Conditions: Soft Tissue Sarcoma, Adult Soft Tissue Sarcoma, Child
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety, tolerability and efficacy of doxorubicin in combination with pembrolizumab in subjects with metastatic or unresectable soft tissue sarcoma. Based on previous studies, pembrolizumab may be an effective study treatment.

Detailed description:
The primary objective of this study is to assess the safety and toxicity profile of doxorubicin and pembrolizumab in previously treated or untreated subjects with unresectable or metastatic soft tissue sarcoma. The secondary objectives are to assess overall survival, and response rate, duration of response, and progression-free survival (PFS) with this regimen using RECIST 1.1 criteria. The exploratory objectives are to assess PFS, overall response rate, duration of response, and disease control rate using the immune-related RECIST (irRECIST) criteria, evaluate the correlation between PD-L1 expression levels and antitumor activity of MK-3475, investigate other biomarkers that may correlate with tumor responses, and evaluate differences in tumor tissue characteristics in biopsies taken during or post-treatment with MK-3475 versus baseline.

Arms:
arm 1: Participants will receive pembrolizumab IV infusion and doxorubicin IV injection on Day 1 of every 21 (+/- 3) days

Interventions: intervention 1: Pembrolizumab intervention 2: Doxorubicin
Intervention descriptions: intervention 1: IV infusion on day 1 of each 3 week cycle, at dose of 200 mg intervention 2: IV injection on day 1 of each 3 week cycle, starting at dose of 60 mg/m2 (may be escalated to 75 mg/m2 per investigator discretion after Cycle 1)

Protocol document:
Prot_SAP_000.pdf: 
Protocol Number:  LCI-SAR-STS-PEM-001 
Version 10:  07/11/2022 
 
1 
Protocol #:  LCI-SAR-STS-PEM-001 
TITLE: A PILOT STUDY EVALUATING THE SAFETY, TOLERABILITY AND 
EFFICACY OF DOXORUBICIN AND PEMBROLIZUMAB IN PATIENTS WITH 
METASTATIC OR UNRESECTABLE SOFT TISSUE SARCOMA 
LAY TITLE: DOXORUBICIN AND PEMBROLIZUMAB IN SOFT TISSUE SARCOMA 
PATIENTS 
Funding Company:  Merck 
 
Coordinating Site: 
Levine Cancer Institute – Research and Academic Headquarters 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator:  
 
Megan Jagosky, MD 
Levine Cancer Institute 
1021 Morehead Medical Dr 
Charlotte, NC 28204 
Telephone: (980) 442-0410  
Email:  megan.jagosky@atriumhealth.org   
 
Study Pathologist: 
William Ahrens, MD 
Carolinas Pathology Group 
1000 Blythe Boulevard 
Charlotte, NC 28203 
Telephone: (704) 355-2251 
Email: william.ahrens@atriumhealth.org   
 
Statistician: 
James Symanowski, PhD  
Levine Cancer Institute  
1021 Morehead Medical Dr 
Charlotte, NC 28204 
Telephone: (980) 442-2348 
Email: james.symanowski@atriumhealth.org  
 


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AH Tissue Procurement & Translational Research: 
Carol Farhangfar, PhD 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte NC, 28204 
Telephone: 980-442-3227 
Email: Carol.Farhangfar@atriumhealth.org 
 
Investigational drug: 
Pembrolizumab 
 
Investigational New Drug (IND)#: 133024 
Throughout this document, symbols indicating proprietary names (, TM) are not displayed.  
Hence, the appearance of product names without these symbols does not imply that these names 
are not protected. 
 
______________________________________________________________________________ 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether in 
part or in full - to parties not associated with the clinical investigation, or its use for any other 
purpose, without the prior written consent of the Sponsor-Investigator is not permitted. 
 
 
 
 
 
 


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                            Original Phase 2 / Version 9 /  April 13, 2021 
PROTOCOL SUMMARY 
A. Study Title 
A pilot study evaluating the safety, tolerability and efficacy of doxorubicin in 
combination with pembrolizumab in patients with metastatic or unresectable 
soft tissue sarcoma 
B. Indication 
Metastatic/unresectable soft tissue sarcoma 
C. Clinical Phase II 
 
D. Summary of 
Rationale 
 
 
Based on previous studies, pembrolizumab may be an effective treatment for 
patients with solid tumors.  The purpose of this study is to determine whether 
the addition of pembrolizumab to doxorubicin will yield an acceptable response 
rate in subjects with advanced soft tissue sarcoma.  We will also examine if PD-
L1 expression in sarcoma can predict for therapeutic response to 
pembrolizumab in subjects with soft tissue sarcoma. 
E. Study 
Objectives 
The primary objective of this study is to assess the safety and toxicity profile of 
doxorubicin and pembrolizumab in previously treated or untreated subjects with 
unresectable or metastatic soft tissue sarcoma.  The secondary objectives are to 
assess overall survival, response rate, duration of response, and progression-
free survival with this regimen using RECIST 1.1 criteria.  The exploratory 
objectives are to assess PFS, ORR, DoR, and DCR using the immune-related 
RECIST (irRECIST) criteria, evaluate the correlation between PD-L1 
expression levels and antitumor activity of MK-3475, investigate other 
biomarkers that may correlate with tumor responses, evaluate differences in 
tumor tissue characteristics in biopsies taken during treatment with MK-3475 
versus baseline, and evaluate ORR and PFS after second course treatment of 
pembrolizumab. 
F. Sample 
≤ 30 subjects 
G. Inclusion/ 
Exclusion 
• Recurrent/metastatic soft tissue sarcoma not appropriate for surgical 
therapy. 
• No prior anthracycline and/or immunotherapy. 
• ECOG 0 to 1 with normal organ function. 
H. Dosage/ 
Dosage 
Form, Route, 
And Dose 
Regimen 
Pembrolizumab 200 mg will be delivered by 30 minute IV infusion every 3 weeks 
until progression.  Subjects 12-17 years of age will receive pembrolizumab at 2 
mg/kg IV (up to 200 mg) every 3 weeks until progression. Doxorubicin 60-75 
mg/m2 will be delivered by IV infusion per institutional protocol (infusion, IV 
push) every 3 weeks until progression. Subjects will receive doxorubicin 60 
mg/m2 IV on Cycle 1 Day 1.  Escalation to 75 mg/m2 is allowed after Cycle 1 per 
investigator discretion. Re-initiation of pembrolizumab after discontinuation and 
presence of progressive disease is an additional option. Total dose of doxorubicin 
should not exceed cumulative lifetime dose of 450 mg/m2. 
I. Statistical 
Analysis 
Previous reports have demonstrated that the rate of any severe or life-
threatening toxicity with a median of 3 courses of doxorubicin and dacarbazine 
every 3 weeks is 55%.  If it becomes evident that the rate of severe or life-


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threatening toxicity convincingly exceeds 55%, the study will be halted.  
Response rates will be calculated with corresponding 95% confidence intervals 
based on the Clopper-Pearson method.  Duration of response and PFS 
distributions will be estimated using Kaplan-Meier techniques.  Exploratory 
correlative analyses will be conducted on biomarkers using logistic regression 
(response rate) and Cox proportional hazards models (duration of response and 
PFS).  Incident rates for adverse events, SAEs, and deaths on study therapy 
will be summarized.  
   
 
 


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 SCHEMA 
 
 
 
 
 
* Subjects 12-17 years of age will receive pembrolizumab 2 mg/kg IV (up to 200 mg) every 3 weeks 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition of Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
CI 
Confidence interval 
CHF 
Congestive heart failure 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical trial management system 
CrCl 
Creatinine clearance 
DCSI 
Development Core Safety Information 
DNA 
Deoxyribonucleic acid 
DSMC 
Data and Safety Monitoring Committee 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ECI 
Events of clinical interest 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 


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G-CSF 
Granulocyte-colony stimulating factor 
GIST 
Gastrointestinal stromal tumor 
GMP 
Good Manufacturing Practices 
HIV 
Human immunodeficiency virus 
IB 
Investigator brochure 
IDS 
Investigational drug services 
IHC 
Immunohistochemistry 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
irRC 
Immune related response criteria 
IV 
Intravenous 
LCI 
Levine Cancer Institute 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MEL 
Melanoma 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition scan 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OTC 
Over the counter 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Partial thromboplastin 
Q2W 
Every two weeks 
Q3W 
Every three weeks 
RCC 
Renal cell carcinoma 


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RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SOC 
Standard of care 
SOP 
Standard operative procedure 
STS 
Soft tissue sarcoma 
TIL 
Tumor infiltrating lymphocyte 
TSH 
Thyroid stimulating hormone 
UAP 
Unanticipated problem 


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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY ........................................................................................................... 3 
SCHEMA ....................................................................................................................................... 5 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
TABLE OF CONTENTS ............................................................................................................. 9 
1. OBJECTIVES ......................................................................................................................... 12 
1.1. Primary Objective .......................................................................................................... 12 
1.2. Secondary Objectives ..................................................................................................... 12 
1.3. Safety Objectives ........................................................................................................... 12 
1.4. Exploratory Objectives .................................................................................................. 12 
2. BACKGROUND AND RATIONALE .................................................................................. 12 
2.1. Study Disease ................................................................................................................. 12 
2.2. Experience with Pembrolizumab ................................................................................... 13 
2.3. Rationale for Dose Selection/Regimen/Modification .................................................... 15 
2.4. Rationale for Use of irRECIST Criteria ......................................................................... 17 
3. SUBJECT SELECTION ........................................................................................................ 17 
3.1. Subject Accrual .............................................................................................................. 17 
3.2. Eligibility Criteria .......................................................................................................... 17 
3.3. Diet/Activity/Other Considerations ............................................................................... 21 
3.4. Use in Pregnancy ........................................................................................................... 23 
3.5. Use in Nursing Women .................................................................................................. 23 
4. INVESTIGATIONAL PLAN ................................................................................................ 23 
4.1. Overall Study Design ..................................................................................................... 23 
4.2. Informed Consent........................................................................................................... 23 
4.3. Registration/Enrollment/Discontinuation ...................................................................... 24 
4.4. Study Procedures ........................................................................................................... 25 
5. STUDY CALENDAR ............................................................................................................. 33 
5.1. Initial Treatment Period ................................................................................................. 33 
5.2. Second Course Phase ..................................................................................................... 36 
6. TREATMENT PLAN ............................................................................................................ 39 


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6.1. Drug Dosage and Administration .................................................................................. 39 
6.2. Dose Selection ............................................................................................................... 40 
6.3. Dose Modification for Doxorubicin ............................................................................... 40 
6.4. Toxicity-Related Dose Delays/Dose Modifications/Discontinuations for 
Pembrolizumab ............................................................................................................. 40 
6.5. Dose Modification for Pembrolizumab ......................................................................... 41 
6.6. Timing of Doxorubicin/Pembrolizumab Dose Administration ..................................... 45 
6.7. Concomitant Medications/Vaccinations (allowed and prohibited) ................................ 46 
6.8. Rescue Medications & Supportive Care ........................................................................ 48 
6.9. Definition of Pembrolizumab Overdose ........................................................................ 51 
6.10. Treatment Compliance ................................................................................................. 51 
6.11. Duration of Therapy ..................................................................................................... 51 
7. SECOND COURSE PHASE ................................................................................................. 52 
8. DATA AND SAFETY MONITORING PLAN .................................................................... 53 
8.1. Safety Monitoring .......................................................................................................... 53 
8.2. Data Quality Assurance ................................................................................................. 54 
8.3. Communication Between Investigational Sites ............................................................. 54 
9. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES . 54 
9.1. Investigational Product .................................................................................................. 54 
9.2. Doxorubicin ................................................................................................................... 55 
9.3. Packaging and Labeling Information ............................................................................. 55 
9.4. Storage and Handling Requirements ............................................................................. 55 
9.5. Returns and Reconciliation ............................................................................................ 55 
9.6. Drug Accountability....................................................................................................... 55 
9.7. Destruction ..................................................................................................................... 56 
10. 
SAFETY DATA COLLECTION, RECORDING AND REPORTING ................ 56 
10.1. Unanticipated Problem Definition ................................................................................ 56 
10.2. Adverse Event ............................................................................................................. 56 
10.3. Evaluation of Adverse Events ................................................................................... 57 
10.4. Suspected Adverse Reaction Definition ....................................................................... 60 
10.5. “Unexpected” Definition .............................................................................................. 60 


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10.6. Serious Adverse Event Definition ................................................................................ 60 
10.7. Events of Clinical Interest Associated with Pembrolizumab ................................. 62 
10.8. Expedited Safety Reporting to the Sponsor-Investigator ............................................. 62 
10.9. Safety Reporting to the FDA ........................................................................................ 63 
10.10. 
Safety Reporting to the IRB .................................................................................... 63 
10.11. 
Safety Reporting to Merck ...................................................................................... 63 
10.12. 
Protocol-Specific Exceptions to Serious Adverse Event Reporting ................. 64 
11. 
MEASUREMENT OF EFFECT ............................................................................... 64 
11.1. Anti-tumor Effect – Solid Tumor ................................................................................. 64 
12. 
STATISTICAL CONSIDERATIONS ...................................................................... 68 
12.1. Sample Size .................................................................................................................. 68 
12.2. Endpoint Definitions .................................................................................................... 69 
12.3. Analysis Populations .................................................................................................... 70 
12.4. Analysis Methods ......................................................................................................... 71 
12.5. Primary Analysis .......................................................................................................... 71 
12.6. Secondary Analyses ..................................................................................................... 73 
12.7. Safety Analyses ............................................................................................................ 74 
12.8. Exploratory Analyses ................................................................................................... 74 
12.9. Interim Analyses ........................................................................................................... 74 
13. 
STUDY COMPLETION ............................................................................................ 74 
13.1. Completion ................................................................................................................... 74 
13.2. Termination .................................................................................................................. 74 
14. 
RETENTION OF RECORDS ................................................................................... 75 
15. 
PUBLICATION POLICY ......................................................................................... 75 
16. 
ETHICAL AND LEGAL ISSUES ............................................................................ 75 
16.1. Ethical and Legal Conduct of the Study ....................................................................... 75 
16.2. Confidentiality .............................................................................................................. 76 
16.3. Compliance with Trial Registration and Results Posting Requirements ..................... 76 
REFERENCES ............................................................................................................................ 77 
 
 


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1. OBJECTIVES 
 
1.1. 
Primary Objective 
The primary objective of this study is to evaluate the severe and life-threatening 
toxicity rate observed in metastatic or unresectable soft tissue sarcoma subjects treated 
with doxorubicin and pembrolizumab, and compare to historical control.   
 
1.2. 
Secondary Objectives 
 
The secondary objectives are to assess overall survival (OS), and objective response 
rate (ORR), duration of response (DoR), and progression-free survival (PFS) with this 
regimen using RECIST 1.1 criteria. 
 
1.3. 
Safety Objectives 
To assess treatment administration, safety, tolerability and adverse event profile of 
doxorubicin and pembrolizumab. 
1.4. 
Exploratory Objectives 
 
The exploratory objectives of this study include: 
• Assessment of PFS, ORR, and DoR, using the immune-related RECIST 
(irRECIST) criteria 
 Analyze immune response endpoints  
 Concordance analysis relative to standard RECIST 
 Evaluate impact of treating after progression to see impact on 
concordance 
• Evaluate the correlation between PD-L1 expression levels and antitumor 
activity of MK-3475 
• Investigate other biomarkers (e.g. tumor infiltrating lymphocytes) that 
may correlate with tumor responses 
• Evaluate differences in tumor tissue characteristics in biopsies taken 
during treatment with MK-3475 versus baseline 
• Evaluate objective response rate to second course treatment of pembrolizumab  
• Evaluate progression-free survival after second course treatment of 
pembrolizumab (PFS2) 
 
Whole blood samples will also be collected at baseline for germ line DNA analysis in select 
subjects for extended genomic analysis. 
 
2. BACKGROUND AND RATIONALE 
 
2.1. 
Study Disease 
 


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Sarcomas are a heterogeneous group of rare, malignant tumors, with over 50 histologic 
subtypes1 which are generally categorized as bone and soft tissue sarcomas. The exact 
incidence of soft tissue sarcoma is not precisely known.  A recent study in the Rhone-
Alps region in France identified 748 new cases in a cohort of roughly 6 million 
residents2. The estimated world age-standardized incidence rate was, 4.8/100,000, 
which was higher than previously reported (1-3/100,000).  Historically, soft tissue 
sarcomas have been treated similarly.  Doxorubicin-based chemotherapy has been the 
first line standard of care for more than 20 years.  Adding additional cytotoxic agents 
(e.g. ifosfamide, dacarbazine) to doxorubicin improves response rates, but at the 
expense of increased toxicity and no clear increase in survival. Some histologic 
subtypes respond better than others.  Anti-angiogenic and targeted therapies (e.g. 
sunitinib) to this point have been of marginal benefit in the treatment of soft tissue 
sarcomas.  Further progress is needed. 
 
2.2. 
Experience with Pembrolizumab 
 
2.2.1. 
Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of 
neoplastic transformation has been known for decades3. Accumulating 
evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) 
in cancer tissue and favorable prognosis in various malignancies  4-37.  In 
particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-
cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis 
and long-term survival in solid malignancies such as ovarian, colorectal and 
pancreatic cancer, hepatocellular carcinoma, malignant melanoma (MEL) and 
renal cell carcinoma (RCC). TILs can be expanded ex vivo and re-infused, 
inducing durable objective tumor responses in cancers such as MEL38,39. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors 
to suppress immune control.  The normal function of PD-1, expressed on the 
cell surface of activated T-cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions.  
PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to 
CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PDL2).  The 
structure of murine PD-1 has been resolved.  PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of 
PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch 
motif (ITSM).  Following T-cell stimulation, PD1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ 
and ZAP70 which are involved in the CD3 T-cell signaling cascade.  The 


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14 
mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of 
signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs 
and Natural Killer cells.  Expression has also been shown during -thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) 
are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors.  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC--like 
domains in the extracellular region and contain short cytoplasmic regions with 
no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-
cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory 
environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) 
PD-L1, a variety of cancers were demonstrated to express abundant levels of 
this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-
cell expansion in subjects with melanoma (MEL).  This suggests that the PD-
1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal 
antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.  Keytruda 
(pembrolizumab) has recently been approved in the United Stated for the 
treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. 
 
