling, itching and redness) 
could also be widespread throughout the body. More severe skin reactions may 
involve the inside of the  mouth, the surface of the eye and genital areas, and/or 
may cause the top layer of the skin to peel from all over thebody which can cause 
severe infection.  (Severe skin reactions, including Stevens-Johnson syndrome or 
toxic epidermal necrolysis) 
 
RARE, SOME MAY BE SERIOUS   
Out of 100 people who receive pembrolizumab, less than 1 person may have the following: 
 Inflammation of the liver that may make subjects feel sick to the stomach and vomit, 
feel like not eating, feel tired, have a mild fever, a  pain in the right side of the belly, 
yellow eyes and skin, and dark urine (hepatitis) 
 Inflammation of the pituitary gland (a gland in the head), which may cause you to feel 
sick to the stomach or have headaches, changes in  behavior, double vision, few to no 
menstrual cycles, weakness, vomiting and dizziness or fainting. (hypophysitis)   
 Adrenal glands (glands on top of the kidneys) that may not make enough hormone 
which could cause tiredness, weight loss, muscle weakness, feeling faint, having joint, 
muscle and belly aches, nausea, vomiting, loose or watery stools, fever, salt craving, 
and sometimes darkening of the skin like a suntan (adrenal insufficiency). 
 Inflammation of the kidney so subjects may pass less urine or have cloudy or bloody 
urine, swelling and low back pain (nephritis) 
 Inflammation of the muscles so subjects may feel weak or pain in the 
muscles(myositis)  
 Inflammation of the pancreas, (a gland in the abdomen that controls sugar levels) so 
subjects may have severe pain in the top part of the belly that may move to the back, 
feel sick to the stomach, and vomiting that gets worse when subjects eat (pancreatitis) 
 Inflammation of the eye so subjects may have eye redness, blurred vision, sensitivity to 
light, eye pain, see floaters or have headaches (uveitis) 
 Type 1 Diabetes, a condition that can cause too much sugar in the blood, feeling 
thirstier than usual, frequent urination and weight loss. Subjects are likely to need 
regular insulin shots. 


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 Inflammation of the nerves that may cause pain, weakness or tingling in the hands and 
feet, and may spread to the legs, arms and upper body leading to severe muscle 
weakness and possibly temporary paralysis(Guillain-Barré syndrome) . 
 Inflammation of the middle layer ofthe heart wall that may cause the heart to have 
difficulty pumping blood throughout the body, which can cause chest pain, shortness 
of breath and swelling of the legs.  Subjects  may experience a fast or irregular 
heartbeat that may cause dizziness or fainting . (myocarditis)    
 Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. 
This condition may lead to change in heart rate, blood pressure, body temperature, and 
the rate at which food is converted into energy(thyroiditis) .   
 A condition that may make subjects feel weak and tired and may cause drooping of the 
eyelids, blurred or double vision, difficulty swallowing, slurred speech, weakness in 
your arms and legs, or difficulty breathing (myasthenic syndrome/myasthenia gravis 
including exacerbation) 
 The formation of small clusters of immune cells (called granulomas) in parts of the 
body such as the lymph nodes, eyes, skin,  or lungs (sarcoidosis) 
 Inflammation of the brain with confusion and fever. This may also include: 
disorientation, memory problems, seizures (fits), changes in personality and behavior, 
difficulty speaking, weakness or loss of movement in some parts of the body, and loss 
of consciousness (encephalitis) 
 Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the arms 
or legs, bladder or bowel problems including needing to urinate more frequently, 
urinary incontinence, difficulty urinating, and constipation (myelitis) 
 Inflammation of the blood vessels (vasculitis) 
 
Additionally, since pembrolizumab was approved in September 2014, the following side 
effects have been reported by people receiving pembrolizumab.  
 
 
These side effects were voluntarily reported from a group of people of unknown size. It is 
not possible to estimate the frequency of these side effects: 
 
 
Inflammation of the joints which may include joint pain, stiffness and/or swelling 
(arthritis) 
 
Severe responses of the immune system that cause the body to attack its own blood cells, 
spleen, liver, lymph nodes, skin and brain. This may include fever, rash, inflammation of 
the liver, yellowing of the skin, an enlarged liver and spleen, low blood counts, and 
enlarged lymph nodes. The nervous system may also be affected and cause confusion, 
seizures, and even coma. (hemophagocytic lymphohistiocytosis) 
 
Changes in eyesight, eye pain, whitish patches on the skin and hearing  loss (Vogt-
Koyanagi-Harada syndrome) 
 
Inflammation and scarring of the bile ducts (tubes that carry digestive fluid that is made 
in the liver). This can cause symptoms similar to those seen with inflammation of the 
liver (hepatitis) such as pain in right side of your belly, yellow eyes and skin, feeling 
tired, and itching (sclerosing cholangitis). 
 


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In addition to the above, if subjects have had an allogeneic stem cell transplant (a 
procedure in which a person receives blood-forming stem cells from a donor), they may 
experience graft versus host disease (GvHD), which may include diarrhea, skin rashes, 
and liver damage, after receiving pembrolizumab. Sometimes this condition can lead to 
death. 
 
If  subjects have had a solid organ transplant (for example, received a kidney or heart 
transplant), subjects may experience rejection of the transplanted organ. The study doctor 
will monitor subjects and tell them what signs and symptoms they should report 
depending on the type of organ transplant that they have had. 
 
 
Risks of Venipuncture/Intravenous Needle Insertion:  
 
Occasional, some may be serious: Mild pain and discomfort at the injection or needle 
insertion site as well as possible infection, bleeding, bruising, and soreness.  
 
Rare:  Severe pain, swelling, infection from the actual injection, and fainting.  
 
Reproductive risks: Patients should not get pregnant, or breastfeed while in this study. 
The drugs used in this study could be very damaging to an unborn baby. With regard to 
MK-3475, women of child bearing potential must agree to use adequate contraception 
(barrier method of birth control or abstinence) prior to study entry and for the duration of 
study participation through 120 days after receiving the last dose of MK-3473.   
 
8.2 
Carboplatin  
More common 
 
Pain at place of injection  
 
Nausea and vomiting 
 
Unusual tiredness or weakness 
 
Less common 
 
Black, tarry stools 
 
Blood in urine or stools 
 
Cough or hoarseness, accompanied by fever or chills 
 
Fever or chills 
 
Lower back or side pain, accompanied by fever or chills 
 
Numbness or tingling in fingers or toes 
 
Painful or difficult urination, accompanied by fever or chills 
 
Pinpoint red spots on skin 
 
Skin rash or itching 
 
Unusual bleeding or bruising 
 
Unusual tiredness or weakness 
 
Constipation or diarrhea 
 
Loss of appetite 
 
Rare 


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 
Blurred vision 
 
Ringing in ears 
 
Sores in mouth and on lips 
 
Wheezing 
 
This medicine may cause a temporary loss of hair in some people. After treatment with 
carboplatin has ended, normal hair growth should return. 
 
