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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
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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

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
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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.
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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.  
2  
|                                                     | Original Phase 2 / Version 9 / April 13, 2021 PROTOCOL SUMMARY A pilot study evaluating the safety, tolerability and efficacy of doxorubicin in                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
|-----------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| A. Study Title                                      | combination with pembrolizumab in patients with metastatic or unresectable  soft tissue sarcoma                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| B. Indication                                       | Metastatic/unresectable soft tissue sarcoma                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| C. Clinical Phase                                   | II 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 PDL1 expression in sarcoma can predict for therapeutic response to  pembrolizumab in subjects with soft tissue sarcoma.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| D. Summary of  Rationale                            | 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 progressionfree 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| E. Study  Objectives F. Sample                      | ≤ 30 subjects - Recurrent/metastatic soft tissue sarcoma not appropriate for surgical  therapy. - No prior anthracycline and/or immunotherapy. - ECOG 0 to 1 with normal organ function.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| G. Inclusion/  Exclusion                            | 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 . |
| H. Dosage/  Dosage  Form, Route,  And Dose  Regimen | Previous reports have demonstrated that the rate of any severe or lifethreatening 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-                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| I. Statistical  Analysis                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |  
3  
| 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

| 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                         |  
Version 10: 07/11/2022  
| Version 10: 07/11/2022   |                                       |
|--------------------------|---------------------------------------|
| 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                  |  
| 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