2.2.2. 
Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure (IB) for preclinical and clinical data. 
 
2.2.3. 
Experience with Doxorubicin 
 
Doxorubicin is a cytotoxic antibiotic of the anthracycline family of 
compounds. Its cytotoxic effects are believed to stem from intercalation with 
DNA nucleotides and binding to cellular membrane lipids. Investigations of 
cellular exposure to doxorubicin have shown morphological changes 
associated with apoptosis.  Currently, doxorubicin is the standard of care for 


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most subtypes of unresectable locally advanced or metastatic STS for disease 
which is not resectable for cure. 
 
In the 1970s, this anthracycline was studied in a clinical trial as monotherapy 
directed against disseminated sarcomas.40 Of 36 patients, 9% experienced a 
CR and 32% a PR. Patients who had these responses also had prolonged 
survival. Since then, doxorubicin has been used as single-agent therapy in the 
treatment of advanced and/or metastatic STS and has shown to be the most 
effective single agent in this setting, alternative treatments being single agent 
ifosfamide and more recently gemcitabine plus/minus taxotere. Comparison of 
doxorubicin monotherapy versus epirubicin monotherapy has shown slightly 
favorable response rates for doxorubicin.41 Although ifosfamide shows a 
similar level of effectiveness against tumor growth, doxorubicin tends to be 
better tolerated.42 
 
Single-agent doxorubicin has also been compared against combination 
therapies with and without doxorubicin. Examples include a two-arm study of 
doxorubicin versus the combination of vincristine plus actinomycin-D plus 
cyclophosphamide,43 and a three-arm study of doxorubicin versus the 
combination therapies of doxorubicin/ifosfamide and 
doxorubicin/mitomycin/cisplatin as first-line treatment.44 In the former study, 
doxorubicin was shown to be more effective, and in the latter, the combination 
treatment arms demonstrated improved response rate compared to single-
agent therapy, but the doxorubicin/ifosfamide combination was significantly 
more myelosuppressive without a clear improvement in clinical benefit.  An 
additional eight randomized, controlled trials have been analyzed to determine 
if doxorubicin combination therapy provided substantial clinical benefits 
compared to single-agent doxorubicin45. With regard to response rate, 
survival, and toxicity across studies, it was determined that improved response 
rate was marginal for combination therapy, survival did not differ between the 
two groups, and the safety profile for combination therapy was worse than 
that of single-agent therapy. 
 
Acute and chronic cardiomyopathy has occurred in patients receiving 
doxorubicin, and the probability of developing such cardiac complications is 
increased with increase in total cumulative dose of doxorubicin. Therefore, IV 
dexrazoxane is indicated for use as a cardioprotective agent in patients 
concurrently receiving a cumulative doxorubicin dose of 300 mg/m2 or 
greater.46 
 
2.3. 
Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety 
and clinical activity of single agent MK-3475.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 


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16 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
MK-3475 showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has 
been identified to date. Recent data from other clinical studies within the MK-3475 
program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days).     
 
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, 
is within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found 
to have a wide therapeutic range based on the melanoma indication.  The differences 
in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins 
of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based 
on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor 
burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure 
between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of 
pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma 
patients, 2) the flat exposure-response relationships of pembrolizumab for both 
efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack 
of effect of tumor burden or indication on distribution behavior of pembrolizumab (as 
assessed by the population PK model) and 4) the assumption that the dynamics of 
pembrolizumab target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) 
are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) 
will maintain individual patient exposures in the exposure range established in 
melanoma as associated with maximal efficacy response and 3) will maintain 
individual patients exposure in the exposure range established in melanoma that are 
well tolerated and safe.  


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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. 
 
The weight-based pediatric dosing regimen of 2 mg/kg Q3W was determined using a 
model-based PK bridging analysis.  The model included PK data from pembrolizumab 
pediatric trial KN051 which also serves to establish safety of this does in pediatric 
subjects.  Analysis of the model showed a dose of 2 mg/kg Q3W (up to 200mg) in 
pediatric subjects displayed similar PK exposures to those in adults using the same 
dose.  The weight based dosing regimen of 2 mg/kg Q3W displayed comparable 
pembrolizumab exposures in pediatric subjects and adults, and PK simulation supports 
the dosing regimen for the pediatric population.  
 
2.4. 
Rationale for Use of irRECIST Criteria 
Immunotherapeutic agents may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses, which may be functionally anergic prior to 
treatment. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and can manifest as a 
clinical response after an initial increase in tumor burden or even the appearance of 
new lesions (transient tumor flare). Thus, standard RECIST criteria may not provide a 
complete response assessment of immunotherapeutic agents, such as pembrolizumab.  
To address this issue, RECIST 1.1 with the adaptation outlined in Section 11.1.2, 
termed irRECIST, will also be used. 
 
3. SUBJECT SELECTION 
 
3.1. 
Subject Accrual 
A maximum of 30 subjects with soft tissue sarcoma will be enrolled as a single cohort 
over a 24-month period.  Both men and women of all races and ethnic groups are 
eligible for this trial. 
 
3.2. 
Eligibility Criteria 
 
3.2.1. 
Inclusion Criteria 
 
Subjects must meet all the following criteria: 
a. Be willing and able to provide written informed consent for the trial. 
b. Must have a diagnosis of unresectable or metastatic soft tissue sarcoma that 
is histologically confirmed and not amenable to curative treatment with 
surgery or radiotherapy.  Patients with Ewing’s sarcoma, osteosarcoma, 
chondrosarcoma, Kaposi’s sarcoma, gastrointestinal stromal tumors 
(GIST), clear cell sarcoma, alveolar soft part sarcoma and any other soft 


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18 
tissue or bone sarcoma felt to be chemotherapy resistant in the opinion of 
the Sponsor-Investigator will be excluded. 
c. Must not have received prior treatment with an anthracycline chemotherapy 
(e.g., doxorubicin) and/or anti-PD-1/PD-L1 therapy. 
d. May have had any number of prior systemic therapies for 
unresectable/metastatic disease. 
e. Must have measurable or non-measurable disease as per RECIST 1.1  
f. All subjects with accessible tumor will be asked to provide a fresh tumor 
biopsy if they can be safely biopsied in the opinion of the investigator. 
Recently obtained archived core or excisional biopsy of a tumor lesion 
(obtained up to 12 months prior to Cycle 1 Day 1) may be substituted only 
if the subject is unwilling or unable (e.g. inaccessible or subject safety 
concern) to undergo a fresh tumor biopsy. Subjects who are unwilling or 
unable to have a fresh tumor biopsy and do not have recently obtained 
archived tissue available may submit an archived specimen (obtained > 12 
months prior to Cycle 1 Day 1) only upon approval from the Sponsor-
Investigator. 
g. Be ≥ 12 years of age on day of signing informed consent.  Assent will be 
obtained in appropriately aged subjects per institutional guidelines. 
h. ECOG performance status 0 or 1. 
i. Life expectancy of at least 3 months per the Investigator. 
j. Have adequate organ function as indicated by the laboratory values in 
Table 1.  All screening labs should be performed within 10 days of study 
treatment initiation. PT/INR and PTT must be performed within 7 days of 
study treatment initiation for subjects on anti-coagulants such as 
coumadin/heparin. 
 
 
Table 1. Adequate Organ Function Lab Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥ 1,500 /mcL 
Platelets 
≥ 100,000 / mcL 
Hemoglobin 
≥ 9 g/dL or ≥ 5.6 mmol/L– without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
Serum creatinine OR measured or  
calculated creatinine clearance (CrCl)a 
(GFR can also be used in place of 
creatinine or CrCl) 
≤ 1.5 X upper limit of normal (ULN) OR 
≥ 60 mL/min for subjects with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with 
total bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver 
metastases 
Albumin 
≥ 2.5 g/dL 
Coagulation 


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International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤ 1.5 X ULN unless the subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
for intended use of coagulants 
≤ 1.5 X ULN unless the subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
for intended use of coagulants 
a Creatinine clearance should be calculated per institutional standard.    
 
k. The subject has left ventricular ejection fraction (LVEF) ≥ 50% assessed 
within 21 days prior to study treatment initiation. 
l. Subjects must not be expecting to conceive or father children within the 
timeframe referenced below. Subjects of childbearing potential must be 
willing to adhere to the contraception requirement as described in Section 
3.3.2 from the day of the screening visit (or 14 days prior to the initiation of 
study treatment for oral contraception) throughout the study period up to 
120 days after the last dose of pembrolizumab and/or up to 180 days after 
the last dose of doxorubicin.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
m. Female subjects of childbearing potential must have a negative urine or 
serum pregnancy test at screening (within 72 hours of first dose of study 
treatment). If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. The serum pregnancy 
test must be negative for the subject to be eligible.  
n. Subject has voluntarily agreed to participate by giving written informed 
consent for the trial. The subject may also provide consent for Optional and 
Future Studies-Biospecimen Collection. However, the subject may 
participate in the main trial without participating in Optional and Future 
Studies. 
 
3.2.2. 
Exclusion Criteria 
 
Subjects must not meet any of the following criteria: 
 
a. Currently participating and receiving study therapy or have participated in 
a study of an investigational agent and received study therapy or used an 
investigational device within 30 days of the first dose of study treatment. 
b. Have a diagnosis of immunodeficiency or are receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 7 days 
prior to the first dose of study treatment. 
 
c. Have a known history of active TB (Bacillus Tuberculosis). 
d. Have had a prior anti-cancer monoclonal antibody (mAb) given to treat 
malignancy within 4 weeks prior to the first dose of study treatment or 
have not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due 
to previous mAbs. 


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20 
e. Have had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy within 2 weeks prior to the first dose of study treatment 
or who have not recovered (i.e. ≤ Grade 1 or at baseline) from adverse 
events due to previous chemotherapy, targeted small molecule therapy, or 
radiation therapy. 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
Note:  If subjects have received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting study treatment as determined by the Investigator.   
f. Have a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin or 
squamous cell carcinoma of the skin that has undergone potentially 
curative therapy or in situ cervical cancer. 
g. Have known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Subjects with previously treated brain 
metastases may participate provided they are stable (without evidence of 
progression by imaging for at least four weeks prior to the first dose of 
study treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to the first dose of the study treatment.  
This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability.   
h. Have active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e. with use of disease modifying agents, corticosteroids 
or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
i. Have known history of, or any evidence of active, non-infectious 
pneumonitis. 
j. Have an active infection requiring systemic therapy (uncomplicated 
urinary tract infection treated with oral antibiotics is permitted). 
k. Have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subjects’ participation for the full duration of the trial, or is not in the best 
interest of the subjects to participate, in the opinion of the treating 
Investigator.   
l. Have known psychiatric or substance abuse disorders that would interfere 
with cooperation with the requirements of the trial as determined by the 
Investigator. 
m. Are pregnant or breastfeeding. 
n. Have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent. 
o. Have a known history of Human Immunodeficiency Virus infection (e.g. 
HIV 1/2 antibodies). 


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21 
p. Have known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. 
HCV RNA [qualitative] is detected). 
q. Have received a live vaccine within 30 days prior to first dose of study 
treatment. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
 
 
For subjects entering the Second Course Phase, see Section 7 for entry criteria. 
 
3.3. 
Diet/Activity/Other Considerations 
 
3.3.1. 
Diet 
 
Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
 
3.3.2. 
Contraception/Reproduction 
 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it 
is not known if pembrolizumab has transient adverse effects on the 
composition of sperm.  For this trial, male subjects will be considered to be of 
non-reproductive potential if they have azoospermia (whether due to having 
had a vasectomy or due to an underlying medical condition).   
 
Female subjects will be considered of non-reproductive potential if they are 
either:  
(1) postmenopausal (defined as at least 12 months with no menses 
without an alternative medical cause; in women < 45 years of age a 
high follicle stimulating hormone (FSH) level in the postmenopausal 
range will be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy).  
 
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks 
prior to screening; documented hysterectomy or oophorectomy must 
be confirmed with medical records of the actual procedure or 
confirmed by an ultrasound. Tubal ligation must be confirmed with 
medical records of the actual procedure otherwise the subject must be 
willing to use two adequate barrier methods throughout the study, 
starting with the screening visit through 120 days after the last dose of 
pembrolizumab and up to 180 days after last dose of doxorubicin as 
specified in the protocol.  
OR  


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(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to 
avoid becoming pregnant or impregnating a partner, respectively, 
throughout the trial starting at the screening visit through 120 days 
after the last dose of pembrolizumab and/or for 180 days after 
receiving the last dose of doxorubicin by complying with one of the 
following:   
 
(1) practice abstinence† from heterosexual activity;  
OR  
 
(2) use (or have their partner use) acceptable contraception during 
heterosexual activity.   
 
Acceptable methods of contraception are‡: 
  
Single method (one of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of male subject or of a female subject’s male partner  
• contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with 
cervical cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill 
or progestin-only pill), contraceptive skin patch, vaginal contraceptive 
ring, or subcutaneous contraceptive injection 
  
Male subjects with pregnant partners must agree to use a condom; no 
additional method of contraception is required for the pregnant partner. 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method 
of contraception if it is consistently employed as the subject’s preferred and 
usual lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g. calendar, ovulation, sympto-thermal, 
post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.  
  
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region. 
 


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23 
Subjects should be informed that taking the study treatment may involve 
unknown risks to the fetus (unborn baby) if pregnancy were to occur during 
the study.  In order to participate in the study, subjects of childbearing 
potential must adhere to the contraception requirement (described above) from 
the day of the screening visit (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days 
after the last dose of pembrolizumab and/or up to 180 days after the last dose 
of doxorubicin.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject 
should not be entered into the study. 
 
3.4. 
Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, 
the subject will immediately be removed from the study treatment. The site will 
contact the subject at least monthly and document the subject’s status until the 
pregnancy has been completed or terminated.  The outcome of the pregnancy will be 
reported to the Sponsor-Investigator and to Merck without delay and within 24 hours 
to the Sponsor-Investigator and within 2 working days to Merck if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor-Investigator.   If a male subject impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to the 
Sponsor-Investigator and to Merck and followed as described above and in Section 10. 
 
3.5. 
Use in Nursing Women 
 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
4. INVESTIGATIONAL PLAN 
 
4.1. 
Overall Study Design   
 
This is a single arm phase II study designed to investigate the safety, tolerability, and 
preliminary efficacy of the combination of pembrolizumab and doxorubicin in subjects 
with metastatic/unresectable soft tissue sarcoma. Following informed consent and 
eligibility check, all enrolled subjects will receive therapy with doxorubicin and 
pembrolizumab. 
 
4.2. 
Informed Consent 


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24 
 
The subject or subject’s legal representative will sign and date the informed consent 
form prior to participating in any study-related procedures. Subjects under 18 years of 
age will sign and date the assent form prior to participating in any study-related 
procedures. Subjects who reach 18 years of age during study participation will sign the 
main consent form. 
 
4.3. 
Registration/Enrollment/Discontinuation 
 
4.3.1. 
Milestone Date Definitions 
Eligibility date:  the date of the last documented criterion that confirmed subject 
eligibility. 
 
Enrollment date:  the date subject initiates treatment with pembrolizumab and 
doxorubicin. 
 
Treatment discontinuation date: the date investigator decides to discontinue subject 
from initial pembrolizumab treatment or the subject withdraws consent.   
 
Second Course discontinuation date: the date the investigator decides to discontinue 
subject from Second Course pembrolizumab treatment. 
 
4.3.2. 
Subject Registration/Enrollment 
Following informed consent or assent, subjects will be registered by the 
Sponsor and assigned a Study ID number. The Study ID will be a four digit 
number sequentially assigned, where 1001 will be the Study ID number 
assigned to the first registered subject. Following eligibility check per 
standard operating procedures, eligible subjects will be enrolled on the first 
date of protocol treatment administration. Study ID numbers assigned to 
registered subjects not ultimately enrolled will not be re-assigned. 
 
4.3.3. 
Subject Withdrawal/Discontinuation Criteria 
 
Any consenting, eligible subject who receives at least one dose of study 
treatment and then is removed from the trial (by self or investigator) is 
considered a “subject withdrawal” and will remain under medical supervision 
until discharge or transfer is medically acceptable. 
 
In all cases, the reason for withdrawal must be documented. Subjects may 
withdraw study consent at any time for any reason or be dropped from the trial 
at the discretion of the Investigator should any untoward effect occur.  In 
addition, a subject may be withdrawn by the Investigator or the Sponsor-


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25 
Investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons.   
 
A subject will be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) 
withdraws study consent 
• The subject is lost to follow-up 
• Investigator’s decision to withdraw the subject 
• Noncompliance with study regimen or procedure requirements 
• Subject death 
 
4.3.4. 
Discontinuation of Study Therapy after Complete Response 
 
Discontinuation of treatment may be considered for subjects who have 
attained a confirmed complete response (CR) in the Initial Treatment Period 
that have been treated for at least 24 weeks with pembrolizumab and had at 
least two treatments with pembrolizumab beyond the date when the initial CR 
was declared.   
 