Hematologic 
 
Hematologic side effects have been reported to include thrombocytopenia with platelet 
counts below 50,000/mm3 in 25% of patients and in 35% of previously treated ovarian 
cancer patients (PTOCP), neutropenia with granulocyte counts below 1,000/mm3 in 16% 
of patients (21% of PTOCP), and leukopenia with WBC counts below 2,000/mm3 in 
15% of patients (26% of PTOCP). 
 
Bone marrow suppression is the dose limiting toxicity of carboplatin. Marrow 
suppression is usually more severe in patients with impaired kidney function. Anemia 
with a hemoglobin count less than 11 g/dL has been observed in 71% of patients who 
started therapy with a baseline above that value. The incidence of anemia increases with 
increasing exposure. Bone marrow depression may be more severe when carboplatin is 
combined with other bone marrow suppressing drugs or with radiotherapy. One study has 
suggested that myelotoxicity could be minimized by the use of regimes based on the 
circadian rhythm of the bone marrow. 
 
Gastrointestinal 
 
Patients previously treated with emetogenic agents (especially cisplatin) have been more 
prone to vomiting. Nausea alone occurs in an additional 10% to 15% of patients. 
Prolonged administration of carboplatin (either by continuous 24 hour infusion or daily 
pulse doses given for 5 consecutive days) was associated with less severe vomiting than 
the single dose intermittent schedule. 
 
Gastrointestinal side effects have included vomiting which occurred in 65% of patients 
and in 81% of PTOCP. In approximately one third of these patients, the vomiting was 
reported as severe. Other gastrointestinal side effects have included pain (17%), diarrhea 
(6%), constipation (6%), and stomatitis. 
 
Nervous system 
 
Nervous system side effects have included peripheral neuropathies which have been 
reported in 4% of patients and 6% of PTOCP, with mild paresthesias occurring most 
frequently. Patients older than 65 years of age or previously treated with cisplatin have 
been reported to have a 10% risk for peripheral neuropathies. Prolonged treatment, 
particularly in cisplatin-pretreated patients, may result in cumulative neurotoxicity. 
 


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Hepatic 
 
Hepatic side effects have included abnormal liver function tests reported in patients with 
normal baseline values receiving standard dosages including total bilirubin (5%), SGOT 
(15%), and alkaline phosphatase (24%), and 5%, 19%, and 37% respectively in PTOCP. 
These abnormalities were mild and reversible in about one-half of the cases.  
 
In patients receiving very high dosages of carboplatin and autologous bone marrow 
transplantation, severe abnormalities of liver function tests have been reported. 
 
Renal 
 
Renal side effects have included abnormalities in 6% of serum creatinine test results 
(10% for PTOCP) and 14% of blood urea nitrogen test results (22% for PTOCP). Most of 
these reported abnormalities have been mild and about one-half of them were reversible. 
There have been at least two case reports in the literature of patients with preexisting 
renal dysfunction deteriorating into renal failure due to intravenous carboplatin therapy. 
In one of the cases, renal failure followed high-dose therapy. In the other patient, acute 
renal failure was reversible. There have also been at least two reports in the literature of 
acute renal failure associated with the use of intraperitoneal carboplatin. Neither patient 
had a full return of renal function to baseline. 
 
Creatinine clearance is the most sensitive measure of renal function in patients receiving 
carboplatin. Creatinine clearance also appears to be the most useful test for correlating 
drug clearance and bone marrow suppression. 
 
Other 
 
Other side effects have included abnormally decreased serum electrolyte values such as 
sodium (29%), magnesium (29%), calcium (22%), and potassium (20%), 47%, 43%, 
31%, and 28% respectively in PTOCP. Electrolyte abnormalities were rarely associated 
with symptoms. 
 
Ototoxicity has been reported with the use of high-dose carboplatin. 
 
The most frequently reported miscellaneous side effects were pain and asthenia. 
 
Hypersensitivity 
 
One study has noted that approximately 40 instances of hypersensitivity have been 
reported. The study further notes that there is generally a slow development of 
hypersensitivity, with reactions evolving only after several cycles of therapy. 
 
Allergic reactions have generally been manageable with standard epinephrine, 
corticosteroid, and antihistamine therapy. 
 


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Hypersensitivity side effects have been reported to include rash, urticaria, erythema, 
pruritus, and rarely bronchospasm and hypotension. Hypersensitivity reactions may be 
common in patients with gynecological malignancies. 
 
Metabolic 
 
Metabolic side effects have included dehydration. 
 
Ocular 
 
Ocular side effects including a case of blindness associated with the use of high dose 
carboplatin have been reported. 
 
8.3 
Nab-paclitaxel  
 
More common 
 
Black or tarry stools 
 
Blurred vision 
 
Burning, numbness, tingling, or painful sensations 
 
Confusion 
 
Cough or hoarseness with fever or chills 
 
Dizziness, faintness, or lightheadedness when getting up suddenly from a lying or 
sitting position 
 
Feeling of warmth 
 
Fever or chills 
 
Lower back or side pain 
 
Painful or difficult urination 
 
Pale skin 
 
Redness of the face, neck, arms, and occasionally, upper chest 
 
Shortness of breath 
 
Skin rash or itching 
 
Sore throat 
 
Sweating  
 
Troubled breathing with exertion 
 
Ulcers, sores, or white spots in the mouth 
 
Unsteadiness 
 
Unusual bleeding or bruising 
 
Unusual tiredness or weakness 
 
Weakness in the arms, hands, legs, or feet  
 
Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of 
pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, 
redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or 
warmth at the injection site 
 
Cracked lips 
 
Diarrhea 
 
Difficulty with swallowing 


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 
Hair loss 
 
Nausea or vomiting 
 
Numbness, burning, or tingling in the hands or feet 
 
Pain in the joints or muscles, especially in the arms or legs 
 
Thinning of the hair 
 
Less common 
 
Blood in the urine or stools 
 
Difficult or labored breathing 
 
Pinpoint red spots on the skin 
 
Shortness of breath (severe) 
 
Slow heartbeat 
 
Tightness in the chest 
 
Wheezing 
 
Incidence not known 
 
Anxiety 
 
Blue lips, fingernails, or skin 
 
Difficult or troubled breathing 
 
Fainting 
 
Fast heartbeat 
 
Irregular, fast or slow, or shallow breathing 
 
Sudden shortness of breath 
 
Hematologic 
 
Hematologic side effects including bone marrow suppression have been the major dose-
limiting toxicity. Neutropenia less than 2,000 cells/mm3 (90%) and less than 500 
cells/mm3 (52%), is the most important hematological toxicity. Neutropenia has been 
both dose and schedule dependent, and generally rapidly reversible. The onset of 
neutropenia generally occurs after 8 to 10 days and recovery generally occurs after 15 to 
21 days. Neutropenia does not appear to increase with cumulative exposure, nor to be 
more frequent or severe for patients previously treated with radiation therapy. 
Leukopenia less than 4,000 cells/mm3 (90%) and less than 1,000 cells/mm3 (17%), 
thrombocytopenia less than 100,000 cells/mm3 (20%) and less than 50,000 cells/mm3 
(7%), and anemia less than 11 g/dl (78%) and less than 8 g/dl (16%) have been reported. 
Infections (30%), bleeding (14%), red cell transfusions (25%) and platelet transfusions 
(2%) have been reported. A case of paclitaxel-induced sickle cell crisis has also been 
reported. 
 
