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or

- Had SD, PR or CR and stopped pembrolizumab treatment after 24 months/35 cycles (see Section 6.11) of study therapy for reasons other than disease progression or intolerability
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and

- Experienced an investigator-determined radiographic disease progression after stopping their initial treatment with pembrolizumab
- Did not receive any anti-cancer treatment since the last dose of pembrolizumab - Completed all required study procedures for Entry into Second Course Phase as detailed in the Study Calendar in Section 5.2
- Has a performance status of 0 or 1 on the ECOG Performance Scale - Demonstrates adequate organ function as detailed in Section 3.2.1 - Female subject of childbearing potential should have a negative serum or urine pregnancy test within 72 hours prior to receiving retreatment with pembrolizumab.  
- Female subject of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of pembrolizumab
(Reference Section 3.3.2). Subjects of child bearing potential are those who have not been surgically sterilized or have been free from menses for > 1 year.  
- Male subject should agree to use an adequate method of contraception starting with the first dose of pembrolizumab through 120 days after the last dose of pembrolizumab.  
- Does not have a history or current evidence of any condition, therapy, or laboratory abnormality that might interfere with the subject's participation for the full duration of the trial or is not in the best interest of the subject to participate, in the opinion of the treating investigator.  
Subjects who restart treatment will be retreated at the same dose and dose interval as when they last received pembrolizumab. Treatment may be administered for up to one additional year.
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8. data and safety monitoring

This protocol will be monitored according to the processes in effect for all Levine Cancer Institute investigator-initiated studies and the protocol-specific monitoring plan, and will abide by standard operating procedures set forth by both the Carolinas HealthCare System Office of Clinical and Translational Research and the Levine Cancer Institute Clinical Trials Office. It is the responsibility of the SponsorInvestigator to monitor the safety data for this study. The Sponsor-Investigator, Statistician, and other team members as needed will meet regularly to monitor subject consents, enrollment and retention, safety data for all subjects [including adverse events (AEs) for all grades and attributions, serious adverse events (SAEs)], study drug administration, and validity/integrity of the data. Documentation of these meetings will be kept with study records. SAEs will be reported to the Food and Drug Administration (FDA) and the IRB per their requirements. Major protocol deviations that result in a threat to subject safety or the integrity of the study will be reported to the IRB per their requirements. The Sponsor-Investigator will submit data to the LCI Data and Safety Monitoring Committee according to the protocol-specific Data and Safety Monitoring Plan. The Sponsor-Investigator will monitor the study accrual data regularly.
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8.2. data quality assurance

This study will be organized, performed, and reported in compliance with the study protocol, standard operating procedures (SOPs) of the Levine Cancer Institute and Atrium Health (AH) Office of Clinical and Translational Research, the FDA, and other applicable regulations and guidelines (e.g. GCP).  
Subjects will be monitored by LCI Research /Data Monitors per the study-specific monitoring plan and LCI/AH SOPs for data quality. This monitoring will be done by comparing source documentation to the eCRFs. Any variation between the two data sets will be discussed with the Treating Investigator, Sponsor- Investigator and/or other study team members as appropriate.  
The study database will be reviewed and checked for omissions, apparent errors, and values requiring further clarification using computerized and manual procedures. Data queries requiring clarification will be generated and addressed by the appropriate study team member. Only authorized personnel will make corrections to the study database and all corrections will be documented in an electronic audit trail.
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8.3. communication between investigational sites

Investigational sites will be required to report AEs for all grades and attributions, SAEs, problems with study treatment administration, deviations, or any other problem that could affect the validity/integrity of the study data to the Sponsor-Investigator. All investigational sites will report AEs, ECIs and SAEs using the eCRFs and SAE reporting form. AEs will be reported within 5 business days of the investigator learning of the event. SAEs and ECIs will be reported within 1 business day of the investigator learning of the event. Problems with study treatment administration or any other problem affecting safety or data integrity should be communicated to the Sponsor-Investigator or designee per standard procedures by email or phone as soon as possible but within 2 business days of the Investigator learning of the event.
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9. labeling packaging storage and

The Sponsor-Investigator shall be accountable for maintaining appropriate records and ensuring appropriate supply, storage, handling, distribution and usage of investigational product in accordance with the protocol and any applicable laws and regulations. Clinical supplies will be provided by Merck as summarized in Table 6. Table 6. Product Descriptions  
| Product Name & Potency    | Dosage Form            |
|---------------------------|------------------------|
| Pembrolizumab 100 mg/ 4mL | Solution for Injection |  
9.2. **Doxorubicin**
Doxorubicin is commercially provided.
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9.3. packaging and labeling information

Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
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9.4. storage and handling requirements

Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol.
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9.5. returns and reconciliation

The Sponsor-Investigator is accountable for keeping accurate records of the clinical supplies received from Merck or designee and the amount dispensed to the subjects.  
Upon completion or termination of the study, all unused investigational product will be destroyed at the site per institutional policy. It is the Sponsor-Investigator's or designee's responsibility to ensure arrangements are made for disposal of all empty or partially used containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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9.6. drug accountability

All study drug will be stored at the investigational site in accordance with Good Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements and will be inaccessible to unauthorized personnel. An adequate record of receipt, distribution, and destruction of pembrolizumab will be kept in the form of a Drug Accountability Form and maintained by the LCI IDS (Investigational Drug Services) Pharmacy. The Investigator, or responsible party designated by the Investigator, will maintain a careful record of the inventory using the Drug Accountability Form. Doxorubicin will be administered commercially.  
9.7. **Destruction**
At the end of the study, unused supplies of pembrolizumab will be destroyed according to LCI IDS pharmacy policies.
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10. safety data collection recording

Safety assessments will consist of monitoring and recording all adverse events and serious adverse events, regular monitoring of hematology, blood chemistry and liver function test values, regular measurement of vital signs, and performance of history and physical examinations. These assessments should be performed per the study calendar. Adverse events will be evaluated continuously throughout the study. Safety and tolerability, relationship to treatment and intensity will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All adverse events (Grades 1 - 5) will be documented in subject study charts, and recorded in the eCRF.
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10.1. unanticipated problem definition

An UAP is any incidence, experience or outcome that is unexpected, given the information provided in research-related documentation (e.g., Investigator's brochure, informed consent) and the study population characteristics that is related or possibly related to participation in the research study and places the participant at an increased risk.
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10.2. adverse event 10.2.1. adverse

An adverse event is defined as any untoward medical occurrence in a study subject who is administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition is also an adverse event. Changes resulting from normal growth and development that do not vary significantly in frequency or severity from expected levels are not to be considered adverse events. Examples of this may include, but are not limited to, typical crying in children and onset of menses or menopause occurring at a physiologically appropriate time in minor subjects.  
Progression of the cancer under study is not considered an adverse event.
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10.3. evaluation of adverse events

A qualified investigator will evaluate all adverse events according to the NCI Common Terminology for Adverse Events (CTCAE), version 4.0.  
Reporting period: AEs will be captured from the time of treatment initiation/reinitiation through 30 days following cessation of study treatment.  
Exception:
- Adverse events that meet the definition of an Event of Clinical Interest (ECI)
as defined in Section 10.11 will be reportable from informed consent if the ECI causes the subject to be excluded from the trial, or is the result of a protocol-specified intervention including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
Please refer to Section 10.11 for the definition and expedited reporting requirements for ECI's.  
Adverse events will be evaluated for relatedness to both doxorubicin and pembrolizumab. All adverse events regardless of CTCAE grade must also be evaluated for seriousness. Adverse events will be evaluated according to Table 7.  
57  
| V4.0 CTCAE   | Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.   |
|--------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|
| Grading      | Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.  |
| Grade 3      | Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated;  disabling; limiting self-care ADL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                             |
| Grade 4      | Life threatening consequences; urgent intervention indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                             |
| Grade 5      | Death related to AE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                             |
| Seriousness  | A serious adverse event is any adverse event occurring at any dose or during any use of study treatment that: †Results in death; or †Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an  adverse event that, had it occurred in a more severe form, might have caused death.); or †Results in a persistent or significant disability/incapacity (substantial disruption of one's ability to conduct normal life functions); or †Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the  hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not  worsened is not a serious adverse event. A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in  the patient's medical history.); or †Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor-Investigator within 24 hours and to Merck  within 2 working days to meet certain local requirements); or Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose of pembrolizumab is considered a serious adverse event for  collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24  hours to the Sponsor-Investigator and to Merck within 2 working days. Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when,  based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes  listed previously (designated above by a †). |                                                                                                             |  
Table 7. Adverse Event Evaluation  
| Duration                          | Record the start and stop dates of the adverse event.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|-----------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Action taken                      | Did the adverse event cause pembrolizumab and/or doxorubicin to be discontinued?                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| Relationship to  study  treatment | Did pembrolizumab and/or doxorubicin cause the adverse event? The determination of the likelihood that pembrolizumab and/or doxorubicin caused the adverse  event will be provided by an investigator who is a qualified physician. The investigator's signed/dated initials on the source document or worksheet that supports the  causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required  regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between  pembrolizumab and/or doxorubicin and the adverse event based upon the available information. The following components are to be used to assess the relationship between pembrolizumab and/or doxorubicin and the AE; the greater the correlation with the  components and their respective elements (in number and/or intensity), the more likely pembrolizumab and/or doxorubicin caused the adverse event (AE): Exposure Is there evidence that the subject was actually exposed to pembrolizumab and/or doxorubicin such as: reliable history, acceptable compliance  assessment (expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? Time Course Did the AE follow in a reasonable temporal sequence from administration of pembrolizumab and/or doxorubicin?  Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors |
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10.3.1. relationship to study drug