Subjects who then experience first documented disease progression (as 
defined in Section 4.4/ Additional Post-Treatment Follow-up Visits) may be 
eligible for up to one year of additional treatment with pembrolizumab via the 
Second Course Phase (See Section 7) at the discretion of the Investigator if no 
anti-cancer treatment was administered since the last dose of pembrolizumab, 
the subject meets the criteria for Entry into Second Course Phase per Section 
7, has completed required study procedures per Entry into Second Course 
Phase requirements in the Study Calendar per Section 5.2, and the trial is 
open.  Subjects will resume therapy at the same dose and schedule. 
 
4.3.5. 
Screen Failures 
 
A subject who, for any reason (i.e. failure to satisfy the eligibility criteria or 
withdraws consent), terminates the study before receiving first dose of study 
treatment is regarded as a “screen failure.”   
 
 
4.4. 
Study Procedures 
 
Study procedures are listed in Section 5 – Study Calendar. 
 
Demographics and Medical/Treatment History.  Demographics and 
medical/treatment history will be collected during the screening visit. Medical and 
treatment history (oncological and relevant non-oncological) will be collected. 
Medical history will include all active conditions, and any condition diagnosed within 


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26 
the prior 10 years that are considered to be clinically significant by the Investigator.  
Cancer history will be obtained and the following information (including but not 
limited to): 
 
•    Date of first histological/cytological diagnosis 
•    Primary tumor site 
•    Tumor histology and characteristics 
•    Prior cancer therapy 
 
All relevant medical history findings that occurred prior to the subject signing 
informed consent will be documented including baseline signs and symptoms present 
at the time of informed consent. Updated medical history and baseline signs and 
symptoms findings will be recorded during the Entry into Second Course Phase (if 
applicable). 
 
Pregnancy Test.  A pregnancy test will be performed at screening/Entry into Second 
Course Phase (if applicable) and as clinically indicated for women of childbearing 
potential. Women who are pregnant and/or breast-feeding are ineligible for study 
participation. Women of child-bearing potential will be counseled regarding risk of 
teratogenicity and need to use contraception through the course of the study. Men will 
also be counseled on the need to use contraception for all sexual encounters. 
 
Office Visit.  Physical exam and documented evaluation by body system, height 
(screening only), weight, and body surface area (BSA) will be documented during 
screening/Entry into Second Course Phase (if applicable), repeated at Cycle 1 Day 1 
(only if screening/Entry into Second Course Phase visit not done within 7 days of 
initiation/re-initiation of study treatment) and at each treatment visit during the Initial 
Treatment Period and Second Course Phase (if applicable). Vital signs will be 
recorded and should include temperature, pulse rate, blood pressure and either 
respiratory rate or oxygen saturation.  ECOG performance status will be assessed.  
 
ECG. ECG will be performed during screening. After discontinuation of doxorubicin, 
ECGs will be performed at the frequency described in the Study Calendars (Sections 
5.1 and 5.2). 
 
Echocardiogram.  Echocardiogram will be performed during screening and after 
every third dose of doxorubicin (approximately 14-21 days after dose but prior to 
subsequent dose). After discontinuation of doxorubicin, echocardiograms will be 
performed at the frequency described in the Study Calendars (Sections 5.1 and 5.2). 
 
Adverse Event Evaluation and Monitoring.  All adverse events and serious adverse 
events will be monitored and documented (regardless of grade or attribution) and 
reported to applicable agencies on an ongoing basis as described in Section 10 during 
the Initial Treatment Period and Second Course Phase (if applicable). Investigators 
should refer to the Safety Information section of the current IB for pembrolizumab.  


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27 
As with any agent, there is always the potential for unexpected AEs, including 
hypersensitivity reactions.   
 
The Investigator or qualified designee will assess each subject to evaluate for potential 
new or worsening AEs as specified in the Study Calendar (Section 5.1 and 5.2) and 
more frequently if clinically indicated.  Adverse experiences will be graded and 
recorded throughout the study and during the follow-up period according to NCI 
CTCAE Version 4.  Toxicities will be characterized in terms regarding seriousness, 
causality, toxicity grading, and action taken with regard to study treatment.  
 
For subjects receiving treatment with pembrolizumab, all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is 
possibly an event of clinical interest (ECI) of a potentially immunologic etiology 
(termed immune-related adverse events, or irAEs). 
 
Concomitant Medications. All medication that is considered necessary for the 
subject’s welfare, and which is not expected to interfere with the evaluation of the 
study treatment, may be given at the discretion of the Investigator. All medications 
taken within 28 days prior to initiation/re-initiation of study treatment and during 
study treatment must be recorded in the subject’s medical record according to standard 
practice. Treatment for the disease for which the subject has enrolled in this study will 
be recorded separately and not listed as a prior medication. Acceptable and prohibited 
concomitant therapy during screening and treatment is listed in Section 6.7.  
 
The Exclusion Criteria describes other concomitant medications which are prohibited 
in this trial. 
 
Laboratory Tests.  Required laboratory tests are outlined in Table 2.  Labs will be 
performed according to the schedule in Section 5.1 and 5.2.  All screening/Entry into 
Second Course Phase (if applicable) labs should be performed within 10 days of 
treatment initiation/re-initiation. PT/INR and PTT must be performed within 7 days of 
treatment initiation/re-initiation for subjects on anti-coagulants such as 
coumadin/heparin. Results must be reviewed by the Investigator or qualified designee 
and found to be acceptable prior to each dose of study treatment. 


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28 
Table 2. Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total triiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   


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29 
 
Tissue and Blood Correlative Studies.   
Tissue: Subjects who have disease that can be safely biopsied will be asked to have a 
tumor biopsy prior to initiation of study treatment (Initial Treatment Period only). 
However, if the subject is unwilling to undergo a tissue biopsy or it is determined by 
the Investigator to be unsafe to biopsy, recently obtained archival tissue will be 
acceptable if obtained within 12 months prior to initiation of study treatment on Cycle 
1 Day 1. Subjects for whom recently obtained samples cannot be provided may submit 
an archived specimen collected more than 12 months prior to initiation of study 
treatment only upon approval from the Sponsor-Investigator. An additional optional 
tumor biopsy will be collected at any timepoint during study treatment only if the 
subject consents. 
 
Biopsies will be obtained only if they can be performed under local anesthesia. 
General anesthesia will not be used to obtain biopsies that are to be used only for 
research purposes.  
 
Biopsies performed for research purposes will only be obtained after the procedure has 
been explained to the subject, and per institution policy, the institution specific 
informed consent has been secured. 
 
Archived tissue specimens will be collected at baseline (after enrollment) and stored at 
the AH Biorepository for future analyses. 
 
Blood: Mandatory samples [(2) 8 ml CPT tubes, (1) 10 ml red top, and (1) 10 ml 
purple top)] will be collected on all subjects at the following timepoints:  
• Anytime during screening/Entry into Second Course Phase (if applicable) prior 
to initiation/re-initiation of pembrolizumab  
• Pre-dose prior to every other (odd numbered) cycle (Initial Treatment Period 
and Second Course Phase if applicable) starting with Cycle 3 
• Subjects in the Initial Treatment Period: First documented disease 
progression (as defined later in this section in Additional Post-Treatment 
Follow-up Visits) or at the Post-Treatment Safety Follow-up Visit.  
• Subjects in the Second Course Phase: Second documented disease 
progression (as defined later in this section in Additional Post-Treatment 
Follow-up Visits) or at the Post-Treatment Safety Follow-up Visit. 
 
Additional blood [(1) 2.5 ml PAXgene tube)] will be collected only from subjects who 
consent (optional) at the same timepoints as described above for the mandatory blood 
correlatives.   
 
Exploratory biomarker arrays may be used in analysis. Future tissue and blood-based 
biomarkers not described in this protocol may also be examined. 
 
Radiology and Tumor Measurements.   


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Initial Treatment Period: Following consent, a computed tomography (CT) scan  (IV 
contrast preferred) of the primary tumor, chest, abdomen and pelvis will be performed 
within 28 days prior to the first dose of study treatment (screening/baseline scan). 
Scans will then be performed every 6 weeks from study treatment initiation (± 7 days) 
until first documented disease progression or start of new anti-cancer therapy. Subjects 
who discontinue study treatment and have not had first documented disease 
progression or started new anti-cancer therapy should have tumor imaging per 
investigator discretion at a suggested frequency of every 9 weeks. After 1 year of 
follow-up, tumor imaging frequency can decrease to 12 week intervals per investigator 
discretion.  
 
Second Course Phase (if applicable): It is recommended that scans are performed 
within 28 days of re-initiation of pembrolizumab but the interval may be determined 
per investigator discretion. Scans will then be performed per investigator discretion at 
a recommended interval of every 6-9 weeks until second documented disease 
progression or start of new anti-cancer therapy. Subjects who discontinue study 
treatment and have not had second documented disease progression or started new 
anti-cancer therapy should have tumor imaging per investigator discretion at a 
suggested frequency of every 9 weeks. After 1 year of follow-up, tumor imaging 
frequency can decrease to 12 week intervals per investigator discretion. 
 
A contrast-enhanced MRI (contrast preferred) of the abdomen and pelvis and a non-
contrasted CT scan of the chest may be substituted if clinically necessary; however, 
subsequent studies must be performed using the same imaging modality throughout 
the study period.  
 
Post-Doxorubicin Cardiac Monitoring 
• Subjects who have symptoms of cardiac disease during or after discontinuation 
of doxorubicin will be referred to cardiology for evaluation and management. 
The frequency of cardiac procedures (e.g. ECGs, echocardiograms, etc) will be 
determined by cardiology. 
• All other subjects who do not have symptoms of cardiac disease will have post-
doxorubicin ECGs and echocardiograms performed per the frequency 
described in the Study Calendars (Sections 5.1 and 5.2).  
 
Post-Treatment Safety Follow-up Visit.  The mandatory Safety Follow-Up Visit 
should be conducted approximately 30 days (± 7 days) after the last dose of study 
treatment (required for both Initial Treatment Period and Second Course Phase) or 
before the initiation of a new anti-cancer treatment, whichever comes first. The 
Investigator or qualified designee will review new anti-neoplastic therapy initiated 
after the last dose of study treatment. If a subject initiates a new anti-cancer therapy 
within 30 days after the last dose of study treatment, the Post-Treatment Safety 
Follow-Up Visit must occur before the first dose of the new therapy. Once new anti-
cancer therapy (non-palliative) has been initiated, the subject will move into survival 
follow-up. 
 


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All AEs that occur prior to 30 days after the last dose of study treatment should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of 
the AE to Grade 0-1 or until the beginning of a new anti-cancer treatment, whichever 
occurs first.  SAEs that occur within 90 days of the last dose of study treatment or 30 
days if new anti-cancer therapy is initiated should also be followed and recorded.  
Subjects who are eligible for retreatment with pembrolizumab (Second Course Phase 
as described in Section 7) may have up to two safety follow-up visits, one after the 
Initial Treatment Period and one after the Second Course Phase. 
 
Additional Post-Treatment Follow-Up Visits.  Only subjects who discontinue study 
treatment without documented disease progression or initiation of new anti-cancer 
therapy move into the Additional Post-Treatment Follow-Up Phase and should be 
assessed by radiologic imaging to monitor disease status as described earlier in this 
section (Radiology and Tumor Measurements) and the Study Calendars in Section 5.   
Documented disease progression is defined as: 
• Confirmed radiographic disease progression in subjects currently 
receiving pembrolizumab, or  
• Unconfirmed radiographic disease progression in clinically unstable 
subjects currently receiving pembrolizumab  
• Unconfirmed radiographic disease progression in subjects in the 
Additional Post-Treatment Follow-up Phase previously discontinued 
from pembrolizumab for reasons other than documented disease 
progression or initiation of new anti-cancer therapy, or 
• Subjective disease progression as determined by the investigator 
 
First documented disease progression is the disease progression meeting the criteria 
above that occurs during or following study treatment administered during the Initial 
Treatment Period. Second documented disease progression is the disease progression 
meeting the criteria above that occurs during or following pembrolizumab 
administered during the Second Course Phase. 
 
Every effort should be made to collect information regarding disease status until the 
start of initial anti-cancer treatment, documented disease progression, death, or end of 
the study.   
 
Subjects who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 7 will move from the Follow-Up Phase to the Second Course Phase 
after they experience first documented disease progression.  
 
Survival Follow-Up.  Once subjects experience documented disease progression or 
start a new anti-cancer therapy, the subjects move into the Survival Follow-Up Phase 
and should be contacted by telephone approximately every 6 months from the Post-
Treatment Safety Follow-up Visit to assess for survival status until death, withdrawal 
of consent, or the end of the study, whichever occurs first. 
 
 


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33 
 
5. STUDY CALENDAR 
5.1. Initial Treatment Period 
 
 
Initial Treatment Period 
Treatment Cyclesu 
Post-Treatment 
Treatment Cycle/Title: Screening 
Visit 
1 
2  
3 
4 
To be repeated 
beyond 7 cycles  
 
 
After last 
dose of 
doxorubicint 
Post-Tx 
Safety 
Follow- Up 
Visita 
Additional 
Follow-Up 
Visits 
Survival 
Follow-Up 
5 
6 
7 
Every 
6 
weeks 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
From 
C1D1  
± 7 
30 days  
(±7 days) 
after last 
dose of 
doxorubicin 
 
30 days (± 
7 days) 
post last 
dose of 
study 
treatment 
Suggested 
every 9 
weeks x 1 
year; then 
every 12 
weeks  
Approximately 
every 6 months 
from Post-Tx 
Safety Follow-
up Visit 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical Historyr  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Doxorubicin Administrationk 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pembrolizumab Administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Post-treatment anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Survival Status 
 
X 
Review Adverse Eventsa 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Physical Examination, Weight and ECOG 
Performance Statusb 
X 
Xb 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
Xt 
 
 
 


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Initial Treatment Period 
Treatment Cyclesu 
Post-Treatment 
Treatment Cycle/Title: Screening 
Visit 
1 
2  
3 
4 
To be repeated 
beyond 7 cycles  
 
 
After last 
dose of 
doxorubicint 
Post-Tx 
Safety 
Follow- Up 
Visita 
Additional 
Follow-Up 
Visits 
Survival 
Follow-Up 
5 
6 
7 
Every 
6 
weeks 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
From 
C1D1  
± 7 
30 days  
(±7 days) 
after last 
dose of 
doxorubicin 
 
30 days (± 
7 days) 
post last 
dose of 
study 
treatment 
Suggested 
every 9 
weeks x 1 
year; then 
every 12 
weeks  
Approximately 
every 6 months 
from Post-Tx 
Safety Follow-
up Visit 
ECHO (Echocardiogram) 
Xj 
 
 
 
Xh,t 
 
 
Xh,t 
 
Xt 
Xt 
Pregnancy Test – Urine or Serum -HCGd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differentialm 
Xp 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Comprehensive Serum Chemistry Paneli,m 
Xp 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Urinalysis 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging and Assessmentsf 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 Recently Obtained Tissue Collection 
(Archived if unable to obtain biopsy) 
Xn, 
 
Xl 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collectiong 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Optional Studies Blood Collectiono 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
Archived Tissueq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: Subjects will be followed for adverse events through 30 days after last dose of study treatment and for serious adverse events through 90 days after last dose of study treatment 
(or for 30 days if new anti-cancer therapy is initiated). Subjects who develop symptoms of cardiac disease as determined by the investigator after initiation of doxorubicin will be 
referred to cardiology. 
b: Height will be measured at screening visit only. C1D1 Physical Exam/Performance Status/Weight not required if done within 7 days of screening exam/PS/weight.  
c: To include temperature, pulse rate, blood pressure, and either respiratory rate or oxygen saturation 


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d: Collect within 72 hours prior to administration of study treatment in women of childbearing potential  
e. Must be done within 7 days of C1D1 if on anti-coagulants such as warfarin/heparin. Otherwise to be done within 10 days of C1D1. 
f: Perform every 6 weeks from C1D1 (+/- 7 days). Subjects who discontinue study treatment and have not had first documented disease progression or started new-anti-cancer 
therapy should have tumor imaging per investigator discretion at a suggested frequency of every 9 weeks (± 7 days) to monitor disease status. After 1 year of follow-up, tumor 
imaging frequency can decrease to 12 week intervals per investigator discretion. 
g. Includes [(2) 8 ml CPT tubes, (1) 10 ml red top and (1) 10 ml purple top)]. Collect at screening, prior to dose administration every other (odd numbered) cycle (starting with 
Cycle 3), and at first documented disease progression or at the Post-Treatment Safety Follow-up Visit.  The screening sample should ideally be collected after eligibility has been 
confirmed, preferably on C1D1 prior to study treatment initiation. 
h. After every third dose of doxorubicin (approximately 14-21 days after dose but prior to subsequent dose) during treatment with doxorubicin. . 
i. See Table 2 for complete list of required chemistries 
j. LVEF must be assessed within 21 days of initiation of study treatment 
k. Total dose of doxorubicin should not exceed cumulative lifetime dose of 450 mg/m2  
l. Optional fresh tumor biopsy will be collected anytime during study treatment only in subjects who consent 
m: After cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing  
n: Subjects who have accessible tumor that can be safely biopsied will be asked to have a tumor biopsy prior to initiation of study treatment. However, if the subject is unwilling or 
unable to undergo a tissue biopsy, recent archival tissue will be acceptable if obtained within 12 months prior to initiation of treatment on C1D1. If fresh or recent archived tissue is 
not available, archived tissue collected more than 12 months prior to C1D1 may be submitted only upon approval from the Sponsor-Investigator. 
o. Optional blood correlatives (1) 2.5 ml Paxgene only to be collected in subjects who consent. Collected at screening, prior to dose administration every other (odd numbered) 
cycle (starting with Cycle 3), and at first documented disease progression or at the Post-Treatment Safety Follow-up Visit.  The screening sample should ideally be collected after 
eligibility has been confirmed, preferably on C1D1 prior to study treatment initiation. 
p. All screening labs must be done within 10 days of C1D1 
q. Archived tissue specimens will be collected at baseline (after enrollment) and stored at the AH Biorepository for future analyses 
r. To include baseline signs and symptoms  
t. Subjects who do not have symptoms of cardiac disease as determined by the investigator will have an ECG and echocardiogram performed 30 days (± 7 days) after the last dose 
of doxorubicin. Echocardiogram will be repeated every 5 years (± 90 days) after the last dose of doxorubicin. These assessments are required regardless of the number of 
doxorubicin doses administered during the study. Subjects who develop symptoms of cardiac disease at any time after initiation of doxorubicin will be referred to cardiology. In 
this case, the frequency of cardiac evaluations will be determined by cardiology. 
u. Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not related to study treatment. However, subjects should be placed back on study 
treatment within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor-Investigator. 
 