Fever (12% of all treatment courses) has been reported. Fatal infectious episodes (1%) 
including sepsis, pneumonia and peritonitis have been reported. 
 
Bleeding episodes (4% of all courses and 14% of all patients) have been reported. Most 
of the episodes were localized. 
 


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Hypersensitivity 
 
The frequency and severity of hypersensitivity reactions were not affected by the dose or 
schedule of administration. Severe symptoms have primarily been reported to occur 
within the first hour of the infusion. 
 
Single dose intravenous dexamethasone can be used in combination with appropriated 
ancillary medications to prevent paclitaxel-related hypersensitivity reactions. 
 
Hypersensitivity side effects (41%) including severe reactions (2%) have been reported. 
The most frequent symptoms observed during the severe reactions were dyspnea, 
flushing, chest pain, and tachycardia. Minor hypersensitivity reactions consisted mostly 
of flushing (28%), rash (12%), hypotension (4%), dyspnea (2%), tachycardia (2%), and 
hypertension (1%). Three patients with transient pulmonary infiltrates caused by 
hypersensitivity reactions (after receiving treatment with paclitaxel and carboplatin) have 
been reported. A case of pneumonitis responsive to high-dose corticosteroids and a case 
of bullous fixed drug eruption have also been reported. 
 
 
Cardiovascular 
 
Cardiovascular side effects have included vital sign changes including bradycardia (3%) 
and hypotension (12%) during the first 3 hours of infusion as stated by the manufacturer. 
Significant cardiovascular events (1%) including syncope, rhythm abnormalities, 
hypertension and venous thrombosis have also been reported. A report from the Johns 
Hopkins oncology center stated that asymptomatic sinus bradycardia occurred in up to 
29% of patients in phase 2 trails, and that other cardiac disturbances including 
atrioventricular conduction and bundle branch blocks, ventricular tachycardia, and 
possible ischemic manifestations had been reported (3%). A case of fatal myocardial 
infarction potentially induced by paclitaxel has also been reported. 
 
The manufacturer further states that abnormal ECG readings have been reported in 23% 
of all patients receiving paclitaxel and in 14% of the patients with normal baseline ECGs. 
The most frequently reported ECG modifications were nonspecific repolarization 
abnormalities, sinus bradycardia, sinus tachycardia and premature beats. 
 
Nervous system 
 
Nervous system side effects including neurotoxicity, primarily including peripheral 
neurosensory manifestations (60%), have generally been mild to moderate in severity. 
However, severe symptoms (3%) have also been reported. Other serious neurologic 
events (less than 1%) have been reported including grand mal seizures, syncope, ataxia, 
neuroencephalopathy and autonomic neuropathy resulting in paralytic ileus. Disturbances 
of the optic nerve (19%) have also been reported. 
 


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The frequency and severity of neurologic manifestations have been dose dependent and 
cumulative. One study found that although the neurotoxicity was frequent, it remained 
mild or subclinical up to at least 1400 mg/m2 administered over 8 cycles. 
 
Peripheral neuropathy may appear within 24 to 72 hours when high doses are 
administered. The frequency of peripheral neuropathy also has been reported to have 
increased with cumulative dose. It usually presents as a "stocking-and-glove" numbness 
and paresthesia. 
 
At least 3 cases of phantom limb pain associated with paclitaxel use have been reported. 
 
Gastrointestinal 
 
Gastrointestinal effects can generally be treated with standard antiemetic antidiarrheal 
therapy and dietary changes. 
Mucositis occurs most frequently in patients receiving high doses. It is schedule-
dependent, occurring more frequently with 24 and 96 hour infusions. 
 
The author of one of the case reports of pancreatitis suggested that it was the companion 
agent, cremophor that was the cause, rather than the paclitaxel itself. 
 
Gastrointestinal side effects including nausea and vomiting (52%), diarrhea (38%) and 
mucositis (31%) have been reported. Intestinal obstruction, intestinal perforation and 
ischemic colitis have been reported rarely. Three cases of pancreatitis have also been 
reported. 
 
Hepatic 
 
Hepatic side effects including elevations in bilirubin (7%), alkaline phosphatase (22%) 
and AST (SGOT) (19%) have been reported in patients with normal baseline levels. 
Hepatic necrosis and hepatic encephalopathy leading to death have been reported rarely. 
A case of fatal hepatic coma has also been reported. 
 
Prolonged exposure to paclitaxel has not been associated with cumulative hepatic 
toxicity. 
 
Renal 
 
Renal side effects including edema have been reported in 21% of all patients receiving 
paclitaxel and 17% of patients without baseline edema. Severe edema has been reported 
in 1% of patients. 
 
Dermatologic 
 
Dermatologic side effects including transient skin changes due to hypersensitivity 
reactions and skin abnormalities related to radiation recall have been reported. Alopecia 


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(87%) and cumulative loss of body hair have also been reported. Some reports suggest 
that paclitaxel may cause vesicant reactions when extravasated. Nail changes including 
changes in pigmentation or discoloration of the nail bed have been reported (2%). Two 
cases of cutaneous lupus erythematosus and one case of systemic lupus erythematosus 
have been reported. Two cases of scleroderma-like reactions have been reported. A case 
of paclitaxel administration via a central vein producing a recall reaction at a site of prior 
paclitaxel extravasation has also been reported. A case of severe mucocutaneous toxicity 
and a case of cutaneous systemic sclerosis have been reported. 
 
Alopecia usually begins 1 to 2 weeks after treatment and is usually reversible. 
 
Respiratory 
 
Respiratory side effects including radiation recall pneumonitis have been reported. 
 
Musculoskeletal 
 
Symptoms were usually transient, occurred two or three days after drug administration 
and resolved within five to seven days. Symptoms are more frequent and severe in 
patients receiving doses greater than 200 mg/m2. 
 