The relationship to study drug therapy should be assessed using the following definitions: Not Related: Evidence exists that the AE has an etiology other than the study drug (i.e., pre-existing condition, underlying disease, intercurrent illness, or concomitant medication). This includes events that are considered remotely or unlikely related to study drug. Related: A temporal relationship exists between the event onset and administration of the study drug. It cannot be readily explained by the subject's clinical state, intercurrent illness, or concomitant therapies. In the case of cessation or reduction of the dose, the event abates or resolves and reappears upon rechallenge. It should be emphasized that ineffective study drug treatment should not be considered as causally related in the context of AE reporting. This includes events that are considered possibly, probably, or definitely related to study drug. All adverse events (including event name, grade, start/stop date and attribution) will be documented in the medical record and/or research chart and recorded on the case report form for this protocol. The Investigator is responsible for verifying and providing source documentation for all adverse events and assigning the attribution for each event for all subjects enrolled on the trial.
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10.4. suspected adverse reaction definition

A SAR is an adverse event in which there is reasonable possibility that the study drug caused the adverse event as defined by 21 CFR 312.32. The Investigator is responsible for judging whether it is a reasonable possibility that the study drug caused the adverse event.
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10.5. "unexpected" definition

An AE or SAR is to be considered unexpected if the event is not listed in the current Investigator Brochure, package insert or label or is not listed in the severity or specificity observed.
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10.6. serious adverse event definition

An AE or SAR is to be considered serious if the Investigator deems it as such and the event results in any of the following outcomes:
- Death; - Life-threatening situation (patient is at immediate risk of death);
- Inpatient hospitalization or prolongation of an existing hospitalization
(excluding those for study drug administration, protocol-related procedures,
palliative or hospice care, or placement of an indwelling catheter, unless associated with other serious events);
- Persistent or significant disability/incapacity;
- Congenital anomaly/birth defect in the offspring of a subject who received study treatment;
- Development of a new cancer (that is not a condition of the study)
- Overdose of pembrolizumab as defined in Section 6.9, that is associated with an adverse event even if no other seriousness criteria are met;
- Other: Important medical events that may not result in death, be immediately life-threatening, or require hospitalization, may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the subject or may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
o **Examples of such events are:**
Intensive treatment in an emergency room or at home for allergic bronchospasm; Blood dyscrasias or convulsions that do not result in hospitalization; Development of drug dependency or drug abuse.  
An AE or SAR is to be considered life-threatening if the Investigator deems it as such and the event poses an immediate threat of death.
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pregnancy and lactation

Although pregnancy and lactation are not considered adverse events, pregnancies and lactations must be reported from informed consent through 120 days after last dose of pembrolizumab, or 30 days if the subject initiates new anti-cancer therapy, whichever is earliest. All reported pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as SAEs. If the pregnancy continues to term, the outcome (health of infant) must also be reported.
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10.7. events of clinical interest

Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI). ECIs for this trial include:
- An overdose of pembrolizumab, as defined in Section 6.9, that is not associated with clinical symptoms or abnormal laboratory results.  
- An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology
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10.8. expedited safety reporting to