 
 
 
 
 
 
 


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36 
 
5.2. Second Course Phase 
Second Course Phase 
Treatment Cyclesn 
Post-Treatment 
Treatment Cycle/Title: 
Entry into 
Second 
Course 
Phase 
1 
2  
3 
4 
To be repeated 
beyond 7 cycles  
 
Post-Tx 
Safety 
Follow- Up 
Visit 
Additional 
Follow-Up 
Visits 
Survival 
Follow-Up 
5 
6 
7 
Every 
6-9 
weeks 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
From 
C1D1  
± 7 
30 days (± 7 
days) post 
last dose of 
study 
treatment 
Suggested 
every 9 weeks  
x 1 year; then 
every 12 
weeks  
Approximately
every 6 months 
from Post-Tx 
Safety Follow-
up Visit 
Medical History Reviewm 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Pembrolizumab Administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-treatment anticancer therapy status 
 
 
 
 
 
 
 
 
 
X 
 
X 
Survival Status 
 
X 
Review Adverse Eventsa 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Physical Examination, Weight and ECOG 
Performance Status 
X 
Xb 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 ECHO (Echocardiogram) 
Xh 
Pregnancy Test – Urine or Serum -HCGd 
X 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
Xe 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential j 
Xl 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Comprehensive Serum Chemistry Panel i,j 
Xl 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Urinalysis 
Xl 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
Xl 
 
 
 
 
 
 
 
 
 
 
 


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37 
Second Course Phase 
Treatment Cyclesn 
Post-Treatment 
Treatment Cycle/Title: 
Entry into 
Second 
Course 
Phase 
1 
2  
3 
4 
To be repeated 
beyond 7 cycles  
 
Post-Tx 
Safety 
Follow- Up 
Visit 
Additional 
Follow-Up 
Visits 
Survival 
Follow-Up 
5 
6 
7 
Every 
6-9 
weeks 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
From 
C1D1  
± 7 
30 days (± 7 
days) post 
last dose of 
study 
treatment 
Suggested 
every 9 weeks  
x 1 year; then 
every 12 
weeks  
Approximately
every 6 months 
from Post-Tx 
Safety Follow-
up Visit 
Tumor Imaging and Assessmentsf 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Correlative Studies Blood Collectiong 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Optional Studies Blood Collectionk 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
a. 
Subjects will be followed for adverse events through 30 days after last dose of study treatment and for serious adverse events through 90 days after last dose of study 
treatment (or through 30 days if new anti-cancer therapy is initiated)  
b. 
C1D1 Physical Exam/Performance Status/Weight not required if done within 7 days of Entry into Second Course Phase exam. 
c. 
To include temperature, pulse rate, blood pressure, and either respiratory rate or oxygen saturation 
d. 
Collect within 72 hours prior to administration of study treatment in women of childbearing potential. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required 
e. 
Must be done within 7 days of C1D1 if on anti-coagulants such as warfarin/heparin. Otherwise to be done within 10 days of C1D1. 
f. 
It is recommended that scans are performed within 28 days of re-initiation of pembrolizumab but the interval may be determined per the investigator. Scans will then be 
performed per investigator discretion at a recommended interval of every 6-9 weeks. Subjects who discontinue study treatment and have not had second documented 
disease progression or started new anti-cancer therapy should have tumor imaging per investigator discretion at a suggested frequency of every 9 weeks (±7 days) to 
monitor disease status. After 1 year of follow-up, tumor imaging can go from 9 to 12 week intervals per investigator discretion. 
g. 
Includes [(2) 8 ml CPT tubes, (1) 10 ml red top and (1) 10 ml purple top)]. Collect at Entry into Second Phase, prior to dose administration every other (odd numbered) 
cycle (starting with Cycle 3), and at second documented disease progression or at the Post-Treatment Safety Follow-up Visit 
h. 
Subjects who do not have symptoms of cardiac disease as determined by the investigator will have an echocardiogram to monitor LVEF every 5 years (± 90 days) from 
the last dose of doxorubicin. This is required regardless of the number of doxorubicin doses administered during the Initial Treatment Period. Subjects who develop 
symptoms of cardiac disease any time after initiation of doxorubicin will be referred to cardiology. In this case, the frequency of cardiac evaluations will be determined 
by cardiology.  
i. 
See Table 2 for complete list of required chemistries 
j. 
After cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing 
k. 
Optional blood correlatives (1) 2.5 ml Paxgene only to be collected in subjects who consent. Collected at Entry into Second Phase, prior to dose administration every 
other (odd numbered) cycle (starting with Cycle 3), and at second documented disease progression or at the Post-Treatment Safety Follow-up Visit 
l. 
All Entry into Second Course Phase labs must be done within 10 days of C1D1 


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38 
m. To include baseline signs and symptoms present at the time of Entry into Second Course Phase 
n. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not related to study treatment. However, subjects should be placed back on 
study treatment within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor-Investigator. 
 
 
 


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39 
 
6. TREATMENT PLAN 
 
6.1. 
Drug Dosage and Administration 
 
The study drug (pembrolizumab) must be exclusively used for the investigation 
specified in this protocol and it will only be accessible to authorized staff.  Treatment 
with doxorubicin IV and pembrolizumab IV will be administered every 3 weeks (21 
days) +/- 3 days during the Initial Treatment Period.  Day 1 of the cycle will be 
defined as the day that pembrolizumab is administered. In the event of a delay in 
pembrolizumab administration, doxorubicin may be continued to be administered 
every 21 days. This may result in more than one doxorubicin administration within a 
cycle. In the event of doxorubicin discontinuation due to toxicity, pembrolizumab will 
be allowed to continue until any of the criteria in Section 6.11 are met.  In the event 
that the maximum allowable doxorubicin dosage of 450 mg/m2 is reached and no 
toxicity has occurred, subjects will discontinue treatment with doxorubicin, but will 
continue treatment with pembrolizumab until any of the criteria in Section 6.11 are 
met.  In the event of toxicity requiring discontinuation of pembrolizumab, treatment 
with doxorubicin on study will be discontinued. Subjects in the Second Course Phase 
will receive monotherapy pembrolizumab every 3 weeks (21 days) +/- 3 days.  
 
Table 3.  Drug dose and administration 
 
a 
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 and +10 minutes 
is permitted. A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration to remove any adventitious particles.  If 
the infusion set does not contain 0.2 to 5 µm in-line filter, it is recommended to use 0.2 to 5 µm 
add-on filter which may contain an extension line 
b 
A single, 12mg dose of dexamethasone may be given prior to administration of doxorubicin.  
Administer doxorubicin intravenously over 10 (± 5) minutes. Decrease the rate of doxorubicin 
administration if erythematous streaking along the vein proximal to the site of infusion or facial 
flushing occurs. Dexrazoxane may be administered at a 10:1 ratio (dexrazoxane: doxorubicin) at the 
investigator’s discretion, within 30 minutes prior to each doxorubicin infusion for prevention of 
cardiotoxicity. It is recommended that all subjects receiving 5 or more cycles of doxorubicin 
receive dexrazoxane.   
c     All subjects should initiate doxorubicin at a dose of 60 mg/m2 at Cycle 1 Day 1. Dose may be 
escalated to 75 mg/m2 per investigator discretion after Cycle 1. Total dose of doxorubicin should 
not exceed cumulative lifetime dose of 450 mg/m2.  
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Pembrolizumaba 
200 mg or 
2mg/kg (up to 
200 mg)d 
 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Doxorubicinb 
60- 75 mg/m2 c 
Cycle 1 Day dose 
= 60 mg/m2 
Q3W 
IV injection 
Day 1 of each 3 week 
cycle 1 


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40 
d 
Subjects 18 years of age or older will receive 200 mg IV every 3 weeks. Subjects 12-17 years of 
age will receive 2 mg/kg IV (calculated from weight at screening) (up to 200 mg) every 3 weeks. If 
the subject’s (aged 12-17 years old) weight changes by more than 10% from the screening weight, 
the pembrolizumab dose should be recalculated. Subjects who turn 18 during treatment will receive 
the 200 mg dose after the 18th birthday. 
 
Study treatment will begin on the day of enrollment. Study treatment will continue 
until any of the criteria in Section 6.11 are met.  Subjects who stop treatment with 
pembrolizumab in the Initial Treatment Period may be retreated if they meet the 
criteria specified in Section 7. 
 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of study drug in accordance with the protocol and any applicable laws and 
regulations. 
 
6.2. 
Dose Selection 
 
The rationale for selection of doses to be used in this trial is provided in Section 2.3.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided 
in the Pharmacy Manual.   
 
6.3. 
Dose Modification for Doxorubicin 
 
Dose modifications to the administration of doxorubicin will be allowed per package 
insert. Pembrolizumab may be given if doxorubicin is held for toxicity, at the 
discretion of the Investigator. 
 
6.4. 
Toxicity-Related Dose Delays/Dose Modifications/Discontinuations for 
Pembrolizumab 
If a dose of pembrolizumab is withheld for toxicity, then subjects may resume dosing 
with pembrolizumab if that is appropriate at their next scheduled appointment or when 
toxicity has improved as described below. 
 
Pembrolizumab will be withheld for ≥ Grade 3 drug-related toxicity including 
laboratory abnormalities and severe or life-threatening AEs per Table 4.  
 
   Growth factors are allowed for hematologic toxicities. 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, 
pembrolizumab should be discontinued after consultation with the Sponsor-
Investigator. Subjects who require corticosteroids to manage drug-related adverse 
events must be at an equivalent dose of ≤10mg per day of prednisone to resume dosing 
with pembrolizumab. Furthermore, an inability to reduce the corticosteroid dose for 
managing a drug-related adverse event to the equivalent of ≤10 mg prednisone per day 


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41 
within 12 weeks of last pembrolizumab dose should prompt discussion with the 
Sponsor-Investigator regarding the subject’s ability to continue on treatment in the 
trial. Subjects with a laboratory adverse event still at Grade 2 after 12 weeks may 
continue treatment in the trial only if asymptomatic and controlled. This includes 
subjects who experience drug induced hypothyroidism requiring replacement therapy. 
Resumption of pembrolizumab may occur once the subject is stable on adequate doses 
of replacement therapy and is clinically asymptomatic. 
 
For subjects who experience a recurrence of the same AE(s) at the same grade or 
greater with rechallenge of pembrolizumab, a discussion should occur to determine 
whether the subject should continue in the trial. However, for a subject who 
experiences a recurrence of the same serious adverse event at the same grade or greater 
with rechallenge of pembrolizumab, the subject MUST discontinue study treatment.  
Dose increase or decrease of pembrolizumab will not be permitted in individual 
subjects. 
 
6.5. 
Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab and combination therapy  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may, 
including coadministration with additional compounds, represent an immunologic etiology.  
These adverse events may occur shortly after the first dose of pembrolizumab/combination 
treatment or several months after the last dose of treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per below. Doxorubicin should be given as 
described in Section 6.1 if pembrolizumab is withheld for toxicity. 
Table 4. Dose Modification and Toxicity Management for Immune-related Adverse Events 
Associated with Pembrolizumab monotherapy and IO Combinations. 
 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day 
within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid 
taper. 


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42 
irAEs 
Toxicity 
Grade 
(CTCAE v4.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-
up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics 
for opportunistic infections 
•  Monitor participants for 
signs and symptoms of 
pneumonitis 
•  Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
•  Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation (ie, 
peritoneal signs and ileus) 
•  Participants with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and 
performing endoscopy to 
rule out colitis 
•  Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. 
If sufficient oral fluid 
intake is not feasible, fluid 
and electrolytes should be 
substituted via IV infusion 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 


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43 
AST or ALT Elevation or 
Increased Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
T1DM or Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
β-cell failure 
Withhold d 
•  Initiate insulin replacement 
therapy for participants with 
T1DM 
•  Administer antihyperglycemic 
in participants with 
hyperglycemia 
 
•  Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes 
Endocrine disorders- other 
(hypophysitis) 
Grade 2 
Withhold 
•  Administer corticosteroids and 
initiate hormonal 
replacements as clinically 
indicated 
•  Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis: 
grading according to 
increased creatinine or 
acute kidney injury 
Grade 2 
Withhold 
•  Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper 
•  Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological Toxicities 
Grade 2 
Withhold 


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Grade 3 or 4 
Permanently 
discontinue 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative Dermatologic 
Conditions 
Suspected SJS, 
TEN, or 
DRESS 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation 
to confirm etiology or 
exclude other causes 
Confirmed SJS, 
TEN, or 
DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation 
to confirm etiology or 
exclude other causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse 
Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; 
IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of 
normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline 
normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control 
achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing 
cholangitis). 
 
 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study treatment (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study treatment 
within 3 weeks of the scheduled interruption, unless otherwise discussed with the 


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Sponsor-Investigator. The reason for interruption should be documented in the 
subject’s study record. 
 
6.6. 
Timing of Doxorubicin/Pembrolizumab Dose Administration  
 
Doxorubicin 60- 75 mg/m2 will be administered via IV injection on Day 1 of each 
cycle over 10 (+/- 5) minutes for a total dose not to exceed cumulative lifetime dose of 
450 mg/m2. All subjects will receive doxorubicin 60 mg/m2 IV on Cycle 1 Day 1. The 
dose may be escalated to 75 mg/m2 after Cycle 1 per investigator discretion. 
Dexrazoxane may be administered at a 10:1 ratio (dexrazoxane: doxorubicin) at the 
investigator’s discretion, within 30 minutes prior to each doxorubicin infusion for 
prevention of cardiotoxicity. It is recommended that all subjects receiving 5 or more 
cycles of doxorubicin receive dexrazoxane. 
 
Pembrolizumab will be administered as a 30 minute IV infusion on Day 1 of each 
cycle after all procedures/assessments have been completed as detailed in Section 5 
and after administration of doxorubicin (if doxorubicin is administered). Subjects 18 
years of age and older will receive pembrolizumab at a dose of 200 mg. Subjects 12-
17 years of age will receive pembrolizumab at a dose of 2 mg/kg (calculated from 
weigh at screening) (up to 200 mg). If the subject’s (aged 12-17 years old) weight 
changes by more than 10% from the screening weight, the pembrolizumab dose should 
be re-calculated. Subjects who turn 18 during treatment will receive the 200 mg dose 
after the 18th birthday.  
 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration to remove any adventitious 
particles.  If the infusion set does not contain 0.2 to 5 µm in-line filter, it is 
recommended to use 0.2 to 5 µm add-on filter which may contain an extension line. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min). 
 
Day 1 of the cycle will be defined as the day that pembrolizumab is administered. In 
the event of a delay in pembrolizumab administration, doxorubicin may be continued 
to be administered every 21 days. This may result in more than one doxorubicin 
administration within a cycle. 
 
Study treatment may be administered up to 3 days before or after the scheduled day of 
treatment with pembrolizumab and/or doxorubicin due to administrative reasons.  
 
Study treatment will be administered on an outpatient basis. 
 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
 


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6.7. 
Concomitant Medications/Vaccinations (allowed and prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial.  If there is a clinical indication for one of these or 
other medications or vaccinations specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required.  The Sponsor-
Investigator should discuss any questions regarding this with the Merck Clinical team.  
The final decision on any supportive therapy or vaccination rests with the Sponsor-
Investigator and/or the subject's primary physician.  
 
6.7.1. 
Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a subject’s welfare 
with the exception of those listed in Section 6.7.2 may be administered at the 
discretion of the investigator in keeping with the community standards of 
medical care.   
 
All concomitant medications received within 28 days before the first dose of 
study treatment and 30 days after the last dose of study treatment should be 
recorded.  Concomitant medications administered after 30 days after the last 
dose of study treatment should be recorded for SAEs and ECIs as defined in 
Section 10. 
 
Permitted concomitant therapies include: 
 
• Standard therapies for concurrent medical conditions. 
• Supportive care for any underlying illness. 
• Palliative radiation therapy is allowed if the target lesion(s) are not included 
within the radiation field and no more than 10% of the bone marrow is 
irradiated. 
• Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic 
growth factors may be used in the management of acute toxicity, such as 
febrile neutropenia, when clinically indicated or at the Investigator’s 
discretion. However, they may not be substituted for a required dose 
reduction. Subjects are permitted to take chronic erythropoietin. 
• Treatment with nonconventional therapies (such as acupuncture), and 
vitamin/mineral supplements are permitted provided that they do not interfere 
with the study endpoints, in the opinion of the Investigator. 
• Bisphosphonates. 
• Subjects who are therapeutically treated with an agent such as warfarin or 
heparin will be allowed to participate provided that their medication dose and 
INR/PTT are stable. Close monitoring (within 7 days of the treatment 
initiation/re-initiation and as clinically indicated) is mandatory. If either of 
these values are above the therapeutic range, the doses should be modified and 
the assessments should be repeated weekly until they are stable. 


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• Subjects taking narrow therapeutic index medications should be monitored 
proactively (e.g. warfarin, phenytoin, quinidine, carbamazepine, 
Phenobarbital, cyclosporine, and digoxin).  
 