Musculoskeletal side effects including myalgia and/or arthralgia (60%), including severe 
symptoms (8%) have been reported. 
 
Local 
 
Injection site reactions, including reactions secondary to extravasation, were usually mild 
and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. 
 
Local side effects have included injection site reactions. Phlebitis has been reported 
rarely. 
 
Other 
 
Other side effects including cellulitis have been reported rarely. 
 
8.2 
Definitions  
 
8.2.1 
Adverse Event   
 
An adverse event (AE) is any unfavorable or unintended event, physical or 
psychological, associated with a research study, which causes harm or injury to a 
research participant as a result of the participant’s involvement in a research study. The 
event can include abnormal laboratory findings, symptoms, or disease associated with the 
research study. The event does not necessarily have to have a causal relationship with the 


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research, any risk associated with the research, the research intervention, or the research 
assessments.  
 
Adverse events may be the result of the interventions and interactions used in the 
research; the collection of identifiable private information in the research; an underlying 
disease, disorder, or condition of the subject; and/or other circumstances unrelated to the 
research or any underlying disease, disorder, or condition of the subject.  
 
Progression of the cancer under study is not considered an adverse event. 
 
8.2.2   Serious Adverse Events  
 
A serious adverse event (SAE) is any adverse experience occurring at any dose that 
results in any of the following outcomes:  
 Results in death.  
 Is a life-threatening adverse experience.  The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk 
of death at the time of the event.  It does not refer to an adverse event which 
hypothetically might have caused death if it were more severe.  
 Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.  Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization 
may fulfill the criteria of “medically important” and as such may be reportable as 
a serious adverse event dependant on clinical judgment.  In addition where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.  
 Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal 
life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a 
serious adverse experience when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples 
of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood disease or disorders, or 
convulsions that do not result in inpatient hospitalization, or the development 


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of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
8.2.3 Adverse Event Evaluation  
 
The investigator or designee is responsible for ensuring that all adverse events (both 
serious and non-serious) observed by the clinical team or reported by the subject which 
occur after the subject has signed the informed consent are fully recorded in the subject’s 
medical records. Source documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, 
result in a delay or dose modification of study treatment, or judged relevant by the 
investigator), should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the 
following for all adverse events (both serious and non-serious): 
 Event term (as per CTCAE) 
 Description of the event 
 Date of onset and resolution 
 Expectedness of the toxicity 
 Grade of toxicity  
 Attribution of relatedness to the investigational agent- (this must be assigned 
by an investigator, sub-investigator, or treating physician) 
 Action taken as a result of the event, including but not limited to; no changes, 
dose interrupted, reduced, discontinued, etc. or action taken with regard to the 
event, i.e. no action, received conmed or other intervention, etc. 
 Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the 
study drug.  Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 


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 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment 
regimen or the treatment regimen as a whole. 
 
8.3  
SAE Report Form 
 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported 
as instructed below.  The electronic FDA SAE reporting forms should not be used.   
 
8.4  
Reporting Procedures for Serious Adverse Events 
 
For the purposes of safety reporting, all adverse events will be reported that occur starting   
on Cycle 1 Day 1 through 30 days after the final dose of study drug. Adverse events, both 
serious and non-serious, and deaths that occur during this period will be recorded in the 
source documents. All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). 
Related AEs will be followed until resolution to baseline or grade 1 or stabilization.  
 
 
8.4.1 SAE Reporting Requirements 
 
 Participating investigators (all sites) must report all serious adverse events to the 
Lead Site Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of 
discovery or notification of the event. The participating investigator must also 
provide follow-up information on the SAE until final resolution.  
o Joseph Baar, MD 
 The Lead Site Principal Investigator will review the SAE and report the event to 
the FDA, external collaborator(s), and IRB as applicable. 
 It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL 
serious adverse events that occur on the study (e.g. ALL SAEs that occur at each 
enrolling institution) are reported to all participating sites. 
 
8.4.2 Merck Reporting Requirements 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject 
from the time the consent is signed through 90 days following cessation of treatment, or 
the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to 
Merck product, must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will 
be handled in the same manner as SAEs.  


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Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by 
FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or 
other local regulators. Investigators will cross reference this submission according to 
local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the 
time of submission. Additionally investigators will submit a copy of these reports to 
Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in a 
subject (spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before 
treatment allocation/randomization must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, 
must be reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine 
death, miscarriage and stillbirth must be reported as serious events (Important Medical 
Events). If the pregnancy continues to term, the outcome (health of infant) must also be 
reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
8.4.3 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the Adverse Event case report 
forms/worksheets and reported within 24 hours to the Sponsor and within 2 working days 


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to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)Events of 
clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
8.4.4  Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available 
on the treatment of overdose of pembrolizumab. Appropriate supportive treatment should 
be provided if clinically indicated. In the event of overdose, the subject should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
 
8.4.5  Institutional Review Board Reporting Requirements: 
 Investigative sites will report adverse events to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events.  
 
8.4.6   FDA Reporting: 


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The University Hospitals Principal Investigator, as holder of the IND, will be 
responsible for all communication with the FDA.  In accordance with 21 CFR 
312.32, the University Hospitals Principal Investigator is responsible for notifying 
the FDA of SAEs that are serious, unexpected (not listed in the Investigator 
Brochure) and judged to be related (i.e., possible, probable, definite) to the study 
drug.  Events meeting the following criteria need to be submitted to the FDA as 
Expedited IND Safety Reports.    
 
7 Calendar Day IND Safety Report 
Any unexpected fatal or life-threatening suspected adverse event represent 
especially important safety information and, therefore, must be reported more 
rapidly to FDA (21 CFR 312.32(c)(2)).  Any unexpected fatal or life-threatening 
suspected adverse event must be reported to FDA no later than 7 calendar days 
after the University Hospitals Principal Investigator initial receipt of the 
information (21 CFR 312.32(c)(2)). University Hospitals Principal Investigator 
will complete a Medwatch Form FDA 3500A and notify the FDA by telephone or 
facsimile transmission. 
 
7 Calendar Day IND Safety Report 
Any unexpected fatal or life-threatening suspected adverse event represent 
especially important safety information and, therefore, must be reported more 
rapidly to FDA (21 CFR 312.32(c)(2)).  Any unexpected fatal or life-threatening 
suspected adverse event must be reported to FDA no later than 7 calendar days 
after the University Hospitals Principal Investigator initial receipt of the 
information (21 CFR 312.32(c)(2)). University Hospitals Principal Investigator 
will complete a Medwatch Form FDA 3500A and notify the FDA by telephone or 
facsimile transmission. 
 