| TABLE OF CONTENTS                                                                                                                                       |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| PROTOCOL SUMMARY .                                                                                                                                      |
| SCHEMA .                                                                                                                                                |
| LIST OF ABBREVIATIONS                                                                                                                                   |
| TABLE OF CONTENTS ................................................................................................................................... 9 |
| 1. OBJECTIVES                                                                                                                                           |
| 1.1. Primary Objective .                                                                                                                                |
| 12                                                                                                                                                      |
| 12                                                                                                                                                      |
| 12                                                                                                                                                      |
| 2. BACKGROUND AND RATIONALE                                                                                                                             |
| 2.1. Study Disease                                                                                                                                      |
| 2. Experience with Pembrolizumab .                                                                                                                      |
| 2.3. Rationale for Dose Selection/Regimen/Modification                                                                                                  |
| 2.4. Rationale for Use of irRECIST Criteria                                                                                                             |
| 3. SUBJECT SELECTION                                                                                                                                    |
| 3.1. Subject Accrual                                                                                                                                    |
| 3.2. Eligibility Criteria                                                                                                                               |
| 3.3. Diet/Activity/Other Considerations ................................................................................................. 21            |
| 3.4. Use in Pregnancy                                                                                                                                   |
| 3.5. Use in Nursing Women                                                                                                                               |
| 4. INVESTIGATIONAL PLAN                                                                                                                                 |
| 4.1. Overall Study Design                                                                                                                               |
| 4.2. Informed Consent.                                                                                                                                  |
| 4.3. Registration/Enrollment/Discontinuation .                                                                                                          |
| 4. Study Procedures                                                                                                                                     |
| 5. STUDY CALENDAR                                                                                                                                       |
| 5.1. Initial Treatment Period                                                                                                                           |
| 5.2.  Second Course Phase                                                                                                                               |
| 6. TREATMENT PLAN                                                                                                                                       |  
Protocol Number:  LCI-SAR-STS-PEM-001 Version 10: 07/11/2022  
| 6.1. Drug Dosage and Administration                                                                             |                                                                    |
|-----------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| 6.2. Dose Selection                                                                                             |                                                                    |
| 6.3. Dose Modification for Doxorubicin                                                                          |                                                                    |
| 6.4. Toxicity-Related Dose Delays/Dose Modifications/Discontinuations for                                       |                                                                    |
| Pembrolizumab                                                                                                   |                                                                    |
| 6.5. Dose Modification for Pembrolizumab .                                                                      |                                                                    |
| 6.6.  Timing of Doxorubicin/Pembrolizumab Dose Administration .............................................. 45 |                                                                    |
| 6.7.  Concomitant Medications/Vaccinations (allowed and prohibited)                                             |                                                                    |
| 6.8. Rescue Medications & Supportive Care                                                                       |                                                                    |
| 6.9.  Definition of Pembrolizumab Overdose .                                                                    |                                                                    |
| 6.10. Treatment Compliance .                                                                                    |                                                                    |
| 6.11. Duration of Therapy                                                                                       |                                                                    |
| 7. SECOND COURSE PHASE .                                                                                        |                                                                    |
| 8. DATA AND SAFETY MONITORING PLAN                                                                              |                                                                    |
| 8.1. Safety Monitoring .                                                                                        |                                                                    |
| 8.2. Data Quality Assurance                                                                                     |                                                                    |
| 8.3.  Communication Between Investigational Sites                                                               |                                                                    |
| 9. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES . 54                                            |                                                                    |
| 9.1. Investigational Product .                                                                                  |                                                                    |
| 9.2. Doxorubicin .                                                                                              |                                                                    |
| 9.3.  Packaging and Labeling Information .                                                                      |                                                                    |
| 9.4.  Storage and Handling Requirements                                                                         |                                                                    |
| 9.5. Returns and Reconciliation                                                                                 |                                                                    |
| 9.6. Drug Accountability                                                                                        |                                                                    |
| 9.7. Destruction                                                                                                |                                                                    |
| 10.                                                                                                             | SAFETY DATA COLLECTION, RECORDING AND REPORTING ............... 56 |
| 10.1. Unanticipated Problem Definition                                                                          |                                                                    |
| 10.2. Adverse Event                                                                                             |                                                                    |
| 10.3. Evaluation of Adverse Events .                                                                            |                                                                    |
| 10.4. Suspected Adverse Reaction Definition .                                                                   |                                                                    |
| 10.5. "Unexpected" Definition                                                                                   |                                                                    |  
Protocol Number:  LCI-SAR-STS-PEM-001  
| Version 10: 07/11/2022                                                                                                                                                 |                                                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|
| 10.6. Serious Adverse Event Definition .                                                                                                                               |                                                                                     |
| 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                                                                                                                                      |                                                                                     |
| 10.10.                                                                                                                                                                 | Safety Reporting to the IRB.                                                        |
| 10.11.                                                                                                                                                                 | Safety Reporting to Merck.                                                          |
| 10.12.                                                                                                                                                                 | Protocol-Specific Exceptions to Serious Adverse Event Reporting ................ 64 |
| MEASUREMENT OF EFFECT                                                                                                                                                  |                                                                                     |
| 1.                                                                                                                                                                     | 1.1. Anti-tumor Effect - Solid Tumor .                                              |
| 12.                                                                                                                                                                    | STATISTICAL CONSIDERATIONS                                                          |
| 12.1. Sample Size                                                                                                                                                      |                                                                                     |
| 12.2. Endpoint Definitions .                                                                                                                                           |                                                                                     |
| 12.3. Analysis Populations .                                                                                                                                           |                                                                                     |
| 12.4. Analysis Methods ............................................................................................................................................ 71 |                                                                                     |
| 12.5. Primary Analysis .                                                                                                                                               |                                                                                     |
| 12.6. Secondary Analyses .                                                                                                                                             |                                                                                     |
| 12.7. Safety Analyses                                                                                                                                                  |                                                                                     |
| 12.8. Exploratory Analyses .                                                                                                                                           |                                                                                     |
| 12.9. Interim Analyses                                                                                                                                                 |                                                                                     |
| 13.                                                                                                                                                                    | STUDY COMPLETION                                                                    |
| 13.1. Completion .                                                                                                                                                     |                                                                                     |
| 13.2. Termination                                                                                                                                                      |                                                                                     |
| 14.                                                                                                                                                                    | RETENTION OF RECORDS                                                                |
| PUBLICATION POLICY .                                                                                                                                                   |                                                                                     |
| 15.                                                                                                                                                                    |                                                                                     |
| 16.                                                                                                                                                                    | ETHICAL AND LEGAL ISSUES .                                                          |
| 16.1. Ethical and Legal Conduct of the Study                                                                                                                           |                                                                                     |
| 16.2. Confidentiality                                                                                                                                                  |                                                                                     |
| 16.3. Compliance with Trial Registration and Results Posting Requirements ..................... 76                                                                     |                                                                                     |
| REFERENCES                                                                                                                                                             |                                                                                     |
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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.
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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.
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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.
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2. background and rationale 2.1.