6.7.2. 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the 
Screening/Entry into Second Course Phase (if applicable) and the Initial 
Treatment Period/Second Course Phase (if applicable) of this trial: 
• Other investigational treatment during or within 30 days before initiation/re-
initiation of study treatment. 
• Systemic antitumor therapy, including cytotoxic therapy, biologic therapy, 
signal transduction inhibitors, immunotherapy, and hormonal therapy. 
• Bone marrow transplant or stem cell rescue. 
• Use of St. John’s wort (Hypericum perforatum). Use of other herbal remedies 
is discouraged, and is permitted only with the specific assent of the 
Investigator. All herbal and vitamin supplement use must be carefully 
documented. 
•   Radiation therapy  
• Note:  Palliative radiation therapy is allowed if the target lesion(s) are not 
included within the radiation field and no more than 10% of the bone marrow 
is irradiated. 
- 
Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion.  This will be 
recorded as progressive disease, but the subject will be allowed to 
continue treatment with pembrolizumab with Sponsor-Investigator 
approval.   
• 
Live vaccines within 30 days prior to initiation/re-initiation of study 
treatment and while participating in the trial.  Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
•   Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology or as pre-
medication for doxorubicin as specified in Table 3.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor-
Investigator. 
•  Subjects who, in the assessment by the investigator, require the use of any of 
the aforementioned treatments for clinical management should be removed 
from the trial.  Subjects may receive other medications that the investigator 
deems to be medically necessary. 
There are no prohibited therapies during follow-up. 
 


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6.8. 
Rescue Medications & Supportive Care 
 
6.8.1. 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures 
for the management of adverse events with potential immunologic etiology 
are outlined below. Where appropriate, these guidelines include the use of oral 
or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied 
when the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the 
investigator does not need to follow the treatment guidance (as outlined 
below). Refer to Section 6.5 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
• 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, administer oral corticosteroids.  
o 
For Grade 3 or 4 diarrhea/colitis, 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. 
 


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• 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 
o 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
o 
Evaluate subjects 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 
subjects 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): 
o 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) 
are suggested as initial therapy. 
o 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o 
Grade 3-4 hyperthyroidism  
o 
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). 
o 
Treat with IV or oral corticosteroids 
o 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 
to 48 hours.  
o 
When symptoms improve to Grade 1 or less, a steroid taper should 
be started and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o 
For Grade 2 events, treat with corticosteroids. 


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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 5 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 5. 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 study 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 25-50 mg po or 
iv (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) 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Vasopressors 
Corticosteroids 
Epinephrine 
 
No subsequent dosing 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 4: 
Life-threatening; pressor or ventilatory 
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 study treatment administration. 
 
6.9. 
Definition of Pembrolizumab Overdose  
For the 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. 
 
6.10. Treatment Compliance 
 
Subject compliance with the treatment and protocol includes willingness to comply 
with all aspects of the protocol. At the discretion of the Sponsor-Investigator, a subject 
may be discontinued from the protocol for non-compliance with visits or study 
treatment. Administration of study treatment will be witnessed by the Investigator 
and/or trial staff.  
 
6.11. Duration of Therapy 
Treatment will be discontinued (End of Treatment) for any of the following reasons: 
• Documented disease progression as defined in Section 4.4. Note: After 
confirmed progression, clinically stable subjects are allowed to continue on 
therapy beyond confirmed progression if determined to derive clinical benefit in 
the investigator’s opinion, or    
• Unacceptable adverse experiences that prevents further administration of study 
treatment 
• Intercurrent illness that prevents further administration of study treatment 
• The subject has a confirmed positive serum pregnancy test 
• The subject decides to withdraw consent for study treatment 
• Initial Treatment Period: Completed 24 months of uninterrupted treatment with 
pembrolizumab or 35 administrations of pembrolizumab, whichever is first.  
Note: 24 months of pembrolizumab is calculated from the date of first dose. 
Subjects who stop pembrolizumab after 24 months/35 cycles may be eligible 
for up to one year of additional study treatment if they progress after stopping 
study treatment provided they meet the requirements detailed in Section 7.  
• Second Course Phase: Completed (1) year of treatment with pembrolizumab  
• Administrative reasons 
 
Follow-up procedures are listed in Section 4.4. After the last dose of study 
treatment, each subject will be followed for 30 days for adverse event monitoring 


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(serious adverse events will be collected for 90 days after the last dose of study 
treatment or 30 days if new anti-cancer therapy is initiated as described in Section 
4.4).  Subjects who discontinue study treatment for reasons other than 
documented progressive disease will have post-treatment follow-up for disease 
status until documented disease progression, initiating subsequent anti-cancer 
treatment, withdrawing consent, or becoming lost to follow-up. After documented 
disease progression each subject will be followed by telephone or medical visit 
verification for overall survival until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
 
In this trial, a subject may discontinue from study treatment but continue 
treatment with doxorubicin and participation in the regularly post discontinuation 
follow-up scheduled activities, as long as the subject does not withdraw consent 
for participation.  
 
Any subject in the Initial Treatment Phase who stops pembrolizumab with SD or 
better may be eligible for up to one year of additional pembrolizumab therapy if 
they have first documented disease progression after stopping study treatment and 
meet the criteria in Section 7.  
 
7. SECOND COURSE PHASE 
Subjects who stop pembrolizumab in the Initial Treatment Period with SD or better may be 
eligible for up to one year of additional pembrolizumab therapy if they have first documented 
disease progression after stopping study treatment.  This retreatment period is termed the 
Second Course Phase of this study and is only available if the study remains open and the 
subject meets the following conditions: 
 
EITHER 
 
• Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
• Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
• Received at least two treatments with pembrolizumab beyond the date when the 
initial CR was declared 
 
OR 
 
• Had SD, PR or CR and stopped pembrolizumab treatment after 24 months/35 
cycles (see Section 6.11) of study therapy for reasons other than disease 
progression or intolerability 
 
AND 
 


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• Experienced an investigator-determined radiographic disease progression after 
stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Completed all required study procedures for Entry into Second Course Phase   
as detailed in the Study Calendar in Section 5.2 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 3.2.1 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with 
pembrolizumab.   
• Female subject of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for 
the course of the study through 120 days after the last dose of pembrolizumab 
(Reference Section 3.3.2).  Subjects of child bearing potential are those who 
have not been surgically sterilized or have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting 
with the first dose of pembrolizumab through 120 days after the last dose of 
pembrolizumab.   
• Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might interfere with the subject’s participation for 
the full duration of the trial or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator. 
 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab. Treatment may be administered for up to one additional 
year. 
 
8. DATA AND SAFETY MONITORING PLAN 
 
8.1. 
Safety Monitoring 
 
This protocol will be monitored according to the processes in effect for all Levine 
Cancer Institute investigator-initiated studies and the protocol-specific monitoring 
plan, and will abide by standard operating procedures set forth by both the Carolinas 
HealthCare System Office of Clinical and Translational Research and the Levine 
Cancer Institute Clinical Trials Office.  It is the responsibility of the Sponsor-
Investigator to monitor the safety data for this study.  The Sponsor-Investigator, 
Statistician, and other team members as needed will meet regularly to monitor subject 
consents, enrollment and retention, safety data for all subjects [including adverse 
events (AEs) for all grades and attributions, serious adverse events (SAEs)], study 
drug administration, and validity/integrity of the data. Documentation of these 
meetings will be kept with study records. SAEs will be reported to the Food and Drug 
Administration (FDA) and the IRB per their requirements.  Major protocol deviations 
that result in a threat to subject safety or the integrity of the study will be reported to 
the IRB per their requirements. The Sponsor-Investigator will submit data to the LCI 


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54 
Data and Safety Monitoring Committee according to the protocol-specific Data and 
Safety Monitoring Plan. 
 
The Sponsor-Investigator will monitor the study accrual data regularly.  
 
8.2. 
Data Quality Assurance 
 
This study will be organized, performed, and reported in compliance with the study 
protocol, standard operating procedures (SOPs) of the Levine Cancer Institute and 
Atrium Health (AH) Office of Clinical and Translational Research, the FDA, and other 
applicable regulations and guidelines (e.g. GCP).  
 
Subjects will be monitored by LCI Research /Data Monitors per the study-specific 
monitoring plan and LCI/AH SOPs for data quality. This monitoring will be done by 
comparing source documentation to the eCRFs. Any variation between the two data 
sets will be discussed with the Treating Investigator, Sponsor- Investigator and/or 
other study team members as appropriate.  
The study database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures. Data 
queries requiring clarification will be generated and addressed by the appropriate study 
team member. Only authorized personnel will make corrections to the study database 
and all corrections will be documented in an electronic audit trail. 
 
8.3. 
Communication Between Investigational Sites 
 
Investigational sites will be required to report AEs for all grades and attributions, 
SAEs, problems with study treatment administration, deviations, or any other problem 
that could affect the validity/integrity of the study data to the Sponsor-Investigator.  
All investigational sites will report AEs, ECIs and SAEs using the eCRFs and SAE 
reporting form. AEs will be reported within 5 business days of the investigator 
learning of the event.  SAEs and ECIs will be reported within 1 business day of the 
investigator learning of the event. Problems with study treatment administration or any 
other problem affecting safety or data integrity should be communicated to the 
Sponsor-Investigator or designee per standard procedures by email or phone as soon as 
possible but within 2 business days of the Investigator learning of the event. 
 
9. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
 
9.1. 
Investigational Product 
 
The Sponsor-Investigator shall be accountable for maintaining appropriate records and 
ensuring appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 


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Clinical supplies will be provided by Merck as summarized in Table 6. 
 
Table 6.  Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2. 
Doxorubicin 
Doxorubicin is commercially provided. 
 
9.3. 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
9.4. 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at 
the trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the 
protocol. 
 
9.5. 
Returns and Reconciliation 
The Sponsor-Investigator is accountable for keeping accurate records of the clinical 
supplies received from Merck or designee and the amount dispensed to the subjects.  
 
Upon completion or termination of the study, all unused investigational product will 
be destroyed at the site per institutional policy. It is the Sponsor-Investigator’s or 
designee’s responsibility to ensure arrangements are made for disposal of all empty or 
partially used 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. 
 
9.6. 
Drug Accountability 
All study drug will be stored at the investigational site in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements and 
will be inaccessible to unauthorized personnel.  
 
An adequate record of receipt, distribution, and destruction of pembrolizumab will be 
kept in the form of a Drug Accountability Form and maintained by the LCI IDS 
(Investigational Drug Services) Pharmacy. The Investigator, or responsible party 


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designated by the Investigator, will maintain a careful record of the inventory using 
the Drug Accountability Form.  Doxorubicin will be administered commercially. 
 
9.7. 
Destruction 
At the end of the study, unused supplies of pembrolizumab will be destroyed 
according to LCI IDS pharmacy policies. 
 
 
 
 
10. SAFETY DATA COLLECTION, RECORDING AND REPORTING 
 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, regular monitoring of hematology, blood chemistry and liver function test 
values, regular measurement of vital signs, and performance of history and physical 
examinations.  These assessments should be performed per the study calendar. Adverse 
events will be evaluated continuously throughout the study. Safety and tolerability, 
relationship to treatment and intensity will be assessed according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. All adverse events (Grades 1 
– 5) will be documented in subject study charts, and recorded in the eCRF. 
 
10.1. Unanticipated Problem Definition 
 
An UAP is any incidence, experience or outcome that is unexpected, given the 
information provided in research-related documentation (e.g., Investigator’s brochure, 
informed consent) and the study population characteristics that is related or possibly 
related to participation in the research study and places the participant at an increased 
risk.   
 
10.2. Adverse Event  
10.2.1. Adverse Event Definition 
An adverse event is defined as any untoward medical occurrence in a study subject 
who is administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal 
product or protocol-specified procedure, whether or not considered related to the 
medicinal product or protocol-specified procedure.  Any worsening (i.e., any clinically 
significant adverse change in frequency and/or intensity) of a preexisting condition is 
also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly 
in frequency or severity from expected levels are not to be considered adverse events.  


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Examples of this may include, but are not limited to, typical crying in children and 
onset of menses or menopause occurring at a physiologically appropriate time in 
minor subjects. 
 
Progression of the cancer under study is not considered an adverse event.  
 
10.3. Evaluation of Adverse Events 
A qualified investigator will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0.  
 
Reporting period: AEs will be captured from the time of treatment initiation/re-
initiation through 30 days following cessation of study treatment. 
Exception: 
• Adverse events that meet the definition of an Event of Clinical Interest (ECI) 
as defined in Section 10.11 will be reportable from informed consent if the 
ECI causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
Please refer to Section 10.11 for the definition and expedited reporting requirements 
for ECI’s. 
Adverse events will be evaluated for relatedness to both doxorubicin and 
pembrolizumab. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.  
Adverse events will be evaluated according to Table 7.     


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Table 7.  Adverse Event Evaluation 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of study treatment that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor-Investigator within 24 hours and to Merck 
within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose of pembrolizumab is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours to the Sponsor-Investigator and to Merck within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 


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Duration 
Record the start and stop dates of the adverse event.  
Action taken  
Did the adverse event cause pembrolizumab and/or doxorubicin to be discontinued? 
Relationship to 
study 
treatment  
Did pembrolizumab and/or doxorubicin cause the adverse event? The determination of the likelihood that pembrolizumab and/or doxorubicin caused the adverse 
event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between 
pembrolizumab and/or doxorubicin and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between pembrolizumab and/or doxorubicin and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely pembrolizumab and/or doxorubicin caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to pembrolizumab and/or doxorubicin such as: reliable history, acceptable compliance 
assessment (expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of pembrolizumab and/or doxorubicin?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 


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10.3.1. Relationship to Study Drug 
The relationship to study drug therapy should be assessed using the following definitions:   
 
Not Related:  Evidence exists that the AE has an etiology other than the study drug (i.e., 
pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication). This includes events that are considered remotely or unlikely related to 
study drug. 
 
Related:  A temporal relationship exists between the event onset and administration of the 
study drug.  It cannot be readily explained by the subject’s clinical state, intercurrent 
illness, or concomitant therapies.  In the case of cessation or reduction of the dose, the 
event abates or resolves and reappears upon rechallenge. It should be emphasized that 
ineffective study drug treatment should not be considered as causally related in the 
context of AE reporting. This includes events that are considered possibly, probably, or 
definitely related to study drug. 
 
All adverse events (including event name, grade, start/stop date and attribution) will be 
documented in the medical record and/or research chart and recorded on the case report 
form for this protocol. 
 
The Investigator is responsible for verifying and providing source documentation for all 
adverse events and assigning the attribution for each event for all subjects enrolled on the 
trial. 
 
10.4. Suspected Adverse Reaction Definition 
A SAR is an adverse event in which there is reasonable possibility that the study drug 
caused the adverse event as defined by 21 CFR 312.32.  The Investigator is 
responsible for judging whether it is a reasonable possibility that the study drug caused 
the adverse event. 
 
10.5. “Unexpected” Definition 
An AE or SAR is to be considered unexpected if the event is not listed in the current 
Investigator Brochure, package insert or label or is not listed in the severity or 
specificity observed. 
 
10.6. Serious Adverse Event Definition 
An AE or SAR is to be considered serious if the Investigator deems it as such and the 
event results in any of the following outcomes:  
• Death;  
• Life-threatening situation (patient is at immediate risk of death);  
• Inpatient hospitalization or prolongation of an existing hospitalization 
(excluding those for study drug administration, protocol-related procedures, 


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palliative or hospice care, or placement of an indwelling catheter, unless 
associated with other serious events);  
• Persistent or significant disability/incapacity;  
• Congenital anomaly/birth defect in the offspring of a subject who received 
study treatment;  
• Development of a new cancer (that is not a condition of the study) 
• Overdose of pembrolizumab as defined in Section 6.9, that is associated with 
an adverse event even if no other seriousness criteria are met; 
• Other:  Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization, may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.    
o Examples of such events are:  
 Intensive treatment in an emergency room or at home for 
allergic bronchospasm;  
 Blood dyscrasias or convulsions that do not result in 
hospitalization; 
 Development of drug dependency or drug abuse.   
 An AE or SAR is to be considered life-threatening if the 
Investigator deems it as such and the event poses an immediate 
threat of death.   
 
Pregnancy and Lactation 
Although pregnancy and lactation are not considered adverse events, pregnancies and 
lactations must be reported from informed consent through 120 days after last dose of 
pembrolizumab, or 30 days if the subject initiates new anti-cancer therapy, whichever 
is earliest. 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 SAEs. If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
 


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10.7. Events of Clinical Interest Associated with Pembrolizumab 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI). ECIs for this trial include: 
• An overdose of pembrolizumab, as defined in Section 6.9, that is not associated 
with clinical symptoms or abnormal laboratory results.  
• 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 
 
10.8. Expedited Safety Reporting to the Sponsor-Investigator 
SAEs, ECIs, pregnancies and lactation exposure must be reported to the Sponsor-
Investigator within 1 business day of awareness.  
Reporting Period: SAEs and ECIs will be captured from the time of study treatment 
initiation/re-initiation through 90 days after the date of the last study treatment 
administration or 30 days if new anti-cancer therapy is initiated.  
Exceptions: 
• Reportable from informed consent: 
o Events that meet the definition of a SAE that are determined to be 
related and unexpected to a research procedure  
o Pregnancy and lactation; reportable through 120 days after last dose of 
pembrolizumab or 30 days if the subject initiates new anti-cancer 
therapy, whichever is earliest. 
o Events that meet the definition of an ECI (as defined per Section 10.7) 
if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure 
(reportable until study treatment initiation). 
• Reportable from study treatment initiation through duration of the subject’s 
participation on the trial (treatment and follow-up): 
o Events occurring after the 30-day reporting period that are determined 
to be related to study treatment or a research procedure  
 
SAEs will be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, until progression has been stabilized, or until there has been 
acceptable resolution of the event. This may at times cause the follow-up period for 
SAEs to be greater than 90 days. Similarly, the Sponsor-Investigator is responsible for 


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following the subject during the required follow-up period even if the subject lives 
elsewhere or has been released from his or her care and is being treated under another 
service at LCI. 
Please refer to Section 10.11 for the definition and expedited reporting requirements 
for ECI’s. 
 