15 Calendar Day IND Safety Report 
The timeframe for submitting an IND safety report to FDA and all participating 
investigators is no later than 15 calendar days after the University Hospitals 
Principal Investigator determines that the suspected adverse event or other 
information qualifies for reporting (21 CFR 312.32(c)(1)).  This includes any 
serious, unexpected adverse events considered reasonably or possibly related to 
the investigational agent. University Hospitals Principal Investigator will 
complete a Medwatch Form FDA 3500A and notify the FDA by telephone or 
facsimile transmission.  If FDA requests any additional data or information, the 
University Hospitals Principal Investigator must submit it to FDA as soon as 
possible, but no later than 15 calendar days after receiving the request (21 CFR 
312.32(c)(1)(v)).    
 
Follow-up IND Safety Report 
Any relevant additional information that the University Hospitals Principal 
Investigator obtains that pertains to a previously submitted IND safety report must 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as 
the information is available (21 CFR 312.32(d)(2)).  The University Hospitals 


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Principal Investigator will maintain records of its efforts to obtain additional 
information. 
 
 
 
 
 
8.5 
SAEs and OnCore 
 All SAEs will be entered into OnCore.   
 A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded 
into Oncore. 
 
8.6  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial 
(internal or external) are reported to the Case Comprehensive Cancer Center’s Data and 
Safety Toxicity Committee. This submission is simultaneous with their submission to the 
sponsor and/or other regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as 
per CCCC Data and Safety Monitoring Plan. 
 
8.7 
Data and Safety Monitoring Plan (DSMP) 
 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
PHARMACEUTICAL INFORMATION  
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8. 
 
 
9.1  
Investigational Agent 
 
9.1.1  Name of Agent 
Pembrolizumab 
 
Other Names:   
MK-3475  
 
Product description: Pembrolizumab is provided as a white to off white lyophilized 
powder (50 mg/vial) or as a liquid solution (100 mg/vial) in Type I glass vials intended 
for single use only. 
 
Reporting Serious Problems to FDA 
Medwatch Form FDA 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
Telephone: 1-800-332-1088 
Fax: 1-800-FDA-0178 
 
Reporting Serious Problems to FDA 
Medwatch Form FDA 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
Telephone: 1-800-332-1088 
Fax: 1-800-FDA-0178 
 


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Solution preparation: Pembrolizumab Powder for Solution for Infusion, 50 mg/vial, is 
reconstituted with sterile water for injection prior to use. The drug product is stored as a 
stable lyophilized powder or liquid solution under refrigerated conditions (2 to 8°C). 
 
The lyophilized drug product after reconstitution with sterile water for injection, and the 
liquid drug product are a clear to opalescent solutions, essentially free of visible particles. 
The reconstituted lyophilized product and the liquid product are intended for IV 
administration.  
 
The reconstituted drug product solution or the liquid drug product can be further diluted 
with normal saline or 5% dextrose in the concentration range of 1 to 10 mg/mL in 
intravenous (IV) containers made of polyvinyl chloride (PVC) or non-PVC material.  
Reconstituted vials should be immediately used to prepare the infusion solution in the IV 
bag and the infusion solution should be immediately administered. 
 
Storage requirements: Diluted pembrolizumab solutions may be stored at room 
temperature for a cumulative time of up to 4 hours. This includes room temperature 
storage of admixture solutions in the IV bags and the duration of infusion. In addition, IV 
bags can be stored at 2 to 8°C for up to a cumulative time of 20 hours. This 
recommendation is based on up to 24 hours of room temperature and up to 24 hours of 
refrigerated stability data of diluted MK-3475 solutions in the IV bags. 
 
Route of administration: 200 mg IV every 21 days (3 weeks) 
 
Drug Procurement: Pembrolizumab will be supplied for this study by Merck.  
 
Packaging and labeling: Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements. 
 
Drug Accountability: The investigator is responsible for keeping accurate records of the 
clinical supplies received from Merck or designee, the amount dispensed to and returned 
by the subjects and the amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to a rra nge  for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
9.2  
Commercial Agents 
 
9.2.1  Carboplatin  
 


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Product description: Carboplatin is commercially available as a sterile lyophilized 
powder available in single-dose vials containing 50 mg, 150 mg and 450 mg of 
carboplatin.  Each vial contains equal parts by weight of carboplatin and mannitol. 
Refer to the package insert for further information. 
 
Solution preparation:  Immediately before use the content of each vial must be 
reconstituted with either sterile water for injection, USP, 5% dextrose in water, or 0.9% 
sodium chloride injection, USP according to the following schedule: 
 
 
 
Vial Strength 
Diluent Volume 
 
 
 
     50 mg 
        5 ml 
 
 
 
    150 mg 
      15 ml 
 
 
  
    450 mg 
      45 ml 
These dilutions all produce a carboplatin concentration of 10 mg/ml.  When prepared as 
directed carboplatin solutions are stable for eight hours at room temperature.  Since no 
antibacterial preservative is contained in the formulation it is recommended that 
carboplatin solutions be discarded eight hours after dilution. 
Note:  Aluminum reacts with carboplatin causing precipitate formation and loss of 
potency; therefore, needles or intravenous sets containing aluminum parts that may come 
in contact with the drug must not be used for the preparation or administration of 
carboplatin. 
 
Storage and Stability: Unopened vials of carboplatin are stable for the life indicated on 
the package when stored at controlled room temperature and protected from light. 
 
Route of administration: AUC 4.5 IV on Day 1 of 21-day cycle. 
 
Drug Procurement: Carboplatin must be obtained from commercial sources.  
 
 
9.2.2  Nab-paclitaxel 
 
Other Names: Abraxane 
 
Product description:  nab-Paclitaxel must be obtained commercially and is available in 
single-use vials in single count cartons. Each single-use 50 mL vial will contain 
paclitaxel (100 mg) and approximately 900 mg human albumin as a stabilizer. 
 
Solution preparation: nab-Paclitaxel is supplied as a sterile, lyophilized powder for 
reconstitution before use.  
 
Instructions for reconstitution: 
1. Aseptically, reconstitute each vial by injecting 20mL of 0.9% sodium chloride 
injection. 


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2. Slowly inject the 20mL of 0.9% sodium chloride injection over a minimum of 
1 minute, using the sterile syringe to direct the solution flow onto the INSIDE 
WALL OF THE VIAL. 
3. DO NOT INJECT the 0.9% sodium chloride injection directly onto the 
lyophilized cake as this will result in foaming 
4. Once the injection is complete, allow the vial to sit for a minimum of 5 
minutes to ensure proper wetting of the lyophilized cake/powder. 
5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any cake/powder occurs. Avoid generation of foam. 
6. If foaming or clumping occurs, stand solution for at least 15 minutes until 
foam subsides. 
 
Storage requirements: Un-reconstituted nab-paclitaxel should be stored in accordance 
with the product label. 
 