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 RhoneAlps 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.
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2.2. experience with pembrolizumab 2.2.1.

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 Tcells / 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 tyrosinebased 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 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 Tcell 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 antigenpresenting 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 Tcell expansion in subjects with melanoma (MEL). This suggests that the PD1/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.
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2.2.2. preclinical and clinical trial

Refer to the Investigator's Brochure (IB) for preclinical and clinical data.
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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 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 singleagent 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
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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 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. 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.
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2.4. rationale for use of

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.
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3. subject selection 3.1. subject

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.
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3.2. eligibility criteria 3.2.1. inclusion

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
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 SponsorInvestigator.  
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.  
| 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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table 1. adequate organ function

| International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 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 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 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.
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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.  
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).  
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. FluMist®) are live attenuated vaccines, and are not allowed.  
For subjects entering the Second Course Phase, see Section 7 for entry criteria.
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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.
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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 (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. 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.
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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.
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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.
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4. investigational plan 4.1. overall

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.
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4.2. informed consent

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.
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4.3. registration/enrollment/discontinuation 4.3.1. milestone date

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.
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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.
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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- 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
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4.3.4. discontinuation of study therapy

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.
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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."
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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 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. 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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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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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.  
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 noncontrasted 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.
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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 postdoxorubicin 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 anticancer therapy (non-palliative) has been initiated, the subject will move into survival follow-up. 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 PostTreatment 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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5. study calendar 5.1. initial

| Initial Treatment Period                                   | Treatment Cyclesu                 | Post-Treatment                     |            |     |         |                                                          |                                                           |    |    |
|------------------------------------------------------------|-----------------------------------|------------------------------------|------------|-----|---------|----------------------------------------------------------|-----------------------------------------------------------|----|----|
| To be repeated  beyond 7 cycles                            | After last  dose of  doxorubicint | Post-Tx  Safety  Follow- Up Visita | Additional |     |         |                                                          |                                                           |    |    |
| Every  6                                                   | Follow-Up                         | Survival                           |            |     |         |                                                          |                                                           |    |    |
| 5                                                          | 6                                 | 7                                  | Follow-Up  |     |         |                                                          |                                                           |    |    |
| weeks                                                      | Visits                            |                                    |            |     |         |                                                          |                                                           |    |    |
| Treatment Cycle/Title: Screening  Visit                    | 1                                 | 2                                  | 3          | 4   | 30 days | 30 days (± 7 days)  post last  dose of  study  treatment | Suggested  every 9 weeks x 1  year; then  every 12  weeks |    |    |
| (±7 days)                                                  | Approximately  every 6 months  from Post-Tx  Safety Followup Visit                                   |                                    |            |     |         |                                                          |                                                           |    |    |
| after last  dose of  doxorubicin                           |                                   |                                    |            |     |         |                                                          |                                                           |    |    |
| From  C1D1  ± 7                                            |                                   |                                    |            |     |         |                                                          |                                                           |    |    |
| Scheduling Window (Days):                                  | -28 to -1                         | ± 3                                | ± 3        | ± 3 | ± 3     | ± 3                                                      | ± 3                                                       |    |    |
| 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                                 |            |     |         |                                                          |                                                           |    |    |  
| Initial Treatment Period                                                  | Treatment Cyclesu                 | Post-Treatment                     |           |     |         |                                                          |                                                           |    |
|---------------------------------------------------------------------------|-----------------------------------|------------------------------------|-----------|-----|---------|----------------------------------------------------------|-----------------------------------------------------------|----|
| To be repeated  beyond 7 cycles                                           | After last  dose of  doxorubicint | Post-Tx  Safety  Follow- Up Visita |           |     |         |                                                          |                                                           |    |
| Every                                                                     | Additional                        |                                    |           |     |         |                                                          |                                                           |    |
| 6                                                                         | Follow-Up                         | Survival                           |           |     |         |                                                          |                                                           |    |
| 5                                                                         | 6                                 | 7                                  | Follow-Up |     |         |                                                          |                                                           |    |
| Visits                                                                    |                                   |                                    |           |     |         |                                                          |                                                           |    |
| weeks                                                                     |                                   |                                    |           |     |         |                                                          |                                                           |    |
| Treatment Cycle/Title: Screening  Visit                                   | 1                                 | 2                                  | 3         | 4   | 30 days | 30 days (± 7 days)  post last  dose of  study  treatment | Suggested  every 9 weeks x 1  year; then  every 12  weeks |    |
| (±7 days)                                                                 | Approximately  every 6 months  from Post-Tx  Safety Followup Visit                                   |                                    |           |     |         |                                                          |                                                           |    |
| after last  dose of  doxorubicin                                          |                                   |                                    |           |     |         |                                                          |                                                           |    |
| From  C1D1  ± 7                                                           |                                   |                                    |           |     |         |                                                          |                                                           |    |
| Scheduling Window (Days):                                                 | -28 to -1                         | ± 3                                | ± 3       | ± 3 | ± 3     | ± 3                                                      | ± 3                                                       |    |
| 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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5. study calendar 5.1. initial