SAEs, ECIs, pregnancies and lactation exposure must be reported to the SponsorInvestigator within 1 business day of awareness.  
Reporting Period: SAEs and ECIs will be captured from the time of study treatment initiation/re-initiation through 90 days after the date of the last study treatment administration or 30 days if new anti-cancer therapy is initiated. Exceptions:
- Reportable from informed consent:
o Events that meet the definition of a SAE that are determined to be related and unexpected to a research procedure o Pregnancy and lactation; reportable through 120 days after last dose of pembrolizumab or 30 days if the subject initiates new anti-cancer therapy, whichever is earliest.  
o Events that meet the definition of an ECI (as defined per Section 10.7)
if it causes the subject to be excluded from the trial, or is the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure (reportable until study treatment initiation).  
- Reportable from study treatment initiation through duration of the subject's participation on the trial (treatment and follow-up):
o Events occurring after the 30-day reporting period that are determined to be related to study treatment or a research procedure SAEs will be followed until clinical recovery is complete and laboratory tests have returned to baseline, until progression has been stabilized, or until there has been acceptable resolution of the event. This may at times cause the follow-up period for SAEs to be greater than 90 days. Similarly, the Sponsor-Investigator is responsible for following the subject during the required follow-up period even if the subject lives elsewhere or has been released from his or her care and is being treated under another service at LCI. Please refer to Section 10.11 for the definition and expedited reporting requirements for ECI's.
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10.9. safety reporting to the

For investigator-initiated studies where the Sponsor-Investigator holds an IND, safety reporting requirements for the FDA apply in accordance with the regulations set forth in 21 CFR 312.32. The Sponsor-Investigator, or designee, will be responsible for notifying FDA (using a MedWatch form) and all participating Investigators of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar days after the Sponsor's initial receipt of the information. For all other serious and unexpected safety events, the SponsorInvestigator, or designee, will notify the FDA within 15 calendar days.  
It is the responsibility of the Sponsor-Investigator, Investigators and the Protocol Team to ensure SAEs are reported according to the Federal Regulations, ICH E6 Good Clinical Practices, the protocol guidelines, and Institutional Review Board reporting requirements. Planned protocol deviations will be submitted to the FDA for prior approval only if the deviation affects the scientific validity of the study and/or the rights, safety, or welfare of subjects.
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10.10. safety reporting to the

All events occurring during the conduct of a protocol and meeting the definition of a UAP or SAE will be reported to the IRB per their reporting requirements.  
Protocol deviations that, in the Investigator's judgment, potentially caused harm to participants or others or indicates that the participants or others are at an increased risk of harm, or has adversely impacted data integrity will be reported promptly to the IRB per their reporting requirements.
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10.11. safety reporting to merck

Any serious adverse event or ECI, or follow up to a serious adverse event or ECI, including death due to any cause other than progression of the cancer under study that occurs to any subject from the time of study treatment initiation/re-initiation through 90 days following cessation of study treatment, or 30 days if new anti-cancer therapy is initiated, whichever is earlier, whether or not related to pembrolizumab, will be reported within 2 working days of Sponsor-Investigator awareness to Merck Global Safety by the Sponsor-Investigator. SAEs that cause the subject to be excluded from the trial, or is a result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure are reportable to Merck from the time period beginning with informed consent until study treatment initiation/re-initiation. Pregnancies and lactations must be reported from informed consent through 120 days after last dose of pembrolizumab, or 30 days if the subject initiates new anti-cancer therapy, whichever is earliest. Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be related to pembrolizumab that is brought to the attention of the investigator at any time outside of the time period specified in the previous paragraph also must be reported immediately to the Sponsor-Investigator and to Merck. SAE/ECI and pregnancy/lactation reports and any other relevant safety information are to be forwarded to Merck by the Sponsor-Investigator to Global Safety facsimile number: +1-215-993-1220 If the Sponsor-Investigator holds an IND, a copy of all 15 Day Reports and Annual Progress Reports are to be submitted as required by the FDA or other local regulators. Investigators will cross reference this submission according to local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to the appropriate regulatory agency.
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10.12.protocol-specific exceptions to serious adverse

Efficacy endpoints as outlined in this section will not be reported to Merck unless there is evidence suggesting a causal relationship between pembrolizumab and the event. Any such event will be submitted to the Sponsor-Investigator within 24 hours and to Merck Global Safety within 2 working days either by electronic or paper media. Specifically, the suspected/actual events covered in this exception include any event that is disease progression of the cancer under study. The Sponsor-Investigator will monitor unblinded aggregated efficacy endpoint events and safety data to ensure the safety of the subjects in the trial. Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a SAE.
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11. measurement of effect 11.1.