Reconstituted nab-paclitaxel should be used immediately. If not used immediately, the 
vial of reconstituted nab-paclitaxel must be placed in its carton and be placed in a 
refrigerator at 2° to 8°C (36° to 46°F) for a maximum of 8 hours. Both forms should be 
stored in an area free of environmental extremes and must be accessible only to study 
personnel. 
 
Route of administration:  Short intravenous infusion over approximately 30-40 minutes. 
 
Drug Procurement: Abraxane must be obtained by commercial sources. 
 
 
10.0 
EXPLORATORY or CORRELATIVE STUDIES 
 
The following translational analyses will be coordinated by Shaveta Vinayak, MD.  
 
We will correlate these independent measures with response to this chemo-
immunotherapy combination: 1) pathology-based TIL scores (intratumoral and stromal) 
and quantitative computer-based TILs assessment; 2) gene expression-based TNBC 
subtypes; 3) gene expression-based immune signatures and immune cell subsets; and 4) 
immune cell subsets by multiplex IHC/IF in mTNBC.  Lastly, we will integrate all four 
independent immune cell assessments, and correlate this integrative evaluation with 
response to the chemo-immunotherapy combination in mTNBC.  
 
The following standard operating procedures (SOPs) are a guideline for collection of 
preoperative tissue core biopsies and of tissue at the time of surgery for these clinical 
trials. It is expected that minor differences in tissue handling may be necessary due to 
variation in institutional practice; however, it is important to adhere as closely as possible 
to these SOPs to maintain optimal conditions for tissue collection and processing. Where 
possible, options will be provided to allow flexibility in the SOP.  Deviation from these 
SOPs MUST be recorded to allow for quality control and quality assurance. 
 


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The Translational Research and Pharmacology Core (TRPC) under the direction of John 
Pink Ph.D., will coordinate acquisition, processing and storage of correlative study 
specimens. Contact information for personnel responsible for these studies: 
 
Patients enrolled at UH/CMC 
Translational Research & Pharmacology Core 
ATTN  Erin Hohler 
University Hospitals of Cleveland 
11100 Euclid Avenue 
Seidman Cancer Center, Room 3608 
Cleveland, OH 44106 
Telephone: 216-286-3889/216-386-3890 
Pager: 33471 
E-mail: emh14@case.edu 
 
Patients enrolled at CCF: 
Cleveland Clinic Central Biorepository: Department of Pathology L25 
9500 Euclid Avenue  
Cleveland, Ohio 44195 
(216) 444-0047 
tisscenterao@ccf.org 
 
Biopsy Collection  
 Coordination between the clinical team and the study personnel responsible for 
freezing the cores is essential in order to freeze the cores immediately after they’ve 
been taken.  
 Core biopsies may be obtained by radiology or by surgery. It is STRONGLY 
RECOMMENDED that image guidance be used to localize the primary tumor for 
collection of core biopsy material. This can be achieved in the radiology suite, at 
the time of clip placement, sentinel node sampling or other procedure as a separate 
'research only' biopsy and is typically performed under US guidance. MRI 
guidance is also acceptable. If the surgeon is taking the biopsy it can be done using 
a handheld ultrasound, or similar device. If such a device is not available then 
biopsies may be obtained without image guidance although the likelihood of 
collecting invasive cancer is reduced by 10-20% in this case.  
 Four (4) 14-18 gauge cores of  a metastatic  tumor nodule should be obtained at 
each biopsy time point. If it is not possible to obtain four cores, as many as 
possible should be collected.  
 
Specimen Processing: 
 
Four (4) 14-18 gauge cores (prefer a 14-gauge needle but can use a smaller diameter 
needle to a minimum of 18 gauge) of a metastatic tumor nodule should be obtained at 
each biopsy time point if possible. If it is not possible to obtain four cores, as many as 
possible should be collected.  
 


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Processing should proceed in the following order for the 4 biopsies: 
 
#1: Fixed in 10% Neutral Buffered Formalin (40ml container) 
#2: Snap frozen in a sterile RNAse-free cryovial 
#3: Frozen in OCT 
#4: Snap frozen in a sterile RNAse-free cryovial 
 
Timely processing of the specimens is critical, please contact TRPC or CCF Central 
Biorepository personnel prior to biopsy procedure to arrange for transportation and 
processing. 
 
Specimens will be frozen over dry ice, or in liquid nitrogen (if available), and stored at    
-80˚C until processed. 
 
Formalin fixed specimens will be transported within 1 day to the CaseCCC Tissue 
Resources Core, for completion of fixation processing and embedding. Once embedded 
they will be stored in the Tissue Resources Core until slides are cut and stained. 
Specimens from patients enrolled at CCF will be sent by courier at regular intervals 
(approximately every 3 months) for storage in the TRPC. 
 
Frozen specimens will be stored in the TRPC until processed for RNA and/or DNA 
isolation. 
 
 
 
10.1 
Pathology-Based and Quantitative Computer-Based Tumor Infiltrating 
Lymphocyte (TIL) Assessment 
 
Specimen to be used: Formalin-fixed tumor tissue from metastatic site.  
 
10.1.1 Background  
 
Pathology-based TIL scores (intratumoral and stromal) have been shown to be 
prognostic and predictive of therapy response in TNBC.   
 
10.1.2   Rationale for Analysis 
 
Pathology-based TIL scores (intratumoral and stromal) will be assessed prior to 
treatment and in the post-treatment biopsy in patients, if collected.  International TILs 
working group guidelines by Salgado et al. will be used.  Quantitative computer-based 
methodology has been developed by our Case collaborators (Dr. Madabhushi), which 
will be applied to this cohort of samples.  
 
10.1.3 Collection of Specimens 
 


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FFPE slides will be cut and stained with H&E in batches upon request of the Principal 
Investigator in the Tissue Resources Core and TIL scores will be assessed by Hannah 
Gilmore MD.   Slides will be digitized and quantitative TIL scores will be assessed.   
 
10.2 
Gene Expression Based TNBC subset Analysis 
 
Specimen used: Snap frozen tumor tissue from the metastatic site.  
 
10.2.1 Background  
 
RNA and DNA will be extracted from tumor cores in the Translational Research and 
Pharmacology Core (TRPC) and Affymetrix Human Transcriptome Array (HTA) 2.0 
will be used to generate whole genome gene expression data. After normalization and 
gene-level expression summarization, the Pietenpol molecular subytypes will be 
assessed TNBC using the online “TNBC type” tool (36).   
 
10.2.2   Rationale for Analysis 
 
Given the molecular heterogeneiety of TNBC, TNBC gene-expression subtypes will be 
determined and then response will be assessed within subtypes. TNBC subtyping tool as 
described previously will be applied.  Tumor DNA will be used for other correlatives 
including neoantigen repertoire and T-cell receptor repertoire.   
 