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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5.2. second course phase

| Second Course Phase                                       | Treatment Cyclesn                 | Post-Treatment   |           |     |     |            |     |    |    |
|-----------------------------------------------------------|-----------------------------------|------------------|-----------|-----|-----|------------|-----|----|----|
| To be repeated  beyond 7 cycles                           | Post-Tx  Safety  Follow- Up Visit |                  |           |     |     |            |     |    |    |
| Entry into  Second  Course                                |                                   |                  |           |     |     |            |     |    |    |
| Treatment Cycle/Title:                                    | Phase                             | 1                | 2         | 3   | 4   | Additional |     |    |    |
| Every                                                     | Follow-Up                         | Survival         |           |     |     |            |     |    |    |
| 6-9                                                       |                                   |                  |           |     |     |            |     |    |    |
| 5                                                         | 6                                 | 7                | Follow-Up |     |     |            |     |    |    |
| weeks                                                     | Visits                            |                  |           |     |     |            |     |    |    |
| 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 Followup Visit                                   |                  |           |     |     |            |     |    |    |
| From  C1D1  ± 7                                           |                                   |                  |           |     |     |            |     |    |    |
| Scheduling Window (Days):                                 | -28 to -1                         | ± 3              | ± 3       | ± 3 | ± 3 | ± 3        | ± 3 |    |    |
| 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                                |                  |           |     |     |            |     |    |    |  
| Second Course Phase                   | Treatment Cyclesn                                                                                                                                                       | Post-Treatment   |           |     |     |       |            |
|---------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|-----------|-----|-----|-------|------------|
| To be repeated  beyond 7 cycles       | Post-Tx  Safety  Follow- Up Visit                                                                                                                                       |                  |           |     |     |       |            |
| Entry into  Second  Course            |                                                                                                                                                                         |                  |           |     |     |       |            |
| Treatment Cycle/Title:                | Phase                                                                                                                                                                   | 1                | 2         | 3   | 4   | Every | Additional |
| 6-9                                   | Follow-Up                                                                                                                                                               | Survival         |           |     |     |       |            |
| 5                                     | 6                                                                                                                                                                       | 7                | Follow-Up |     |     |       |            |
| Visits                                |                                                                                                                                                                         |                  |           |     |     |       |            |
| weeks                                 | 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 Followup Visit                  |           |     |     |       |            |
| From  C1D1  ± 7                       |                                                                                                                                                                         |                  |           |     |     |       |            |
| Scheduling Window (Days):             | -28 to -1                                                                                                                                                               | ± 3              | ± 3       | ± 3 | ± 3 | ± 3   | ± 3        |
| 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 |                  |           |     |     |       |            |  
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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5.2. second course phase

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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6. treatment plan 6.1. drug

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.  
| Drug           | Dose/                                                                                              | Dose           | Route of     | Regimen/Treatment            |
|----------------|----------------------------------------------------------------------------------------------------|----------------|--------------|------------------------------|
| Potency        | Frequency                                                                                          | Administration | 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 |
| a              | Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. |                |              |                              |
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table 3. drug dose and

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.
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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.
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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.
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6.4. toxicity-related dose delays/dose modifications/discontinuations

