A Trial of Pembrolizumab in Combination With Doxorubicin as Treatment for Patients With Advanced Sarcomas
Phase: PHASE1
Conditions: Sarcoma
Sponsor: Fred Hutchinson Cancer Center

IRO REC'D OCT 0 11- 2018  
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
1. TITLE 
PROTOCOL: A Trial of Pembrolizumab in Combination with Doxorubicin as 
Treatment for Patients with Advanced Sarcomas 
Current Version: October 3,2018 
Previous Version: July 26th, 2018 
Investigators: 
Investigators 
Title 
Telephone 
Seth M. Pollack, MD 
Assistant Member, FHCRC 
206-667-6629 
Research Coordinator: 
Taylor Hain, CCRC 
206-667-4802 
Jackie Vandermeer 
206-667-6110 
Jeff Gregory 
206-667-5892 
Sabrina McDonnell 
206-667-1583 
FHCRC 1RB Approval 
Statistician: Mary Redman PhD, FHCRC 
OCT 04 2018 
Document Released Date 
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1.1 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab and Doxorubicin 
Trial Phase 
Phase 1/II 
Clinical Indication 
Sarcoma 
Trial Type 
Single arm, open-label 
Type of control 
Historical 
Route of administration 
IV 
Trial Blinding 
None 
Treatment Groups 
Low and high dose doxorubicin/ phase 
expansion 
I and phase II 
Number of trial subjects 
maximum 47 (44 expected) 
Estimated 
enrollment 
period 
24 months 
Estimated duration of trial 
48 months 
Duration of Participation 
48 months 
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1.2 Table of contents: 
Title 
1.1 Trial Summary 
1.2 Table of contents 
1.3 Commonly Used Abbreviations 
Trial Design 
2.1 Introduction 
2.2 Dosing Schedule 
2.3 Management of Normal Doxorubicin Toxicity 
2.4 Assessment of Response 
2.5 Phase I Dose Escalation 
2.6 Phase II Extension 
2.7 Trial Diagram 
Objectives 
3.1 Primary Objectives and Hypothesis 
3.2 Secondary Objectives and Hypothesis 
3.3 Exploratory Objectives 
Background and Rationale 
4.1 Background 
4.2 Rationale 
Methodology 
5. 1 Entry Criteria 
5. 2 Trial Treatments 
5.3 Concomitant Medications/Vaccinations (allowed & prohibited) 
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5.4 Rescue Medications & Supportive Care related to Pembrolizumab 
5.5 Diet/Activity/Other Considerations 
5.6 Subject Withdrawal/Discontinuation Criteria 
5.7 Subject Replacement Strategy 
5.8 Criteria for Early Trial Termination 
Trial Flow Chart 
Trial Procedures 
7.1 Trial Procedures 
7.2 Assessing and Recording Adverse Events 
7.3 Analysis of Biopsy Specimen 
Statistical Analysis and Plan 
8.1 Statistical Analysis and Plan Summary 
8.2 Statistical Analysis Plan 
Labeling, Packaging, Storage and Return of Clinical Supplies 
9.1 Investigational Product 
9.2 Packaging and Labeling Information 
9.3 Clinical Supplies Disclosure 
9.4 Storage and Handling Responsibilities 
9.5 Returns and Reconciliation 
Administrative and Regulatory Details 
10.1 Institutional Review Board 
10.2 Consent 
10.3 Termination of Study 
10.4 Compliance with Trial Registration and Results Posting Requirements 
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10.5 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
Appendix A: Data Safety Monitoring Board Charter Data Safety Monitoring Board 
Charter 
Appendix B: ECOG Performance Status 
Appendix C: Literature Cited 
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1.3 Commonly Used Abbreviations: 
AE 
Adverse Event 
APC 
Antigen Presenting Cell 
APP 
Advanced Practice Provider (Nurse practitioners or physician assistants) 
BMP 
Basic Metabolic Panel 
CBC 
Complete Blood Count 
CMP 
Complete Metabolic Panel 
CR 
Complete Response 
CRF 
Case Report Forms 
CTCAE Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T Lymphocyte 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
IB 
Investigator Brochure 
IV 
Intravenous 
mAb 
Monoclonal Antibody 
MHC 
Major Histocompatibility Complex 
OS 
Overall Survival 
OTC 
Over the Counter 
PD-1 
Programed Death Receptor 1 
PD-Li 
Program Death Receptor Ligands 1 & 2 
&2 
PFS 
Progression-free Survival 
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RECIST Response Evaluation Criteria in Solid Tumors 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SBRT 
Stereotactic Body Radiation Therapy 
STS 
Soft Tissue Sarcoma 
TSH 
Thyroid Stimulating Hormone 
Treg 
Regulatory T cell 
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2.0 TRIAL DESIGN 
2.1 Introduction 
This is a Phase I/II, non-randomized, open-label, interventional study of Pembrolizumab 
combined with doxorubicin for patients with advanced sarcoma. Most patients will receive 
this as front line therapy. As a rule, the trial is generally inclusive for most sarcoma subtypes. 