Response and progression will be evaluated in this study using the Revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1. Clinically stable patients may continue to be treated beyond radiologic progression per the Investigator's discretion, however, at the time of RECIST-defined progression, progressive disease will be documented in the study records.
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11.1.1. methods for evaluation of

All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. Baseline evaluations prior to Second Course Phase will be performed per the investigator's discretion. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during followup. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the anti-tumor effect of a treatment. The Sponsor-Investigator or designee will be responsible for performing tumor measurements. The tumor measurements will be recorded on the eCRF.
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complete response

- Target lesion: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.  
- Non-target lesion: Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (<10 mm short axis).
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partial response

- Target lesion: At least a 30% decrease in the sum of diameters of target, taking as reference the baseline sum diameters.  
- Non-target lesion: Not applicable
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stable disease

- Target lesion: Neither sufficient shrinkage to qualify for a partial response, nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.  
- Non-target lesion: Not applicable.
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progressive disease

- Target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the *smallest sum on study* (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (*Note:* the appearance of one or more new lesions is also considered progression).  
- Non-target lesion: *Unequivocal progression* (as described in RECIST
version 1.1) of existing non-target lesions. (*Note:* the appearance of one or more new lesions is also considered progression).
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non-complete response / non-progressive disease

- Target lesion: Not applicable - Non-target lesion: Persistence of one or more non-target lesion(s)  
| Table 8. Summary of RECIST 1.1 (Subjects with measurable disease) Target  Non-target Lesions New Lesions Overall  Best Response for this Lesions Response Category also requires CR CR No CR Documented at least once  ≥ 4 weeks from baseline CR Non-CR/Non-PD No PR CR Not evaluated No PR Documented at least once  ≥ 4 weeks from baseline PR Non-PD or not all  evaluated No PR SD Non-PD or not all  Documented at least once  evaluated No SD ≥ 4 weeks from baseline Not all  evaluated Non-PD No NE N/A PD Any Yes or No PD Any PD* Yes or No PD No prior SD, PR or CR Any Any Yes PD * In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, and  NE = inevaluable.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Table 9. Summary of RECIST 1.1 (Subjects with non-measurable disease only)  
| Non-target Lesions   | New Lesions   | Overall Response   |
|----------------------|---------------|--------------------|
| CR                   | No            | CR                 |
| Non-CR/Non-PD        | No            | Non-CR/ Non-PD     |
| Not all evaluated    | No            | NE                 |
| Unequivocal PD       | Yes or No     | PD                 |
| Any                  | Yes           | PD                 |  
RECIST 1.1 will be adapted as follows to account for the unique tumor response seen in this class of therapeutics, **irRECIST**.  
If imaging shows PD, tumor assessment should be repeated ≥ 4 weeks later in order to confirm PD with the option of continuing treatment for clinically stable subjects as discussed below in Table 10.  
Clinically stable is defined by the following criteria:
- Absence of signs and symptoms indicating disease progression
- No decline in ECOG performance status - Absence of rapid progression of disease
- Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent alternative medical intervention
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table 10. irrecist imaging and