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 SponsorInvestigator. 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 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.
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6.5. dose modification and toxicity

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.  
| Version 9: 04/13/2021                                                                                                                                                                                                    |                                                             |                                                                                                    |                              |                            |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|----------------------------------------------------------------------------------------------------|------------------------------|----------------------------|
| Toxicity  Grade                                                                                                                                                                                                          | Action With                                                 | Corticosteroid and/or Other                                                                        | Monitoring and Followup                              |                            |
| (CTCAE v4.0)                                                                                                                                                                                                             | Pembrolizumab                                               | Therapies                                                                                          |                              |                            |
| irAEs                                                                                                                                                                                                                    | Grade 2                                                     | Withhold                                                                                           | - Administer corticosteroids | - Monitor participants for |
| (initial dose of 1 to 2 mg/kg                                                                                                                                                                                            | signs and symptoms of                                       |                                                                                                    |                              |                            |
| Recurrent  Grade 2,  Grade 3 or 4                                                                                                                                                                                        | Permanently  discontinue                                    | prednisone or equivalent)                                                                          | pneumonitis                  |                            |
| followed by taper                                                                                                                                                                                                        | - Evaluate participants with                                |                                                                                                    |                              |                            |
| - Add prophylactic antibiotics                                                                                                                                                                                           | suspected pneumonitis                                       |                                                                                                    |                              |                            |
| Pneumonitis                                                                                                                                                                                                              | for opportunistic infections                                | with radiographic imaging  and initiate corticosteroid  treatment                                  |                              |                            |
| Grade 2 or 3                                                                                                                                                                                                             | Withhold                                                    | - Administer corticosteroids                                                                       | - Monitor participants for   |                            |
| (initial dose of 1 to 2 mg/kg                                                                                                                                                                                            | signs and symptoms of                                       |                                                                                                    |                              |                            |
| prednisone or equivalent)                                                                                                                                                                                                | enterocolitis (ie, diarrhea,                                |                                                                                                    |                              |                            |
| followed by taper                                                                                                                                                                                                        | abdominal pain, blood or                                    |                                                                                                    |                              |                            |
| Recurrent  Grade 3 or  Grade 4                                                                                                                                                                                           | Permanently  discontinue                                    | 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                                                                                                                                            |                                                             |                                                                                                    |                              |                            |
| Diarrhea/Colitis                                                                                                                                                                                                         | 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 |                                                             |                                                                                                    |                              |                            |
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6.5. dose modification and toxicity