However, it excludes patients with prior anthracycline treatment. Patients with Ewings 
Sarcoma, Osteosarcoma, and some Rhabdomyosarcomas are excluded as these histologic 
sarcoma subtypes have well-established, evidence-based treatment paradigms combining 
anthracyclines with other chemotherapy. 
The Phase I stage will evaluate two dose levels of doxorubicin (45 and 75 mg/m2) combined 
with Pembrolizumab. The 75 mg/m2  doxorubicin dose is widely considered standard of care 
for sarcoma, as is being used as the "control" arm for recent and on-going phase III trials 
(NCT02451943) (Judson, Verweij et al. 2014). All patients will receive Pembrolizumab at 
the flat dose of 200 mg given intravenously every 3 weeks. Unless serious adverse events are 
observed, the Phase II expansion will combine the 75 mg/m2  dose of doxorubicin with 
Pembrolizumab. 
The phase II portion will use a two stage design treating an initial 20 patients with the 
combination of Doxorubicin and Pembrolizumab. If two or more objective responses are 
seen (either complete or partial responses), an additional 15 patients will be treated for a total 
of 35 patients. In summary, we expect that 44 patients will be treated on the trial (9 in the 
phase I portion and 35 on the phase II portion). If an additional 3 patients needed to be 
treated in the initial phase I cohort this could potentially increase to a maximum enrollment 
of 47. 
2.2 Dosing Schedule 
In order to "prime" the immune system prior to combination therapy, patients will receive 
one cycle of Pembrolizumab as a single agent before starting the combination of doxorubicin 
and Pembrolizumab. Patients will receive a maximum of 6 cycles of doxorubicin. After this, 
patients with clinical benefit may continue on study with single agent Pembrolizumab. 
Pembrolizumab has been given q2 weeks and q3 weeks and the optimal schedule is unclear. 
However, it is approved by the FDA for use every 3 weeks, and this dosing will also 
minimize the necessary infusion center visits. Patients will receive Pembrolizumab and 
doxorubicin sequentially at the same infusion center visit. Doxorubicin will be given first. 
Patients with SD, PR or CR may continue to take Pembrolizumab for 2 years (and no more 
than 35 cycles). After this, they must discontinue Pembrolizumab. If the patient had been 
responding prior to discontinuation and they immediately progress 8-12 weeks after 
discontinuation, they may then resume pembrolizumab for one year or until progression. 
2.3 Management of Normal Doxorubicin Toxicity and use of Growth Factors 
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Dosing will be every 3 weeks as is standard of care when doxorubicin is used as a single 
agent. There are no restrictions any other anti-emetics (NK1 or 5HT3 inhibitors) however, 
steroids are occasionally used as antiemetics for doxorubicin but are not recommended for 
patients on this trial as they may interfere with the efficacy of Pembrolizumab. 
In general, supportive care will be given according to standard practice. No serious toxicities 
have been observed to date when Pembrolizumab has been combined with filgastrim and 
peg-filgastrim so these medications will be generally be allowed to support patients receiving 
doxorubicin. However, during the first cycle combining doxorubicin with Pembrolizumab 
(cycle 2) while in the phase I dose escalation portion of the trial, no growth factor will be 
given. This will allow a simplified look at the safety of the Pembrolizumab and doxorubicin 
combination. 
Patients on single agent doxorubicin sometimes have dose delays secondary to toxicity. Dose 
delays up to 3 weeks for toxicity not otherwise outlined in section 5.2 will be permitted with 
PI approval. 
Lab abnormalities may also necessitate delay in doxorubicin. Detailed 
information about delays and dose reductions for patients on doxorubicin is given in section 
5.2. Should either drug be delayed for any reason, the other drug may be given at the 
discretion of the treating physician in order to minimize infusion center appointments for 
patients and focus study on the combination. 
If a toxicity is clearly attributable to only one drug, the other may be continued per protocol. 
2.4 Assessment of Response 
Response assessment will be based on RECIST 1.1. Patients with clinical benefit (SD, PR, 
CR) after 6 cycles of doxorubicin will continue on single agent Pembrolizumab until 
confirmed progression RECIST, severe toxicity (see Section 5), or 2 years of therapy 
whichever comes first. Patients who receive a CR will be treated until they have had at least 
24 weeks of treatment and have been treated for at least 2 cycles after their CR was declared. 
Patients who are able to be brought to a CR surgically should be treated just as if they had a 
CR in response to the medication. Patients confirmed to have a CR who have been taken off 
treatment will continued to be monitored radiographically every 12 weeks. Upon relapse they 
can be re-treated with Pembrolizumab for up to one year. 
While, all patients will start therapy with unresectable/metastatic disease, it is possible that a 
responding patient becomes surgically resectable so that they have no evidence of disease. 