| Clinically Stable    | Clinically Unstable          |                                                                                                                                                                                                                                                                      |                                     |     |
|----------------------|------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|-----|
| Imaging              | Treatment                    | Imaging                                                                                                                                                                                                                                                              | Treatment                           |     |
| 1st radiologic       | Repeat imaging at > 4        |                                                                                                                                                                                                                                                                      |                                     |     |
| evidence of PD       | weeks at site to  confirm PD | May continue study  treatment at the  Investigator's  discretion while  awaiting confirmatory  scan by site                                                                                                                                                          | Discontinue treatment               |     |
| N/A                  |                              |                                                                                                                                                                                                                                                                      |                                     |     |
| Repeat scan confirms | No additional imaging        | Discontinue                                                                                                                                                                                                                                                          |                                     |     |
| PD                   | required                     | treatment. In the event  of confirmed  progression, if the  subject is clinically  stable and in the  investigator's opinion  would derive clinical  benefit from  remaining on  pembrolizumab, the  subject may continue  treatment beyond  confirmed  progression. | N/A No additional imaging  required | N/A |  
Repeat scan shows SD, PR or CR  
Continue regularly scheduled imaging assessments  
| Continue regularly  scheduled imaging  assessments   | Continue study  treatment at the  Investigator's  discretion   | N/A   | N/A   |
|------------------------------------------------------|----------------------------------------------------------------|-------|-------|  
In determining whether or not the tumor burden has increased, decreased or stayed stable, site investigators should consider all target lesions as well as non-target lesions. Any subject deemed clinically unstable should be discontinued from study regimen at first evidence of progressive disease by tumor imaging and is not required to have repeat tumor imaging for confirmation.  
For a clinically stable subject with first radiologic evidence of progressive disease (i.e., unconfirmed progression of disease), it is at the discretion of the site investigator to continue treating the subject with the assigned treatment per protocol until progression of disease is confirmed at least 28 days from the date of the tumor imaging first suggesting PD. If progression is not confirmed on the subsequent tumor imaging, the subject should continue to receive study therapy and have tumor imaging performed every 6 weeks (± 7 days) to monitor disease status. If radiologic progression is confirmed by subsequent tumor imaging, then the subject will be discontinued from study treatment. NOTE: If a subject with confirmed progression by tumor imaging (i.e. 2 scans at least 28 days apart demonstrating progressive disease) is clinically stable or clinically improved, and there is no further increase in the tumor burden at the confirmatory scan, an exception may be considered to continue treatment upon consultation with the Sponsor-Investigator. Subjects exhibiting unacceptable toxicity from trial therapy may NOT continue to receive trial therapy.  
NOTE: In subjects who discontinue study therapy without first documented disease progression, every effort should be made to continue monitoring disease status by tumor imaging with a suggested interval of every 9 weeks in the first year and every 12 weeks (after year 1 per investigator discretion until (1) the start of new anti-cancer treatment, (2) documented disease progression (3) death, or (4) the end of the study, whichever occurs first. The same imaging modality (i.e. CT or MRI), acquisition and technical parameters should be used throughout the study for a given subject.
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12. statistical considerations 12.1. sample

This study is primarily designed to assess the safety of doxorubicin (60-75 mg/m2)
and pembrolizumab (200 mg) in previously treated or untreated subjects with unresectable or metastatic soft tissue sarcoma. Based on the Bayesian stopping rules described in Section 12.5, 30 subjects will enable an assessment regarding whether or not the severe or life-threatening treatment emergent adverse event rate convincingly exceeds 0.55.  
48
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12.2. endpoint definitions 12.2.1. severe

Severe or life threatening adverse event will be determined for each subject indicating whether or not the event meets all criteria listed below:
- Meets the definition of seriousness as defined in Section 10.6, and - Pembrolizumab-related or doxorubicin-related toxicity per the Sponsor-Investigator and
- Considered to be clinically significant by the Sponsor-Investigator as to contribute to the stopping rule.
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12.2.2. progression-free survival

Progression-free survival (PFS) is defined as the duration of time from the start of protocol treatment to first occurrence of either progressive disease or death. Disease progression can be objectively determined as per Section 11 or progression can be subjective as determined by the investigator. Evidence for subjective progression must be documented in the medical records. For objective disease progression, the date of PD is the date of the radiologic assessment that identified RECIST-defined progressive disease. For subjective disease progression, the date of PD is the date that the clinician makes the determination of disease progression. If the subject died without documented disease progression, the date of progression will be the date of death. For surviving subjects who do not have documented disease progression, PFS will be censored at the date of last radiologic assessment. For subjects who receive subsequent anti-cancer therapy prior to documented disease progression, PFS will be censored at the date of last radiologic assessment prior to the commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at the date of the last assessment prior to those missed assessments. For participants with only one missed assessment, the documented progressive disease status and assessment date will be used. PFS will be determined for each subject using both the RECIST 1.1 and irRECIST criteria.
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12.2.3. overall survival

Overall survival (OS) is defined as the duration of time from the start of protocol treatment to death from any cause. Subjects who are alive or lost to follow-up at the time of the analysis will be censored at the last known date they were alive.
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12.2.4. objective response

Objective response will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of CR or PR. Objective response will be determined for each subject with measurable disease at baseline using both the RECIST 1.1 and irRECIST criteria.
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12.2.5. duration of response

Duration of response will be determined for each subject achieving an objective response. Duration of response will be defined from time that response was initially documented until progression or death. The censoring mechanism for duration of response will be the same as that described for PFS. Duration of response will be determined for each subject using both the RECIST 1.1 and irRECIST criteria.
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12.2.6. safety endpoints