10.9. Safety Reporting to the FDA 
For investigator-initiated studies where the Sponsor-Investigator holds an IND, safety 
reporting requirements for the FDA apply in accordance with the regulations set forth 
in 21 CFR 312.32. The Sponsor-Investigator, or designee, will be responsible for 
notifying FDA (using a MedWatch form) and all participating Investigators of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but 
in no case later than 7 calendar days after the Sponsor's initial receipt of the 
information. For all other serious and unexpected safety events, the Sponsor-
Investigator, or designee, will notify the FDA within 15 calendar days. 
 
It is the responsibility of the Sponsor-Investigator, Investigators and the Protocol Team 
to ensure SAEs are reported according to the Federal Regulations, ICH E6 Good 
Clinical Practices, the protocol guidelines, and Institutional Review Board reporting 
requirements. 
 
Planned protocol deviations will be submitted to the FDA for prior approval only if the 
deviation affects the scientific validity of the study and/or the rights, safety, or welfare 
of subjects. 
 
10.10. Safety Reporting to the IRB 
All events occurring during the conduct of a protocol and meeting the definition of a 
UAP or SAE will be reported to the IRB per their reporting requirements. 
 
Protocol deviations that, in the Investigator’s judgment, potentially caused harm to 
participants or others or indicates that the participants or others are at an increased risk 
of harm, or has adversely impacted data integrity will be reported promptly to the IRB 
per their reporting requirements. 
 
10.11. Safety Reporting to Merck 
Any serious adverse event or ECI, or follow up to a serious adverse event or ECI, 
including death due to any cause other than progression of the cancer under study that 
occurs to any subject from the time of study treatment initiation/re-initiation through 
90 days following cessation of study treatment, or 30 days if  new anti-cancer therapy 
is initiated, whichever is earlier, whether or not related to pembrolizumab, will be 
reported within 2 working days of Sponsor-Investigator awareness to Merck Global 
Safety by the Sponsor-Investigator. SAEs that cause the subject to be excluded from 
the trial, or is a result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure are 


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reportable to Merck from the time period beginning with informed consent until study 
treatment initiation/re-initiation. Pregnancies and lactations must be reported from 
informed consent through 120 days after last dose of pembrolizumab, or 30 days if the 
subject initiates new anti-cancer therapy, whichever is earliest. 
 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to pembrolizumab 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-Investigator and to 
Merck. 
 
SAE/ECI and pregnancy/lactation reports and any other relevant safety information 
are to be forwarded to Merck by the Sponsor-Investigator to Global Safety facsimile 
number:  +1-215-993-1220 
 
If the Sponsor-Investigator holds an IND, a copy of all 15 Day Reports and Annual 
Progress Reports are to be submitted as required by the FDA 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 the 
appropriate regulatory agency. 
 
 
10.12. Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck unless 
there is evidence suggesting a causal relationship between pembrolizumab and the 
event. Any such event will be submitted to the Sponsor-Investigator within 24 hours 
and to Merck Global Safety within 2 working days either by electronic or paper media. 
 
Specifically, the suspected/actual events covered in this exception include any event 
that is disease progression of the cancer under study. 
 
The Sponsor-Investigator will monitor unblinded aggregated efficacy endpoint events 
and safety data to ensure the safety of the subjects in the trial.  
 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be 
considered a SAE. 
 
11. MEASUREMENT OF EFFECT 
 
11.1. Anti-tumor Effect – Solid Tumor 
Response and progression will be evaluated in this study using the Revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1.  Clinically stable 


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patients may continue to be treated beyond radiologic progression per the 
Investigator’s discretion, however, at the time of RECIST-defined progression, 
progressive disease will be documented in the study records. 
 
11.1.1. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the 
beginning of the treatment. Baseline evaluations prior to Second Course Phase 
will be performed per the investigator’s discretion. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up. Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used to assess the anti-tumor 
effect of a treatment.  The Sponsor-Investigator or designee will be 
responsible for performing tumor measurements.  The tumor measurements 
will be recorded on the eCRF. 
 
11.1.2. Response Criteria 
 
Response will be evaluated using RECIST 1.1 criteria.47 
 Complete Response: 
• Target lesion: Disappearance of all target lesions. Any pathological lymph  
nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
• Non-target lesion: Disappearance of all non-target lesions. All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
 
Partial Response: 
• Target lesion: At least a 30% decrease in the sum of diameters of target, 
 
taking as reference the baseline sum diameters. 
• Non-target lesion: Not applicable 
 
Stable Disease: 
• Target lesion: Neither sufficient shrinkage to qualify for a partial response, 
nor sufficient increase to qualify for progressive disease, taking as 
reference the smallest sum diameters while on study. 
• Non-target lesion: Not applicable. 
 
Progressive Disease: 
• Target lesion: At least a 20% increase in the sum of diameters of target  
 
 
lesions, taking as reference the smallest sum on study (this includes the  
 


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baseline sum if that is the smallest on study). In addition to the relative  
 
 
increase of 20%, the sum must also demonstrate an absolute increase of at 
 
least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
• Non-target lesion: Unequivocal progression (as described in RECIST 
version 1.1) of existing non-target lesions. (Note: the appearance of one 
or more new lesions is also considered progression). 
 
Non-Complete Response / Non-Progressive Disease: 
• Target lesion: Not applicable 
• Non-target lesion: Persistence of one or more non-target lesion(s) 
 
 
 
Table 8. Summary of RECIST 1.1 (Subjects with measurable disease) 
 
Table 9. Summary of RECIST 1.1 (Subjects with non-measurable disease only) 
Target 
Lesions 
Non-target Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category also requires 
CR 
CR 
No 
CR 
Documented at least once 
≥ 4 weeks from baseline 
CR 
Non-CR/Non-PD 
No 
PR 
Documented at least once 
≥ 4 weeks from baseline 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Documented at least once 
≥ 4 weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
N/A 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, and  
NE = inevaluable. 


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RECIST 1.1 will be adapted as follows to account for the unique tumor 
response seen in this class of therapeutics, irRECIST.   
 
If imaging shows PD, tumor assessment should be repeated ≥ 4 weeks later in 
order to confirm PD with the option of continuing treatment for clinically 
stable subjects as discussed below in Table 10.   
 
Clinically stable is defined by the following criteria:   
• Absence of signs and symptoms indicating disease progression  
• No decline in ECOG performance status  
• Absence of rapid progression of disease  
• Absence of progressive tumor at critical anatomical sites (e.g., cord 
compression) requiring urgent alternative medical intervention 
 
Table 10. irRECIST: Imaging and Treatment after 1st Radiologic Evidence of PD  
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging at > 4 
weeks at site to 
confirm PD 
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting confirmatory 
scan by site 
 
N/A 
Discontinue treatment 
Repeat scan confirms 
PD 
No additional imaging 
required 
Discontinue 
treatment. In the event 
of confirmed 
progression, if the 
subject is clinically 
stable and in the 
investigator’s opinion 
would derive clinical 
benefit from 
remaining on 
pembrolizumab, the 
subject may continue 
treatment beyond 
confirmed 
progression. 
N/A 
No additional imaging 
required 
N/A 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/ Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 


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Repeat scan shows 
SD, PR or CR 
Continue regularly 
scheduled imaging 
assessments  
Continue study 
treatment at the 
Investigator’s 
discretion 
 
N/A 
 
N/A 
 
In determining whether or not the tumor burden has increased, decreased or 
stayed stable, site investigators should consider all target lesions as well as 
non-target lesions. 
 
Any subject deemed clinically unstable should be discontinued from study 
regimen at first evidence of progressive disease by tumor imaging and is not 
required to have repeat tumor imaging for confirmation.  
 
For a clinically stable subject with first radiologic evidence of progressive 
disease (i.e., unconfirmed progression of disease), it is at the discretion of the 
site investigator to continue treating the subject with the assigned treatment 
per protocol until progression of disease is confirmed at least 28 days from 
the date of the tumor imaging first suggesting PD.  If progression is not 
confirmed on the subsequent tumor imaging, the subject should continue to  
receive study therapy and have tumor imaging performed every 6 weeks (± 7 
days) to monitor disease status. If radiologic progression is confirmed by 
subsequent tumor imaging, then the subject will  
be discontinued from study treatment.  
 
NOTE: If a subject with confirmed progression by tumor imaging (i.e. 2 
scans at least 28 days apart demonstrating progressive disease) is clinically 
stable or clinically improved, and there is no further increase in the tumor 
burden at the confirmatory scan, an exception may be considered  
to continue treatment upon consultation with the Sponsor-Investigator. 
Subjects exhibiting unacceptable toxicity from trial therapy may NOT 
continue to receive trial therapy.  
 
NOTE:  In subjects who discontinue study therapy without first documented 
disease progression, every effort should be made to continue monitoring 
disease status by tumor imaging with a suggested interval of every 9 weeks 
in the first year and every 12 weeks (after year 1 per investigator discretion 
until (1) the start of new anti-cancer treatment, (2) documented disease 
progression (3) death, or (4) the end of the study, whichever occurs first. The 
same imaging modality (i.e. CT or MRI), acquisition and technical 
parameters should be used throughout the study for a given subject. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1. Sample Size  
This study is primarily designed to assess the safety of doxorubicin (60-75 mg/m2) 
and pembrolizumab (200 mg) in previously treated or untreated subjects with 


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unresectable or metastatic soft tissue sarcoma.  Based on the Bayesian stopping rules 
described in Section 12.5, 30 subjects will enable an assessment regarding whether or 
not the severe or life-threatening treatment emergent adverse event rate convincingly 
exceeds 0.55.48 
 
12.2. Endpoint Definitions 
 
12.2.1. Severe or Life-Threatening Adverse Event 
Severe or life threatening adverse event will be determined for each subject 
indicating whether or not the event meets all criteria listed below: 
• Meets the definition of seriousness as defined in Section 10.6, and 
• Pembrolizumab-related or doxorubicin-related toxicity per the 
Sponsor-Investigator and 
• Considered to be clinically significant by the Sponsor-Investigator as 
to contribute to the stopping rule.  
 
12.2.2. Progression-Free Survival 
 
Progression-free survival (PFS) is defined as the duration of time from the 
start of protocol treatment to first occurrence of either progressive disease or 
death. Disease progression can be objectively determined as per Section 11 or 
progression can be subjective as determined by the investigator. Evidence for 
subjective progression must be documented in the medical records. For 
objective disease progression, the date of PD is the date of the radiologic 
assessment that identified RECIST-defined progressive disease. For subjective 
disease progression, the date of PD is the date that the clinician makes the 
determination of disease progression. If the subject died without documented 
disease progression, the date of progression will be the date of death. For 
surviving subjects who do not have documented disease progression, PFS will 
be censored at the date of last radiologic assessment. For subjects who receive 
subsequent anti-cancer therapy prior to documented disease progression, PFS 
will be censored at the date of last radiologic assessment prior to the 
commencement of subsequent therapy. Subjects who have an initial PFS event 
immediately following 2 or more consecutive missed assessments will be 
censored at the date of the last assessment prior to those missed assessments. 
For participants with only one missed assessment, the documented progressive 
disease status and assessment date will be used. 
 
PFS will be determined for each subject using both the RECIST 1.1 and 
irRECIST criteria. 
 
12.2.3.   Overall Survival 
 
Overall survival (OS) is defined as the duration of time from the start of 
protocol treatment to death from any cause. Subjects who are alive or lost to 


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follow-up at the time of the analysis will be censored at the last known date 
they were alive. 
 
12.2.4. Objective Response 
 
Objective response will be determined for each subject as a binary variable 
indicating whether or not the subject achieved a best overall response of CR 
or PR.  Objective response will be determined for each subject with 
measurable disease at baseline using both the RECIST 1.1 and irRECIST 
criteria. 
 
12.2.5. Duration of Response 
 
Duration of response will be determined for each subject achieving an 
objective response.  Duration of response will be defined from time that 
response was initially documented until progression or death.  The censoring 
mechanism for duration of response will be the same as that described for 
PFS.  Duration of response will be determined for each subject using both the 
RECIST 1.1 and irRECIST criteria.  
 
12.2.6. Safety Endpoints 
 
Safety endpoints will include treatment administration (total number of doses 
taken, and total doses taken as a percent of total number of intended doses), 
AEs, SAEs, and deaths while on study therapy. 
 
12.2.7. Second Course Objective Response 
 
Second Course Objective response will be determined for those subjects who 
initiate second course treatment of pembrolizumab as a binary variable 
indicating whether or not the subject achieved a best overall response of CR 
or PR after starting second course treatment with pembrolizumab.  Second 
Course Objective response will be determined for each subject with 
measurable disease at entry into Second Course Phase using both the RECIST 
1.1 and irRECIST criteria. 
 
12.2.8. Second Course Progression-Free Survival (PFS2) 
 
PFS2 will be calculated for those subjects who initiate second course 
treatment of pembrolizumab in the same fashion as described in Section 
12.2.2. The start date for PFS2 will be the first dose of second course 
treatment of pembrolizumab. PFS2 will be determined for each subject using 
both the RECIST 1.1 and irRECIST criteria. 
 
12.3. Analysis Populations 


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All subjects starting study therapy will be included in the analysis of safety data, OS, 
and PFS.  Objective response will be analyzed on the population of subjects who begin 
study treatment and have measurable disease at baseline.  Duration of response will be 
analyzed on the population of subjects who achieve an objective response. Second 
course response rate and progression free survival will be conducted on subjects who 
initiate second course treatment of pembrolizumab. 
 
12.4. Analysis Methods 
 
12.4.1. Timing of Analysis 
 
Analyses on this study will be conducted on a continuous basis in order to 
assess the Bayesian stopping rules for toxicity described in Section 12.5.  An 
analysis of all endpoints will occur after the best overall response for each 
subject has been determined for all subjects.  An updated analysis of the study 
will be conducted after the PFS censoring rate reduces to 20% or when all 
subjects have been on study at least two years (whichever occurs first).  A 
final analysis of the study will be conducted after the overall survival 
censoring rate reduces to 20% or when all subjects have been on study at least 
five years (whichever occurs first).   
  
12.4.2. Subject Disposition 
 
An accounting of all consenting subjects will be provided at the end of the 
study. This will include a breakdown of subjects who consented, were treated, 
discontinued treatment, died, and were lost to follow-up or withdrew consent. 
 
12.4.3. Baseline Subject and Disease Characteristics 
 
A summary of subject demographics and disease-related characteristics will 
be completed. 
 
12.5. Primary Analysis 
A maximum of 30 evaluable subjects with soft tissue sarcoma will be enrolled as a 
single cohort.   It is not anticipated that the addition of pembrolizumab to standard 
chemotherapy will increase the rate of severe or life-threatening toxicity.  It has been 
reported that the rate of any severe or life-threatening toxicity of doxorubicin and 
dacarbazine every 3 weeks is 55%48.   
 
If it becomes evident that the rate of severe or life-threatening toxicity convincingly 
exceeds 55%, enrollment to the study will be halted. 
 


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The stopping rule will hold enrollment if the posterior probability of severe or life-
threatening toxicity risk exceeding 0.55 is 75% or higher. In this event, data will be 
evaluated to inform the subsequent conduct of the study. The prior for this monitoring 
rule is beta (11,9).  This means that our prior assumption regarding the proportion of 
severe or life-threatening toxicity is 0.55, and there is 90% probability that this 
proportion is between 0.368 and 0.726.  The operating characteristics of the stopping 
rule are given in Table 11 and are based on 5000 simulations: 
 
 
 
 


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Table 11. Operating characteristics of the stopping rule 
 
Number of 
Subjects with 
Severe or Life-
Threatening 
Toxicities 
Max. 
Denominator 
Cutoff for Early 
Stopping 
Posterior 
Probability: 
Pr(Risk>0.55|Data) 
4 
4 
0.7834 
5 
6 
0.7536 
6 
7 
0.8056 
7 
9 
0.7728 
8 
11 
0.7694 
9 
13 
0.7558 
10 
14 
0.7944 
11 
16 
0.7812 
12 
18 
0.7592 
13 
19 
0.8002 
14 
21 
0.7818 
15 
23 
0.7710 
16 
25 
0.7594 
17 
26 
0.7988 
18 
28 
0.7828 
19 
30 
0.7706 
 
12.6. Secondary Analyses 
 
Response rates (based on RECIST 1.1 criteria) will be calculated with corresponding 
95% confidence intervals based on the Clopper-Pearson method.  The duration of 
response, overall survival, and progression free survival (PFS) distributions will be 
estimated using Kaplan-Meier techniques.  Secondary correlative analyses will be 
conducted on baseline subject and disease characteristics, and selected biomarkers 
using logistic regression (response rate) and Cox proportional hazards models 
(duration of response, overall survival, and PFS).   
 
 


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12.7. Safety Analyses 
 
Incident rates for adverse events, treatment-emergent adverse events, SAEs and deaths 
while on study therapy will be summarized.  Treatment-emergent adverse events are 
defined as follows: 
 
• An adverse event that occurs after treatment start that was not present at the 
time of treatment start; or 
• An adverse event that increases in severity after treatment start if the event was 
present at the time of treatment start. 
 
 
12.8. Exploratory Analyses 
 
Analysis of objective response, duration of response, and PFS whereby the endpoints 
are based on irRECIST will be conducted using methods as described in Section 12.6.  
Correlative analysis will be conducted on PD-L1 and other biomarkers using logistic 
regression for objective response and Cox proportional hazards models for time to 
event endpoints. Other exploratory analysis will be conducted as deemed necessary. 
Summaries of second course objective response rate and progression free survival will 
be conducted. 
 