10.3 
Gene expression-based immune signatures and immune cell subsets  
 
Specimen used: Snap frozen tumor tissue from the metastatic site.  
 
 
10.3.1 Background  
 
Immune cell subsets will be determined based on gene expression profiling using 
established computational methodologies such as CIBERSORT.  Nanostring may be 
used as well.   
 
10.3.2   Rationale for Analysis 
 
Pre-defined immune signatures and immune cell subset methodologies will be scored for 
each sample (38).  These will be correlated with response.   
 
10.4 
Immune cell subsets by multiplex IHC/IF in mTNBC  
 
Specimen to be used: Formalin-fixed tumor tissue from the metastatic sites. Samples for 
PD-L1 testing will be shipped in batches to the central lab, QualTek Molecular 
Labortories at: 
 
QualTek Molecular Laboratories 300 Pheasant Run  


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Newtown, PA 18940  
Phone: 215-504-7402  
Fax: 805-830-6379  
Email: info@qmlabs.com 
 
10.4.1 Background  
 
Multiplex IHC/IF will be used to assess immune cell subsets and checkpoints, including 
PD-L1.  We will assess how these change with therapy and their correlation with 
response.   
 
10.4.2   Rationale for Analysis 
 
Tumor-based changes in immune cell subsets will be assessed in both pre-treatment and 
post-treatment biopsy, if available.  Our pathology core has validated these immune 
markers by IHC already.   
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
General Study Parameters 
The following clinical laboratory tests will be performed:  
 
Serum Chemistry: Comprehensive Panel (including glucose, sodium, potassium, 
chloride, bicarbonate, anion gap, nitrogen urea, creatinine, calcium, albumin, alkaline 
phosphatase (ALP), total protein, asparate aminotransferase (AST), total bilirubin, 
alanine aminotransferace (ALT), thyroid stimulating hormone (TSH), T4Thyroxine, T3 
and magnesium. 
 
*Note for serum chemistries: Tests for AST, ALT, ALP and total bilirubin must be 
conducted concurrently and assessed concurrently.  
 
Hematology: Hematocrit, Hemoglobin, White cell count with differential count, Platelet 
count 
 
Urinalysis (screening only): Macroscopic (including color, clarity, specific gravity, pH, 
leukocyte 
esterase, 
nitrite, 
ketones, 
protein, 
glucose, 
ketones, 
blood, 
bilirubin, 
urobilinogen) 
Microscopic (including red blood cells, white blood cells, bacterial, epithelial cells, 
mucous, cast, crystal  
 
Imaging: Imaging will be done every 3 cycles and a repeat brain CT/MRI will only be 
undertaken to check for brain metastases stability if patients had brain metastases at time 
of enrollment. MRI brain will only be done if there is either a history of prior brain mets 
or the patient presents with suspicious symptoms. Otherwise, the brain MRI will not be 
part of screening or follow up.  
 


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11.1.1 Screening Evaluation  
 
Screening studies and evaluations will be used to determine the eligibility of each subject 
for study inclusion. All evaluations must be completed within 28 days prior to study 
entry.  
 
Screening correlative biopsy will be obtained, preferably will obtain a fresh tissue biopsy. 
Urinalysis will be done at screening only.  
 
11.1.2 Treatment Period 
Treatment will be cycle-based.  
 
C, Carboplatin, will be administered AUC 4.5 IV day 1 of 21-day cycle. 
N, Nab-paclitaxel, will be administered 75 mg/m2 IV days 1, 8 and 15 of 21-day cycle. 
P, Pembrolizumab, will be administered 200 mg IV every 21 days . 
 
Treatment on this regimen will continue until disease progression. 
 
11.1.3 30 Day Follow-Up 
For the purposes of safety reporting, all adverse events will be reported that occur starting   
on Cycle 1 Day 1 through 30 days after the final dose of study drug. Adverse events, both 
serious and non-serious, and deaths that occur during this period will be recorded in the 
source documents. All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). 
Related AEs will be followed until resolution to baseline or grade 1 or stabilization. 
 
11.1.4 Long Term Follow-Up 
Patients will be followed for survival for at least 12 months after their post 30 day follow-
up. A phone call is sufficient for this visit.  
 
11.2 
Calendar  
 
A visit window of +/- 3 days is allowed for labs (hematology and chemistries including 
TSH, T3, T4 and HCG, vital signs, weight and performance status)   
A visit window of +/- 1 day is allowed for treatment. 
A visit window of +/- 7 days is allowed for 3 month follow-up visits. 
A visit window of +/- 3 days is allowed for  the 30 Day follow-up visit. 
 


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Study Days 
Screening 
Cycles  
1-n1 
Day 1 
Cycles  
1-n1 
Day 8 
Cycles  
1-n1 
Day 15 
After 
completion 
of 3 cycles 
of 
treatment 
 
30 Day 
Follow-Up 
 
Long Term 
Follow-Up 
(see section 
11.1.4 for 
details) 
REQUIRED 
ASSESSMENTS 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Height  
X 
 
 
 
 
 
 
Weight and Body Surface 
Analysis 
X 
X 
X 
X 
X 
X 
 
Vitals including blood 
pressure 
X 
X 
X 
X 
X 
X 
 
Physical Examination  
X 
X 
 
 
X 
X 
 
Concomitant medication + 
allergy assessment 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
 
Baseline Symptoms 
X 
 
 
 
 
X 
 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
CBC / diff / platelets  
X 
X 
X 
X 
X 
X 
 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
TSH, T4 Thyroxine, T35 
X 
X 
 
 
 
 
 
ß-HCG,  women of 
childbearing potential 
(Cycle 1 only) 
X 
X 
 
 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
MRI Brain (see section 
11.1 for details) 
X 
X 
 
 
X 
X 
 
CT Chest, Abdomen and 
Pelvis3 
X 
 
 
 
X 
 
 
Bone Scan 
X 
 
 
 
X 
 
 
TREATMENT 
 
 
 
 
 
 
 
Nab-paclitaxel4 
 
X 
X 
X 
 
 
 
Carboplatin4 
 
X 
 
 
 
 
 
Pembrolizumab4 
 
 
 
X 
 
 
 
CORRELATIVE 
 
 
 
 
 
 
 
Biopsy 
X 
 
 
 
X (Optional 
after 
completion 
of 1st 3 
cycles only)2 
 
 
1 Patients may receive treatment for up to 24 months  
2Biopsy must be completed before the initiation of cycle 4 
3Cycle 3 assessment scans must be done at the conclusion of cycle 3 but before the 
 initiation of cycle 4. 
4 Patients who discontinue carboplatin and/or nab-paclitaxel due to experiencing  known 
toxicities to carboplatin and/or nab-paclitaxel  will continue to follow the study calendar 
for all tests and procedures done on Day 1 of each consecutive cycle if they continue to 


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receive carboplatin or on Day1,  8 and 15 of each consecutive cycles if they continue to 
receive nab-paclitaxel. Patients receiving pembrolizumab only will  follow the study 
calendar for all tests and procedures done on Day 15 of each consecutive cycle. 
5 Patients receiving pembrolizumab only will have thyroid testing done on Day 15 of 
each consecutive cycle. 
 