Safety endpoints will include treatment administration (total number of doses taken, and total doses taken as a percent of total number of intended doses), AEs, SAEs, and deaths while on study therapy.
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12.2.7. second course objective response

Second Course Objective response will be determined for those subjects who initiate second course treatment of pembrolizumab as a binary variable indicating whether or not the subject achieved a best overall response of CR or PR after starting second course treatment with pembrolizumab. Second Course Objective response will be determined for each subject with measurable disease at entry into Second Course Phase using both the RECIST 1.1 and irRECIST criteria.
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12.2.8. second course progression-free survival

PFS2 will be calculated for those subjects who initiate second course treatment of pembrolizumab in the same fashion as described in Section 12.2.2. The start date for PFS2 will be the first dose of second course treatment of pembrolizumab. PFS2 will be determined for each subject using both the RECIST 1.1 and irRECIST criteria.
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12.3. analysis populations

All subjects starting study therapy will be included in the analysis of safety data, OS, and PFS. Objective response will be analyzed on the population of subjects who begin study treatment and have measurable disease at baseline. Duration of response will be analyzed on the population of subjects who achieve an objective response. Second course response rate and progression free survival will be conducted on subjects who initiate second course treatment of pembrolizumab.
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12.4. analysis methods 12.4.1. timing

Analyses on this study will be conducted on a continuous basis in order to assess the Bayesian stopping rules for toxicity described in Section 12.5. An analysis of all endpoints will occur after the best overall response for each subject has been determined for all subjects. An updated analysis of the study will be conducted after the PFS censoring rate reduces to 20% or when all subjects have been on study at least two years (whichever occurs first). A final analysis of the study will be conducted after the overall survival censoring rate reduces to 20% or when all subjects have been on study at least five years (whichever occurs first).
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12.4.2. subject disposition

An accounting of all consenting subjects will be provided at the end of the study. This will include a breakdown of subjects who consented, were treated, discontinued treatment, died, and were lost to follow-up or withdrew consent.
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12.4.3. baseline subject and disease

A summary of subject demographics and disease-related characteristics will be completed.
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12.5. primary analysis

A maximum of 30 evaluable subjects with soft tissue sarcoma will be enrolled as a single cohort. It is not anticipated that the addition of pembrolizumab to standard chemotherapy will increase the rate of severe or life-threatening toxicity. It has been reported that the rate of any severe or life-threatening toxicity of doxorubicin and dacarbazine every 3 weeks is 55%48.  
If it becomes evident that the rate of severe or life-threatening toxicity convincingly exceeds 55%, enrollment to the study will be halted.  
The stopping rule will hold enrollment if the posterior probability of severe or lifethreatening toxicity risk exceeding 0.55 is 75% or higher. In this event, data will be evaluated to inform the subsequent conduct of the study. The prior for this monitoring rule is beta (11,9). This means that our prior assumption regarding the proportion of severe or life-threatening toxicity is 0.55, and there is 90% probability that this proportion is between 0.368 and 0.726. The operating characteristics of the stopping rule are given in Table 11 and are based on 5000 simulations:
72  
| Number of  Subjects with  Severe or LifeThreatening  Toxicities    | Max.  Denominator  Cutoff for Early  Stopping   | Posterior  Probability:  Pr(Risk>0.55|Data)   |
|----|-------------------------------------------------|-----------------------------------------------|
| 4  | 4                                               | 0.7834                                        |
| 5  | 6                                               | 0.7536                                        |
| 6  | 7                                               | 0.8056                                        |
| 7  | 9                                               | 0.7728                                        |
| 8  | 11                                              | 0.7694                                        |
| 9  | 13                                              | 0.7558                                        |
| 10 | 14                                              | 0.7944                                        |
| 11 | 16                                              | 0.7812                                        |
| 12 | 18                                              | 0.7592                                        |
| 13 | 19                                              | 0.8002                                        |
| 14 | 21                                              | 0.7818                                        |
| 15 | 23                                              | 0.7710                                        |
| 16 | 25                                              | 0.7594                                        |
| 17 | 26                                              | 0.7988                                        |
| 18 | 28                                              | 0.7828                                        |
| 19 | 30                                              | 0.7706                                        |
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12.6. secondary analyses