12.9. Interim Analyses 
 
This study will be continuously evaluated as described previously in Section 12.4. 
 
13. STUDY COMPLETION 
 
13.1. Completion 
 
The study will be considered complete when one or more of the following conditions 
is met: 
• All subjects have completed all study visits. 
• All subjects have discontinued from the study. 
• The IRB, FDA, LCI DSMC, Sponsor-Investigator or Merck discontinues the 
study because of safety considerations. 
• The Sponsor-Investigator defines an administrative or clinical cut-off date. 
 
13.2. Termination 
 
The study will be terminated when one or more of the following conditions occur: 


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If risk-benefit ratio becomes unacceptable owing to, for example: 
 
• Safety findings from this study (e.g. SAEs) 
• Results of any interim analysis 
• Results of parallel clinical studies 
• Results of parallel animal studies (e.g. toxicity, teratogenicity,  
  carcinogenicity or reproduction toxicity). 
• If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a 
reasonable time frame. 
 
The Sponsor-Investigator has the right to close the trial at any site and at any time. 
For any of the above closures, the following applies: 
 
• Closures should occur only after consultation between involved parties. 
• All affected institutions must be informed as applicable according to local 
law.   
• In case of a partial study closure, ongoing subjects, including those in follow- 
up, must be taken care of in an ethical manner. 
 
Details for individual subject's withdrawal can be found in Section 4.3.3. 
 
14. RETENTION OF RECORDS 
 
Essential documentation (e.g. adverse events, records of study drug receipt and dispensation), 
including all IRB correspondence, will be retained for at least 2 years after the investigation 
is completed.  Documentation will be readily available upon request. 
 
15.  PUBLICATION POLICY 
 
The Investigator must send a draft manuscript of the publication or abstract to Merck, prior to 
submission of the final version for publication or congress presentation. All relevant aspects 
regarding data reporting and publications will be part of the contract between Merck and the 
Investigator. 
 
16. ETHICAL AND LEGAL ISSUES 
 
16.1. Ethical and Legal Conduct of the Study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and  
documentation of this study, are designed to ensure that the Investigator abide by 
Good Clinical Practice (GCP) guidelines and under the guiding principles detailed in 
the Declaration of Helsinki.  The study will also be carried out in keeping with 
applicable local law(s) and regulation(s). 


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Documented approval from appropriate agencies (e.g. DSMC, IRB, FDA) will be 
obtained for all participating centers before start of the study, according to GCP, local 
laws, regulations and organizations.  When necessary, an extension, amendment or 
renewal of IRB approval must be obtained and forwarded to Merck. 
 
Strict adherence to all specifications laid down in this protocol is required for all 
aspects of study conduct; the Investigators may not modify or alter the procedures 
described in this protocol.   
 
Modifications to the study protocol will not be implemented by the Sponsor-
Investigator without discussion and agreement by Merck.  However, the Investigators 
may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to the trial subjects without prior approval from applicable 
agencies.  As soon as possible, the implemented deviation or change, the reasons for it 
and if appropriate the proposed protocol amendment should be submitted to the 
appropriate agencies.  Any deviations from the protocol must be explained and 
documented by the Investigator. 
 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites 
in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration 
of Helsinki.  The Sponsor-Investigator is responsible for personally overseeing the 
treatment of all study subjects.  The Sponsor-Investigator must assure that all study 
site personnel, including sub-investigators and other study staff members, adhere to 
the study protocol and all applicable regulations and guidelines regarding clinical trials 
both during and after study completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the required data will 
be collected and properly documented. 
 
16.2. Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. 
 
16.3. Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.   
 


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Mouridsen HT, Bastholt L, Somers R, et al. Adriamycin versus epirubicin in advanced 
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ICF_001.pdf: 
Official Title:  A Pilot Study Evaluating the Safety, Tolerability, and Efficacy of Doxorubicin 
and Pembrolizumab in Patients With Metastatic or Unresectable Soft Tissue Sarcoma
NCT03056001
IRB-Approved Date:  6/13/2022


Levine Cancer Institute / LCI-SAR-STS-PEM-001  
Page 1 of 17 
 
Michael Livingston, M.D. 
Advarra IRB Approved Version 13 Jun 2022 
 
 
 
 
 
 
 
ATRIUM HEALTH 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY  
For 
SUBJECTS WHO TURN 18 & PARENTAL/GUARDIAN PERMISSION 
 
Sponsor / Study Title: 
  
Levine Cancer Institute / A Pilot Study Evaluating the Safety, 
Tolerability and Efficacy of Doxorubicin and Pembrolizumab in 
Patients with Metastatic or Unresectable Soft Tissue Sarcoma 
Protocol Number: 
 
LCI-SAR-STS-PEM-001 
Principal Investigator: 
 
Michael Livingston, MD 
Telephone: 
 
(24 Hours) 
 (24 Hours) 
 
Address: 
Levine Cancer Institute 
 
 
 
If you are the parent or legal guardian of a child who may take part in this study, permission from 
you is required. The assent (agreement) of your child may also be required.  When “you” appears in 
this form, it may refer to you or your child; “we” means the study doctors and study staff.    
 
INTRODUCTION 
 
Dr. Livingston and his associates (the investigators) are asking you to participate in a research study 
at Levine Cancer Institute (LCI) and Atrium Health (AH) of doxorubicin and pembrolizumab in 
subjects with metastatic (cancer that has spread to new areas) or unresectable (cannot be removed by 
surgery) soft tissue sarcoma. You are being asked to take part in this study because you have 
advanced sarcoma (cancer of the soft tissue inside the body) that has spread (metastatic) or returned 
and/or is unable to be surgically removed (unresectable). The purpose of this study is to determine 
the safety, tolerability (if side effects are acceptable) and efficacy (how well it works) of the drugs 
doxorubicin and pembrolizumab for the study treatment of your sarcoma.   
 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to make your 
decision about taking part. You have also been told that you have the option not to participate. You 
may discuss your decision with your friends and family. You can also discuss it with your health care 
team. If you have any questions, you can ask your study doctor for more explanation. If you decide 
to take part in this study, you must sign and date your name at the end of this form.  You cannot 
take part in this research study until you sign and date this form. 
 


Levine Cancer Institute / LCI-SAR-STS-PEM-001  
Page 2 of 17 
 
Michael Livingston, M.D. 
Advarra IRB Approved Version 13 Jun 2022 
 
 
 
 
 
 
 
This study is being carried out under the support of Dr. Michael Livingston with Levine Cancer 
Institute (LCI).  Merck is the company providing the drug pembrolizumab that will be used in this 
study. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purpose of this study is to evaluate the safety, tolerability and efficacy of doxorubicin in 
combination with pembrolizumab in subjects with metastatic or unresectable soft tissue sarcoma. 
Based on previous studies, pembrolizumab may be an effective study treatment. 
 
Pembrolizumab has been approved by the Food and Drug Administration (FDA) in the United 
States for the treatment of a type of advanced skin cancer, melanoma, certain types of metastatic 
lung cancer (PD-L1+), and recurrent or metastatic squamous cell carcinoma of the head and neck. 
However, it has not been approved for the treatment of soft tissue sarcoma. Doxorubicin is an 
FDA-approved anticancer drug and is a standard chemotherapy used to treat soft tissue sarcoma.   
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
You will be one of approximately 30 people involved in this research project at AH. The length of 
your participation will depend upon your personal treatment and care. The study is expected to be 
open for approximately 5 years. 
 
 
HOW THE STUDY WORKS 
 
Before you begin the study (Screening; one visit): 
You will need to have the following tests and procedures done to determine if you can be in the 
study. These exams, tests, and procedures are part of regular cancer care and may be done even if 
you do not join the study. If you have had some of them recently, they may not need to be repeated. 
This will be up to your study doctor. 
 
• Medical history 
• Physical examination including vital signs (heart rate, blood pressure, breathing rate, 
temperature) and height/weight measurements 
• Documentation of any medicines you are taking 
• You will be asked about the extent of your physical activity and how you are generally feeling 
• CT (computed tomography – special x-ray using computers) scan with contrast dye or MRI 
(magnetic resonance imaging – special x-ray using magnets and a computer) of the tumor 
site, chest, abdomen and pelvis 
• Electrocardiogram (ECG), a paper tracing of the electrical activity of your heart and 
echocardiogram (ECHO), a test of the action of the heart using ultrasound waves 
• Pregnancy test (urine or blood) if you are a female of childbearing potential 
• Blood work to check blood counts, blood chemistry (measure of chemicals in the blood), 
and blood clotting 
• Urine test 


Levine Cancer Institute / LCI-SAR-STS-PEM-001  
Page 3 of 17 
 
Michael Livingston, M.D. 
Advarra IRB Approved Version 13 Jun 2022 
 
 
 
 
 
 
 
 
The following tests and procedures will be done specifically for this study and are not part of regular 
cancer care: 
 
• Tumor biopsy – you will be asked to have a tissue sample taken from an area where your 
disease is located. You will sign a separate consent for this procedure. 
If you are unwilling to have this biopsy or if your study doctor determines that a biopsy 
would be unsafe, we may collect tissue from a recent biopsy within 12 months of beginning 
study treatment.  
• Blood work to test thyroid hormone levels 
• Blood work for correlative (related) studies (looks at certain features in your blood that may 
be related to your disease).  
• You will be asked to have additional blood for correlative studies (optional) if you agree. 
We will further explain the optional blood studies at the end of this consent form. 
 
During the study (Intervention; number of visits/cycles): 
If the exams, tests, and procedures show that you can be in the study, and you choose to take part, 
then you will begin study treatment as described below: 
 
• You will receive doxorubicin (60-75 mg/m2 up to a total dose over time of 450 mg/m2) and 
pembrolizumab by IV (through a vein – intravenous) on Day 1 of each 21-day cycle. Your 
first dose of doxorubicin will be 60 mg/m2. If you tolerate that dose well, your next dose(s) 
may be increased to 75 mg/m2. This will be your study doctor’s decision. If you are 18 years 
of age or older, you will receive 200 mg of pembrolizumab with each dose. If you are 12 to 
17 years of age, the dose of pembrolizumab will be calculated from your weight (2 mg/kg, 
with a maximum dose of 200 mg). 
 
You will be given study treatment on 21-day cycles until the time your disease progresses, you are 
unable to tolerate the side effects of the study treatment, you decide you no longer wish to receive 
study treatment, or if your study doctor decides it is no longer in your best interest to receive study 
treatment. Your study doctor may discontinue the doxorubicin once you have received a specified 
number of doses but the pembrolizumab may continue as long as you are tolerating it and your 
disease is not worsening, but no longer than 24 months or after you have received 35 cycles, 
whichever comes first. If you are having unfavorable side effects, the study treatment may be 
stopped for a while, or the dose may be reduced. Your study doctor will also discuss with you 
whether it is in your best interest to continue study treatment. 
 
During the study, you will need the following exams, tests, and procedures. They are part of regular 
cancer care: 
 
• Physical examination including vital signs and weight measurements. 
• You will be asked about the extent of your physical activity and how you are generally 
feeling. 


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• CT scan (contrast dye preferred but not required) or MRI of the tumor site, chest, abdomen 
and pelvis every 6 weeks while you are receiving study treatment. 
• Blood work for blood counts and blood chemistry. 
• ECHO after every third dose of doxorubicin. 
 
The following tests and procedures will be done specifically for this study and are not part of your 
regular cancer care: 
 
• Blood work for correlative (related) studies prior to every other cycle during your initial 
study treatment and also during the Second Course Phase (possible re-study treatment with 
pembrolizumab that some subjects may be eligible to participate in - please see the next page 
for more information) if you receive this. 
• You will be asked to have additional blood for correlative (related) studies (optional) prior 
to every other cycle during your initial study treatment and also during the Second Course 
Phase if you receive this.  We will further explain the optional blood studies at the end of 
this consent form. 
• You will be asked to have a tumor biopsy (optional) anytime during your initial study 
treatment. We will further explain the optional tumor biopsy at the end of this consent form. 
 
After you complete the intervention (Post-intervention; one visit): 
After you complete study treatment, you will have a post-study treatment safety follow-up visit. You 
will need the following exams, tests, and procedures. They are part of regular cancer care: 
 
• Physical examination including vital signs and weight measurements. 
• You will be asked about the extent of your physical activity and how you are generally 
feeling. 
• CT scan or MRI of the tumor site, chest, abdomen and pelvis. 
• Heart monitoring: 
o ECHO and ECG approximately 30 days after your last dose of doxorubicin. This 
may be required before the post-study treatment safety follow-up visit if you stop 
doxorubicin before you stop pembrolizumab 
 
The following tests and procedures will be done specifically for this study and are not part of your 
regular cancer care: 
 
• Blood work for correlative (related) studies either at your end of study treatment visit or if 
your disease worsens. 
• You will be asked to have additional blood for correlative studies (optional) either at your 
end of study treatment visit or if your disease worsens 
 
Additional Post-Study Treatment Follow-Up: 
After you stop study treatment and have a post-study treatment safety follow-up visit, you will have 
additional post-study treatment follow-up visits to monitor your disease status until your disease 


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worsens or you start new cancer treatment. Your disease status will be monitored per your study 
doctor’s preference approximately every 9 weeks (+/- 7 days) for up to one year and then 
approximately every 12 weeks (+/- 7 days) unless your study doctor feels you need to have more 
frequent scans. You will also have periodic tests to monitor your heart as indicated below. 
 
Heart Monitoring: 
• ECHO approximately once every 5 years from your last dose of doxorubicin 
• If you experience any problems with your heart after treatment with doxorubicin, you will be 
referred to a doctor who specializes in evaluating and treating problems with the heart 
(cardiologist). Any procedures required to monitor your heart function will be determined by 
the cardiologist. 
 
Note: Under certain circumstances, you may be eligible to re-start study treatment with 
pembrolizumab for up to one additional year after you have moved to the follow-up portion of the 
study. This is called the Second Course Phase and will follow the same study treatment plan as 
previously given in the study. You will be evaluated to make sure it is safe to re-start study treatment 
with pembrolizumab before you re-start study treatment. 
 
Survival Follow-Up: 
At the time of disease progression or start of a new anti-cancer therapy, you will move into the 
survival follow-up phase. You will be contacted by telephone every 6 months to check your health 
status until death, withdrawal of consent, or end of the study, whichever comes first. The 
procedures under “Heart Monitoring” in the section above will still be required during Survival 
Follow-up.  
 
RISKS 
 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don’t know all the side effects that may happen. Side 
effects may be mild or very serious. Your health care team may give you medicines to help lessen 
side effects. Many side effects go away soon after you stop taking the drugs. In some cases, side 
effects can be serious, long-lasting, or may never go away. A severe side effect rarely may be life-
threatening. You should tell your study doctor immediately if you experience any side effects.  
 
This study has several risks. First, it is possible that you will get the new study treatment but do less 
well than you have been doing. Second, because the study treatment is new, we may not yet know all 
the side effects and something unexpected could happen. The following known side effects of 
pembrolizumab and doxorubicin are listed below. 
 
Pembrolizumab 
Pembrolizumab, which is approved in the USA and some other countries, is available by 
prescription to treat several different cancers, but may not be approved to treat your type of 
cancer.   
 


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Pembrolizumab works by helping your immune system to fight your cancer. However, 
pembrolizumab can also cause your immune system to attack normal organs and tissues in 
your body and can affect the way they work, which can result in side effects. These side 
effects may be serious (example, causing hospitalization or be life-threatening), may result in 
death, and/or may occur after you stop taking pembrolizumab. These side effects can affect 
more than one of your normal organs and tissues at the same time. 
 
Very common side effects, some may be serious (for example, causing hospitalization, life-
threatening or where noted, may cause death); seen in 20% or more of subjects treated with 
pembrolizumab include the following: 
• Diarrhea (loose or watery stools) 
• Itching of the skin 
• Cough 
• Nausea 
• Fatigue 
 
Common side effects, some may be serious; seen in 5% to less than 20% of subjects treated with 
pembrolizumab include the following: 
• Joint pain 
• Fever 
• Back pain 
• Rash 
• Pain in your belly 
• Loss of skin color 
• Not enough thyroid hormone, so you may feel tired, gain weight, feel cold, 
and/or have infrequent or hard stools (hypothyroidism) 
• Low levels of salt in the blood that may cause you to feel tired, feel confused, 
have a headache, have muscle cramps, and/or feel sick to your stomach 
(hyponatremia) 
 
Uncommon side effects, some may be serious; seen in 1% to less than 5% of subjects treated with 
pembrolizumab include the following: 
• Too much thyroid hormone so you may feel anxious, feel angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, and/or have loose or watery stools (hyperthyroidism) 
• Inflammation of the lungs so you may feel short of breath and cough (pneumonitis) 
• Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or 
watery stools and black, tarry, sticky stools with blood or mucus (colitis) 
• Inflammation of the skin so you may have widespread peeling of the skin, itchiness, and/or 
skin redness. The skin inflammation (for example, peeling, itching and redness) could also be 
widespread throughout your body. More severe skin reactions may involve the inside of your 
mouth, the surface of your eye and genital areas, and/or may cause the top layer of your skin 
to peel from all over your body which can cause severe infection (Severe skin reactions, 


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including Stevens-Johnson syndrome/or toxic epidermal necrolysis, which may be serious or 
potentially life-threatening) 
• Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have a fever 
and/or feel short of breath, experience a decrease in your blood pressure at the time of 
receiving your infusion (IV) or just after, or have pain at the site of infusion. 
 