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|-----------------------------------------------------------------------------------------------|---------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------|-------------------------------|
| Grade 2 a                                                                                     | Withhold                                                            | - Administer corticosteroids                                                                              | - Monitor with liver function |
| (initial dose of 0.5 to 1 mg/kg                                                               | tests (consider weekly or                                           |                                                                                                           |                               |
| prednisone or equivalent)                                                                     | more frequently until liver                                         |                                                                                                           |                               |
| followed by taper                                                                             | enzyme value returned to                                            |                                                                                                           |                               |
| AST or ALT Elevation or  Increased Bilirubin                                                  | 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 |                               |
| New onset  T1DM or  Grade 3 or 4  hyperglycemia  associated with  evidence of  β-cell failure | Withhold d                                                          | - Initiate insulin replacement                                                                            | - Monitor participants for    |
| therapy for participants with                                                                 | hyperglycemia or other                                              |                                                                                                           |                               |
| T1DM                                                                                          | signs and symptoms of  diabetes                                     |                                                                                                           |                               |
| T1DM or Hyperglycemia                                                                         | - Administer antihyperglycemic  in participants with  hyperglycemia |                                                                                                           |                               |
| Grade 2                                                                                       | Withhold                                                            | - Administer corticosteroids and                                                                          | - Monitor for signs and       |
| initiate hormonal                                                                             | symptoms of hypophysitis                                            |                                                                                                           |                               |
| Endocrine disorders- other (hypophysitis)                                                     | Grade 3 or 4                                                        | Withhold or  permanently  discontinue d                                                                   | and adrenal insufficiency)    |
| replacements as clinically                                                                    | (including hypopituitarism                                          |                                                                                                           |                               |
| indicated                                                                                     |                                                                     |                                                                                                           |                               |
| Grade 2                                                                                       | Continue                                                            | - Treat with nonselective beta                                                                                                           | - Monitor for signs and       |
| blockers (eg, propranolol) or                                                                 | symptoms of thyroid                                                 |                                                                                                           |                               |
| Hyperthyroidism                                                                               | Grade 3 or 4                                                        | Withhold or                                                                                               | disorders                     |
| permanently  discontinue d                                                                    | thionamides as appropriate                                          |                                                                                                           |                               |
| Grade 2, 3 or 4                                                                               | Continue                                                            | - Initiate thyroid replacement                                                                            | - Monitor for signs and       |
| hormones (eg, levothyroxine                                                                   | symptoms of thyroid                                                 |                                                                                                           |                               |
| Hypothyroidism                                                                                | or liothyronine) per standard                                       | disorders                                                                                                 |                               |
| of care                                                                                       |                                                                     |                                                                                                           |                               |
| Grade 2                                                                                       | Withhold                                                            | - Administer corticosteroids                                                                              | - Monitor changes of renal    |
| Nephritis: grading according to  increased creatinine or  acute kidney injury                 | Grade 3 or 4                                                        | function                                                                                                  |                               |
| Permanently  discontinue                                                                      | (prednisone 1 to 2 mg/kg or  equivalent) followed by taper          |                                                                                                           |                               |
| Neurological Toxicities                                                                       | Grade 2                                                             | Withhold                                                                                                  |                               |  
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|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------|------------------------------|----------------------------------------------------------|------------------------------|
| Grade 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Permanently  discontinue       | - Based on severity of AE    | - Ensure adequate evaluation  to confirm etiology and/or |                              |
| administer corticosteroids                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | exclude other causes           |                              |                                                          |                              |
| Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Withhold                       | - Based on severity of AE    | - Ensure adequate evaluation                             |                              |
| administer corticosteroids                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | to confirm etiology and/or     |                              |                                                          |                              |
| Grade 2, 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Permanently                    | exclude other causes         |                                                          |                              |
| discontinue                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                |                              |                                                          |                              |
| Myocarditis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Suspected SJS,  TEN, or  DRESS | Withhold                     | - Based on severity of AE                                | - Ensure adequate evaluation |
| administer corticosteroids                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | to confirm etiology or         |                              |                                                          |                              |
| Exfoliative Dermatologic  Conditions                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Confirmed SJS,                 | exclude other causes         |                                                          |                              |
| TEN, or  DRESS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Permanently  discontinue       |                              |                                                          |                              |
| PersistentGrade 2 Withhold                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | - Based on severity of AE      | - Ensure adequate evaluation |                                                          |                              |
| administer corticosteroids                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | to confirm etiology or         |                              |                                                          |                              |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Withhold or  discontinue based | exclude other causes         |                                                          |                              |
| on the event e                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                |                              |                                                          |                              |
| All Other irAEs                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | 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 Sponsor-Investigator. The reason for interruption should be documented in the subject's study record.
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6.6. timing of doxorubicin/pembrolizumab dose

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 1217 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

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 SponsorInvestigator should discuss any questions regarding this with the Merck Clinical team. The final decision on any supportive therapy or vaccination rests with the SponsorInvestigator and/or the subject's primary physician.
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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.  
- Subjects taking narrow therapeutic index medications should be monitored proactively (e.g. warfarin, phenytoin, quinidine, carbamazepine, Phenobarbital, cyclosporine, and digoxin).
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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/reinitiation 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 premedication for doxorubicin as specified in Table 3. The use of physiologic doses of corticosteroids may be approved after consultation with the SponsorInvestigator.  
- 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

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 antiinflammatory 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.
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- 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.
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- 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.  
- **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.
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- 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.
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- 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.  
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).  
| 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                                                                                                                                                                                                                                                                         | 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                                                                                                                                                                                                                               |
| 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) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                    |  
Table 5. Infusion Reaction Treatment Guidelines  
| 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. |                                       |
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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.
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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.
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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 (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.
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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:
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either

- Stopped initial treatment with pembrolizumab after attaining an investigatordetermined 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