Response rates (based on RECIST 1.1 criteria) will be calculated with corresponding 95% confidence intervals based on the Clopper-Pearson method. The duration of response, overall survival, and progression free survival (PFS) distributions will be estimated using Kaplan-Meier techniques. Secondary correlative analyses will be conducted on baseline subject and disease characteristics, and selected biomarkers using logistic regression (response rate) and Cox proportional hazards models (duration of response, overall survival, and PFS).
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12.7. safety analyses

Incident rates for adverse events, treatment-emergent adverse events, SAEs and deaths while on study therapy will be summarized. Treatment-emergent adverse events are defined as follows:  
- An adverse event that occurs after treatment start that was not present at the time of treatment start; or
- An adverse event that increases in severity after treatment start if the event was present at the time of treatment start.
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12.8. exploratory analyses

Analysis of objective response, duration of response, and PFS whereby the endpoints are based on irRECIST will be conducted using methods as described in Section 12.6. Correlative analysis will be conducted on PD-L1 and other biomarkers using logistic regression for objective response and Cox proportional hazards models for time to event endpoints. Other exploratory analysis will be conducted as deemed necessary. Summaries of second course objective response rate and progression free survival will be conducted.
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12.9. interim analyses

This study will be continuously evaluated as described previously in Section 12.4.
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13. study completion 13.1. completion

The study will be considered complete when one or more of the following conditions is met:
- All subjects have completed all study visits. - All subjects have discontinued from the study.  
- The IRB, FDA, LCI DSMC, Sponsor-Investigator or Merck discontinues the study because of safety considerations.  
- The Sponsor-Investigator defines an administrative or clinical cut-off date.
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13.2. termination

The study will be terminated when one or more of the following conditions occur: If risk-benefit ratio becomes unacceptable owing to, for example:  
- Safety findings from this study (e.g. SAEs)
- Results of any interim analysis - Results of parallel clinical studies
- Results of parallel animal studies (e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).  
- If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol compliance) does not suggest a proper completion of the trial within a reasonable time frame.
The Sponsor-Investigator has the right to close the trial at any site and at any time. For any of the above closures, the following applies:  
- Closures should occur only after consultation between involved parties. - All affected institutions must be informed as applicable according to local law.  
- In case of a partial study closure, ongoing subjects, including those in followup, must be taken care of in an ethical manner.
Details for individual subject's withdrawal can be found in Section 4.3.3.
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14. retention of records

Essential documentation (e.g. adverse events, records of study drug receipt and dispensation), including all IRB correspondence, will be retained for at least 2 years after the investigation is completed. Documentation will be readily available upon request.
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15. publication policy

The Investigator must send a draft manuscript of the publication or abstract to Merck, prior to submission of the final version for publication or congress presentation. All relevant aspects regarding data reporting and publications will be part of the contract between Merck and the Investigator.
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16. ethical and legal issues

The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this study, are designed to ensure that the Investigator abide by Good Clinical Practice (GCP) guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study will also be carried out in keeping with applicable local law(s) and regulation(s).  
Documented approval from appropriate agencies (e.g. DSMC, IRB, FDA) will be obtained for all participating centers before start of the study, according to GCP, local laws, regulations and organizations. When necessary, an extension, amendment or renewal of IRB approval must be obtained and forwarded to Merck.  
Strict adherence to all specifications laid down in this protocol is required for all aspects of study conduct; the Investigators may not modify or alter the procedures described in this protocol.  
Modifications to the study protocol will not be implemented by the SponsorInvestigator without discussion and agreement by Merck. However, the Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial subjects without prior approval from applicable agencies. As soon as possible, the implemented deviation or change, the reasons for it and if appropriate the proposed protocol amendment should be submitted to the appropriate agencies. Any deviations from the protocol must be explained and documented by the Investigator.  
The Sponsor-Investigator is responsible for the conduct of the clinical trial at the sites in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Sponsor-Investigator is responsible for personally overseeing the treatment of all study subjects. The Sponsor-Investigator must assure that all study site personnel, including sub-investigators and other study staff members, adhere to the study protocol and all applicable regulations and guidelines regarding clinical trials both during and after study completion.  
The Sponsor-Investigator will be responsible for assuring that all the required data will be collected and properly documented.
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16.2. confidentiality

All records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available.
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16.3. compliance with trial registration

Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the trial is solely responsible for determining whether the trial and its results are subject to the requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate trials for their disease conditions and pursue participation by calling a central contact number for further information on appropriate trial locations and trial site contact information.
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