Rare side effects, some may be serious; seen in less than 1% of subjects treated with pembrolizumab 
include the following: 
• Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like 
not eating, feel tired, have a mild fever, pain in the right side of your 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 
your stomach or have headaches, changes in your behavior, double vision, few to no 
menstrual cycles, weakness, vomiting and dizziness or fainting (hypophysitis)  
• Adrenal glands (glands on top of the kidneys) 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 you may pass less urine or have cloudy or bloody urine, 
swelling, and low back pain (nephritis) 
• Inflammation of the muscles so you may feel weak or have pain in the muscles (myositis) 
• Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you 
may have severe upper abdominal pain that may move to your back, feel sick to your 
stomach, and have vomiting that gets worse when you eat (pancreatitis) 
• Inflammation of the eye so you may have eye redness, blurred vision, sensitive to light, have 
eye pain, see floaters or have headaches (uveitis) 
• Type 1 Diabetes, a condition that can cause too much sugar in your blood feeling thirstier 
than usual, frequent urination and weight loss. You are likely to need regular insulin shots 
• Inflammation of the nerves that may cause pain, weakness, or tingling in your hands and 
feet, and may spread to your legs, arms and upper body leading to severe muscle weakness 
and possible temporary paralysis (inability to move) (Guillain-Barré syndrome) 
• Inflammation of the middle layer of your heart wall that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness of 
breath and swelling of the legs. You 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 your heart rate, blood pressure, body temperature, and the 
rate at which food is converted into energy (thyroiditis) 
• A condition that may make you 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) 


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• The formation of small clusters of immune cells (called granulomas) in parts of your body 
such as your lymph nodes, eyes, skin or lungs (sarcoidosis) 
• Inflammation of the brain (encephalitis) 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 your body, and loss of 
consciousness 
• Inflammation of the spinal cord (myelitis) 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 
• 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 this side 
effect: 
• 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 the right side of your belly, yellow eyes and skin, feeling tired, and 
itching (sclerosing cholangitis) 
• Hypoparathyroidism, a condition in which the body produces abnormally low levels of 
parathyroid hormone (PTH) which results in low blood levels of calcium and high blood 
levels of phosphorus.  Some symptoms include tingling or burning in the fingertips, toes and 
lips, muscle aches or cramps in the legs, feet, stomach or face, twitching or spasms of 
muscles, particularly around the mouth, but also in the hands, arms and throat, and fatigue 
(tiredness)or weakness.  
 
In addition to the above, if you have had an allogeneic stem cell transplant (a procedure in which a 
person receives blood-forming stem cells from a donor), you 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 you have had a solid organ transplant (for example, if you have received a kidney or heart 
transplant), you may experience rejection of the transplanted organ. Your study doctor will monitor 
you and should tell you what signs and symptoms you should report depending on the type of organ 
transplant that you have had. 
 


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Doxorubicin 
Possible side effects of doxorubicin include: 
 
Common (more than 20%) 
• Hair loss 
• Vomiting 
• Red colored urine, saliva, or sweat 
 
Less Common (4% to 20%) 
• Heart failure or heart attack which may cause shortness of breath, swelling of ankles, cough 
or tiredness which may occur years after the dose  
• Swelling of the body which may cause shortness of breath  
• Swelling and redness at the site of the study drug injection or area of previous radiation  
• Belly pain  
• Sores in the mouth, throat or stomach  
• Nausea, diarrhea  
• Hepatitis (liver infection) which may cause yellow eyes and skin  
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat  
• Cancer of the bone marrow (leukemia) caused by chemotherapy  
• Damage to organs which may cause infection, bleeding, may require transfusions (receiving 
blood from another person)  
• Darkening of the nail beds or skin or hands and feet  
• Loss of nails  
 
Rare but Serious (3% or less) 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Severe blood infection 
 
Reproductive Risk: 
You should not become pregnant or father a baby while on this study and for 4 months after the last 
dose of pembrolizumab and 6 months after the last dose of doxorubicin because the drugs in this 
study can affect an unborn baby. Women should not breastfeed a baby while on this study and for 4 
months after the last dose of pembrolizumab and 6 months after the last dose of doxorubicin. If you 
are of childbearing potential, you must agree to use an acceptable method of birth control during the 
study and for 4 months after the last dose of pembrolizumab and 6 months after the last dose of 
doxorubicin. Your study doctor will discuss with you which birth control methods are considered 
acceptable. 
 
Should you become pregnant or suspect you are pregnant while on this study, you should inform 
your study doctor immediately.  
 


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If you become pregnant, you will be removed from the study and may also be asked questions about 
your pregnancy and the baby. Male subjects should also inform the study doctor immediately if their 
sexual partners become pregnant while the subject is receiving study treatment. 
 
Allergic Reaction 
As with all medications, side effects may include allergic reaction. Allergic reactions may range from 
mild to severe reactions, such as itching or rash, to major life-threatening reactions which can result 
in death.  
 
Blood Drawing 
Risks associated with blood drawing may include pain, bruising, and infection. Rarely, a person 
faints. 
 
CT Scan/MRI 
A CT scan exposes you to a small dose of radiation. Although all radiation you receive builds up 
over a lifetime, this amount of radiation should not create a significant risk to your health. Contrast 
dye is usually injected when you a get a CT scan. The contrast dye may cause pain or burning when 
it is injected and may worsen kidney function in people who already have kidney disease or who are 
dehydrated (have not had enough liquids for that day). The contrast dye may also cause an allergic 
reaction, which could be severe and life threatening. 
 
There are risks from an MRI if you are pregnant or have one of the following: an artificial heart 
valve, pacemaker, metal plate, pin, or other metallic objects in your body (including gun shot or 
shrapnel). You may also become anxious from lying in a tight space without moving. The MRI scan 
does not cause any pain and does not expose you to x-ray radiation. 
 
ECG 
The risks from an ECG can include skin irritation and a rash from the gel that is used or from 
wearing or removing patches.  
 
Tumor Biopsy 
The risks of a biopsy can include bleeding, pain, and infection. To reduce these risks, the site of the 
biopsy will be numbed, and sterile techniques will be used. You will sign a separate consent for this 
procedure. 
 
Specimen Confidentiality 
There is a small risk that your protected health information may be released during the processing of 
your specimens for research. Everything possible will be done to ensure your privacy and 
confidentiality is maintained. Your specimens will be labeled with a code that does not identify you. 
Only your study doctor, clinic staff, and a small number of study staff will know your identity.  
 


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WILL I BENEFIT FROM PARTICIPATING IN THIS STUDY? 
 
This study may or may not improve your condition. The information gained from your participation 
may benefit others with your condition. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
 
You do not need to take part in this research study.  Your study doctor is willing to discuss the 
benefits and side effects of other forms of treatment other than this study that are available. These 
include: 
 
• Other usual chemotherapy for your type of cancer. 
• Other investigational research studies with chemotherapy, hormones, radiation therapy, or 
new anti-cancer agents that may be available for your disease. 
• Choosing no further treatment. If you decide that you don’t want any more active treatment, 
one of your options is called “comfort care”, also called palliative care.  This type of care 
helps reduce pain, tiredness, appetite problems and other problems caused by the cancer.  It 
does not treat the cancer directly, but instead tries to improve how you feel.  Comfort care 
tries to keep you as active and comfortable as possible. If you think you might prefer 
comfort care, please discuss this with your family, friends and your doctor. 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
 
Some of the tests or treatments used in this study may be part of your standard care used to 
maintain your health even if you did not take part in this study. You and/or your health 
plan/insurance will need to pay for some or all of the costs related to your standard treatment. The 
study drug pembrolizumab, tests, and procedures done for the sole purpose of the study [including 
the tissue biopsy and blood correlative (related) studies done for research purposes] will be 
provided at no cost to you. If you require a biopsy as part of your standard care during any of the 
time-points when a research biopsy is required, the cost of the biopsy will be billed to you or your 
insurance. After tissue has been collected from a biopsy, a portion of the tissue will be used for the 
purposes of the study. If you do not require a biopsy as part of your standard  care during the 
time-point when a research biopsy is required, you will have a biopsy for research purposes only 
and the cost of the biopsy will not be billed to you or your insurance. 
 
Doxorubicin is a standard chemotherapy drug that is commercially available and will not be covered 
by the study. 
 
You will not receive payment for taking part in this study. For more information on clinical trials 
and insurance coverage, you can visit the National Cancer Institute’s web site at 
http://cancer.gov/clinicaltrials/understanding/insurance-coverage   You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this web site.  Another way to get the 
information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.  
 


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You may wish to discuss coverage with your insurance company before agreeing to participate in 
this research study. 
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
 
If you become ill or are hurt while you are in the study, get the medical care that you need right 
away. 
 
In the event that you are harmed as a result of your participation in this study, inform your study 
doctor immediately so you can access medical treatment. You and/or your health plan will be 
charged for this treatment in the usual manner. The study will not pay for standard medical 
treatment.  
 
You still have the right to make a claim through the legal system even if you sign and date this form, 
accept medical care, or accept payment for medical expenses. 
 
WHAT IF I WANT TO QUIT THE STUDY LATER ON? 
 
Your participation in this study is completely voluntary. You should feel under no pressure to be in 
the study.  If you decide not to be in the study, that will not in any way harm your relations with 
your doctors or with Atrium Health.  You are free to stop being in the study if you change your 
mind after entering it.  This would not harm your relations with your doctors or Atrium Health. 
 
Information contributed to the study will remain in the study even if you choose to withdraw.  If 
you choose to withdraw from the study, please notify the study doctor in writing at: 
 
Michael Livingston, MD 
 
 
The study doctor may choose to involuntarily withdraw you from the study for any reason. 
 
We will tell you about new medical findings that may affect your willingness to continue in the 
study. 
 
If you stop taking part in this study, any specimens which may have already been collected and 
processed will remain de-identified and part of the study. Any specimens which may have been 
collected but have not yet been processed may be destroyed upon your written request. No 
specimens will be returned to you.  
 
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? 
 
The records of this study will be kept private.  In any sort of report we might publish, we will not 
include any information that will make it possible to identify a patient.  Your record for this study 
may, however, be reviewed and/or photocopied by Atrium Health, Merck, Inc. (funding company), 


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or by representatives of the Food and Drug Administration or other government agencies.  To that 
extent, confidentiality is not absolute. 
 
To ensure that your information collected for this study will be kept private, your name will not be 
used whenever possible.  A code will be used instead of your name.  All of your study data will be 
kept in a secure location. 
 
Your de-identified specimens for research (with only your unique ID number) will be stored in a 
biospecimen repository (a “bank” of specimens) at Atrium Health. 
 
Your specimens may be used to determine the sequence of some or all of your genes (DNA – traits 
passed in families). However, this study is not intended to identify diseases causing mutations that 
can affect the health of close family members (such as your parents, siblings, or children). All 
specimens for research collected for the purposes of this study will be considered donated materials 
and will be stored indefinitely.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
  
If you wish to take part in this clinical study, you will be asked to sign this consent form.  It allows 
the study Sponsor-Investigator (Dr. Livingston) to collect and process any relevant personal health 
information collected from you during the study.  These are activities routinely carried out during all 
clinical studies.  
 
You have been told that personal information about you (including sensitive personal health 
information, such as your medical history and your racial/ethnic origin if relevant to the study) will 
be reviewed, collected on a computer database, stored in electronic or manual files, audited, and/or 
otherwise processed by: 
 
• the clinical study sponsor-investigator, investigators and research staff,  
• regulatory or other governmental authorities of the United States and other countries, 
• other persons authorized by the study sponsor, 
• Merck, Inc. employees, 
• Atrium Health employees, 
• other persons or agencies as required by law or allowed by federal regulations. 
 
You have been told that your personal data are being collected and processed to: 
 
• check your suitability to take part in the study, 
• monitor your treatment with the study drug, 
• compare and pool study treatment results with those of other subjects in clinical studies, 


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• support the development of the study drug, 
• support the licensing application for regulatory approval of the study drug in the world  
• support the marketing, distribution, sale and use of the study drug anywhere in the world.    
 
You have been told that your personal information may be processed within the U.S. or elsewhere in 
the world or transferred to or from the U.S. for review, processing and/or storage by an associated 
company or a carefully selected third-party organization.   
 
By signing this document, you explicitly consent to the transfer of your personal information, 
including sensitive personal information, collected during this clinical study, for review, processing 
and/or storage.  Your personal health information may be further shared by the groups above.  If 
shared by them, the information will no longer be covered by the Privacy Rule.  However, the 
groups are committed to keeping your personal health confidential. 
 
You may refuse this authorization to transfer your personal information.  If you choose not to agree 
to this authorization, you might be ineligible to participate in the study.  If you decide not to sign 
this authorization, that will not harm your relations with your doctors or with Atrium Health.   
 
You have the right to inspect your medical record at any time.  Your research record may be 
unavailable until the conclusion of the study.  At that point, it will be available.  Please speak with 
the study doctor if you desire to access your record. 
 
You have been told whenever your personal information is processed, it will be kept confidential 
and secure, to the best of our ability.  It will be used only for the purpose for which it was collected. 
 
This Authorization does not have an expiration date. You have been told that according to the 
guidelines for good clinical practice, the study investigator and sponsor will keep your personal 
information for at least 6 years. If you do not withdraw this Authorization in writing, it will remain 
in effect indefinitely.  If you wish to revoke authorization to use your personal information, you will 
notify the study doctor in writing at the address and telephone number listed on the first page of this 
form. Some of the data obtained from your record prior to your revocation may still be used if 
considered necessary for the study.   
 
FINANCIAL DISCLOSURE  
 
None of the study doctors asking you to participate in this study have received or will receive money 
or other benefits for personal use from the company (Merck, Inc.) that developed the drug 
pembrolizumab used in this study. However, Merck, Inc. will give money or other benefits to a 
research fund, foundation, educational institution, or other organization with which the study doctor 
or study staff is associated. 
 


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WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study, please contact the Investigator at the telephone 
number listed on the first page of this consent document.  If you seek emergency care, or 
hospitalization is required, alert the treating physician that you are participating in this research 
study.   
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects.  If you have any questions about your rights as a research subject, and/or 
concerns or complaints regarding this research study, contact: 
 
• By mail: 
Study Subject Adviser 
 
 
• or call toll free:        
 
• or by email:              
 
 
Please reference the following number when contacting the study subject adviser: Pro00020377. 
 
OPTIONAL AND FUTURE STUDIES – BIO SPECIMEN COLLECTION 
The study doctor and his associates (the investigators) are asking you to allow your blood and tissue 
to be collected, tested, and/or banked (stored) for the purposes of research. All information for the 
main study’s informed consent form still applies to this part of the informed consent. Your study 
doctor would like to collect blood samples from you for research. Some of these blood samples are 
optional and part of this study, while some may be used for future, currently unplanned research. 
Regardless of your decision to participate in this optional blood collection, you may still participate 
in the main study, if you choose to. However, you must participate in the main study in order to be 
eligible for participation in optional blood collections. 
 
If you agree to participate in the optional and future research - blood collection, we will ask to 
collect blood prior to the start of study treatment on this study, before every other cycle of study 
treatment, at the time of disease progression or at your end of treatment study visit. If you re-start 
pembrolizumab on the Second Course Phase, the blood collection timepoints will be the same as 
during initial study treatment with pembrolizumab. 
 
If you agree to participate in the optional and future research tumor biopsy, we will ask you to have 
a tumor biopsy anytime during study treatment. This will only be done during your initial study 
treatment with pembrolizumab (not during the Second Course Phase study treatment if you receive 
it). 
 


Levine Cancer Institute / LCI-SAR-STS-PEM-001  
Page 16 of 17 
 
Michael Livingston, M.D. 
Advarra IRB Approved Version 13 Jun 2022 
 
 
 
 
 
 
 
If you agree to donate samples, they will be stored at the Atrium Health Biospecimen Repository, a 
place where human samples are securely stored and where any of your remaining samples will be 
stored. 
 
If you decide, at a later date to withdraw your consent for any reason, you have the option not to 
allow Levine Cancer Institute to use your blood samples or tissue collected for testing by contacting 
the study doctor at the telephone number or address listed on the first page of this form. Blood and 
tissue samples will be destroyed only if they have not already been tested. 
 
Participation in this collection is optional and refusing to participate will not affect your eligibility for 
the main study or the study treatment given. 
 
1. Do you give permission to have optional blood samples collected as described above to be 
stored for research? 
 
Yes____________________ No____________________ Initials____________________ 
 
2. Do you give permission to have an optional tumor biopsy collected anytime during initial 
study treatment to be stored for research? 
 
Yes____________________ No____________________ Initials____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Levine Cancer Institute / LCI-SAR-STS-PEM-001  
Page 17 of 17 
 
Michael Livingston, M.D. 
Advarra IRB Approved Version 13 Jun 2022 
 
 
 
 
 
 
 
STATEMENT OF CONSENT   
 
I have read this form and its contents were explained to me.  I agree to be in this research study for 
the purposes listed above.  All of my questions were answered to my satisfaction.  I will receive a 
signed and dated copy of this form for my records.  I am not giving up any of my legal rights by 
signing and dating this form.  
 
___________________________ 
____/____/____  _________ 
Signature of Research Subject (if subject is age 18 or older) 
Date 
Time 
 
___________________________________ 
Printed Name of Research Subject  
 
___________________________ 
____/____/____  _________ 
Signature of Parent/Legal Guardian (if subject is under age 18) 
Date 
 
Time 
 
_________________________________ 
Printed Name of Parent/Legal Guardian (if subject is under age 18) 
 
 
STATEMENT OF PERSON EXPLAINING CONSENT  
 
I have carefully explained to the subject or the subject’s parent/legal guardian the nature and 
purpose of the above study.  There has been an opportunity for the subject or the subject’s 
parent/legal guardian to ask questions about this research study.  I have been available to answer any 
questions that the subject or the subject’s parent/legal guardian has about this study. 
 
 
___________________________________ 
____/____/____  _________ 
Signature of Person Explaining Consent 
Date 
 Time 
 
___________________________________ 
Printed Name of Person Explaining Consent