12.0  MEASUREMENT OF EFFECT  
 
Clinical response will be scored according to RECIST Criteria v1.1.  
As an exploratory objective, we will score clinical response using irRECIST criteria [40].  
 
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
 
The OnCore® and Forte EDC Databases will be utilized, as required by the Case 
Comprehensive Cancer Center, to provide data collection for both accrual entry and trial 
data management. OnCore® is a Clinical Trials Management System housed on secure 
servers maintained at Case Western Reserve University. Forte EDC is an electronic data 
capture system which supports 21 CFR Part 11 compliance. Access to data through Forte 
EDC is restricted by user accounts and assigned roles. Once logged into the OnCore ®  
and Forte EDC systems with a user ID and password, defined roles for each user limit 
access to appropriate data. User information and password can be obtained by contacting 
the OnCore ®Administrator at OnCore-registration@case.edu. 
 
OnCore®  and Forte EDC are  designed with the capability for study setup, activation, 
tracking, reporting, data monitoring and review, and eligibility verification. This study 
will utilize electronic Case Report Form completion in the Forte EDC database. A 
calendar of events and required forms are available in OnCore® and Forte EDC 
 
13.2 
Regulatory Considerations 
 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 
13.2.1 Written Informed Consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject 


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should be given the opportunity to ask questions and be allowed time to consider the 
information provided.  
The original, signed written Informed Consent Form must be kept with the Research 
Chart in conformance with the institution’s standard operating procedures. A copy of the 
signed written Informed Consent Form must be given to the subject. Additionally, 
documentation of the consenting process should be located in the research chart. 
13.2.2 Subject Data Protection 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to 
subject’s medical information that includes all hospital records relevant to the study, 
including subjects’ medical history.  
 
13.2.3  Retention of Records 
 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted.  
 
13.2.4  Audits and Inspections  
 
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonization (ICH), and any 
applicable regulatory requirements.  For multi-center studies, participating sites must 
inform the sponsor-investigator of pending audits.  
 
14.0 STATISTICAL CONSIDERATIONS  
 
Aim 1. Determine ORR in patients treated with CNP. 
 
Clinical response will be scored using Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) criteria. In order to determine the sample size of this study, a confidence 
interval approach was used. Under the proposed treatment, the expected clinical response 
is about 35%.  With the precision of the 2-sided 95% confidence interval for the response 
rate set to 0.17 (the distance to the expected response rate of 35%), then the sample size 
required for the study is 30 patients.  The true response rate of the therapy for this patient 


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population will be estimated based on the number of responses using a binomial 
distribution and its confidence intervals will be estimated using Wilson’s method [41]. 
The same method will be used to estimate disease control rate. Safety/tolerability data 
will be summarized using descriptive statistics. 
 
 
Aim 2. Determine PFS in patients treated with CNP. 
 
The Kaplan-Meier method [42] will be used to estimate PFS.  Factors including 
pathologic and genomic correlates that predict survival outcomes will be identified by 
Cox model [43] or extensions of Cox model [44]. 
 
Aim 3. Identify pathologic and genomic correlates of response to CNP. 
 
The IHC, morphometric and genomic correlates will be assessed by comparing 
responders and non-responders with each specific marker as a continuous variable (TIL, 
Immune scores) or dichotomous variable (TNBC subtypes, Pathway analysis, IHC for 
PDL1). T-test and chi-square test will be used for the comparison of continuous variables 
and dichotomous variable, respectively.  Furthermore, the pathologic and genomic 
predictors on overall response (CR+PR) and disease control (CR+PR+SD) will be 
identified using logistic regressions.  With the limited the sample size, the analysis will 
be exploratory in nature.  
15.0 
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APPENDIX I 
 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Description 
 
0 
 
Normal activity. Full active, able 
to carry on all pre-disease 
performance without restriction.  
 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
 
2 
In bed < 50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% if waking hours. 
 
3 
In bed > 50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours. 
 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX II 
Immune-mediated Adverse Reactions 
 
Immune-mediated Adverse Reactions 
 
Endocrinopathies: The median time to onset of hypophysitis was 1.7 months (range 1 day to 6.5 
months). The median duration was 3.3 months (range 0.8 months to 12.7 months). 
Hypophysitis led to discontinuation of KEYTRUDA in 4 (0.3%) subjects. Hypophysitis resolved 
in 5 subjects. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 21.9 
months). The median duration was 2.8 months (range 1.4 weeks to 12.8 months). 
Hyperthyroidism led to discontinuation of KEYTRUDA in 2 (0.1%) subjects. 
 
Hyperthyroidism resolved in 25 subjects. The median time to onset of hypothyroidism was 3.5 
months (range 5 days to 18.9 months). The median duration was 6.4 months (range 0.9 weeks to 
24.3 months). No subjects discontinued KEYTRUDA due to hypothyroidism. 
Pneumonitis: The median time to onset of pneumonitis was 3.1 months (range 2 days to 19.3 
months). The median duration was 1.7 months (range 0.3 weeks to 15.1 months). 
 
Pneumonitis led to discontinuation of KEYTRUDA in 20 (1.3%) subjects. Pneumonitis resolved 
in 28 subjects. 
 
Colitis: The median time to onset of colitis was 3.4 months (range 1.3 weeks to 9.7 months). 
The median duration was 1.2 months (range 0.6 weeks to 7.2 months). Colitis led to 
discontinuation of KEYTRUDA in 7 (0.4%) subjects. Colitis resolved in 19 subjects. 
 
Hepatitis: The median time to onset of hepatitis was 3.1 weeks (range 1.1 weeks to 21.4 months). 
The median duration was 1.3 months (range 1.1 weeks to 2.2 months). Hepatitis led to 
discontinuation of KEYTRUDA in 2 (0.1%) subjects. Hepatitis resolved in 6 subjects. 
 
Nephritis: The median time to onset of nephritis was 6.8 months (range 1.7 weeks to 12.8 
months). The median duration was 1.1 months (range 2.1 weeks to 3.3 months). Nephritis led to 
discontinuation of KEYTRUDA in 1 (0.1%) subject. Nephritis resolved in 3 subjects. 

ICF_001.pdf: 
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