These patients may undergo surgery and afterwards should be followed as if they had a CR, 
with the rules regarding progression and restarting treatment. 
Patients will have their first post-treatment scan after 3 cycles of doxorubicin, prior to 
receiving their fourth cycle of doxorubicin. Patients with PR or SD will have their second 
post treatment scan 3-6 weeks after their last (sixth) cycle of doxorubicin. Responses will be 
determined by RECIST 1.1. After 6 cycles of doxorubicin have been completed and 
Pembrolizumab is being given as a single agent, scans will be performed every 12 weeks (+/-
1 week) until progression. 
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Subjects with an unconfirmed progression of disease may discontinue but will be encouraged 
to continue trial treatment until progression is confirmed following two additional cycles of 
therapy or until disease progression becomes symptomatic. However, subjects may only 
receive study treatment while waiting for confirmation of PD if the following criteria are 
met: 
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 
2.5 Phase I dose Escalation of Doxorubicin 
A dose limiting toxicity (DLT) will be defined as a possibly-related, unexpected SAE of 
grade 3 or higher or any adverse event at least possibly related to either agent requiring 
discontinuation of either drug. The DLT monitoring period will be six weeks (2 cycles) after 
the patient receives both Doxorubicin and Pembrolizumab. 
The Phase I dose escalation will use a "3+3" phase I trial design. All patients will receive a 
flat dose of 200 mg Pembrolizumab every 3 weeks. Patients will have "priming" with a dose 
of single agent Pcmbrolizumab before receiving the combination of Pembrolizumab with 
doxorubicin. Three patients will be treated at the 45mg/m2  dose of doxorubicin. Although 
this is lower and has considerably less toxicity than the standard of care dosing of 75 mg/m2, 
this dose has clinical activity and is still within the range of acceptable dosing, particularly 
for sarcoma patients with poor performance status or comorbidities (O'Bryan, Baker et al. 
1977). In order to prevent accumulation of unexpected serious adverse events (SAEs), the 
second patient will not start treatment with Pembrolizumab until 10 days after the first patient 
has received the combination of Pembrolizumab with doxorubicin. Patients will be monitored 
for adverse events that might be study related until their last study related visit 30 days after 
discontinuation of therapy. If the first patient develops a DLT, a data safety monitor board 
(DSMB) will meet before the second patient is treated in order to discuss the toxicity and 
make recommendations regarding trial modifications. 
If at least one of the first three patients develops DLT, a total of six patients will be treated at 
this dose level. If two patients develop DLT at the 45mg/m2  dose level, the trial will 
immediately stop accrual and a data safety monitoring board (DSMB) will meet to discuss 
whether to modify, stop or continue the trial. 
Dose escalation to the 75 mg/m2  dose of doxorubicin will be contingent upon acceptable 
safety data following the combination of Pembrolizumab and doxorubicin at the 45 mg/m2  
dosing. If only one of the six patients develops a DLT, a DSMB will meet prior to dose 
escalation to review the specific nature of the toxicity and determine if any protocol 
modifications are necessary prior to proceeding with the dose escalation. If there is no DLT 
among the first three patients, the trial may proceed immediately to the 75 mg/m2  once the 
third patient receives cycle three (the second cycle including both Pembrolizumab and 
doxorubicin) without DSMB review. 
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As was done in the previous cohort, the second patient at the 75 mg/m2  dose will not start 
treatment until 10 days after the first patient has received the combination of Pembrolizumab 
and doxorubicin at the 75 mg/m2  dose level. If the first patient treated has a DLT, a DSMB 
will meet prior to treatment of the second patient. If two of the first six patients treated using  
75 mg/m2  doxorubicin develop a DLT, the phase II extension will occur using the 45 mg/m 
dosing. The DSMB will meet prior to the phase II expansion. After this, the DSMB will 
continue to meet at least every six months while the study is enrolling. 
During the dose escalation period of the trial (up to the first six patients at each dose level), 
patients will be monitored for 4 hours in the clinical trials unit after receiving their first 
infusion with the drug combination; monitoring is not required for the Cycle 1 dose of single 
agent pembrolizumab. After this first combination dose, patients may leave the infusion 
center immediately after receiving their infusions. 
2.6 Phase H extension 
The phase II extension will use a SWOG 2-stage design (modified Simon's 2 stage design) in 
order to detect a response rate (CR + PR) of 35%. This is based on a predicted overall 
response rate for single agent doxorubicin of 15%. 20 patients will be treated in the first 
stage. If 2 or more patients have CR or PR, an additional 15 patients will be treated. If at least 
10 CR or PR's are seen, this will be considered a positive study. Patients treated in the phase 
I portion of the study will not be included in the phase II analysis. Any toxicity defined as a 
DLT for the phase I portion will also trigger a meeting of the DSMB during the phase II 
portion of the trial. Should 2 of these events occur, enrollment must halt until the DSMB 
meets. 
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2.7 Trial Diagram 
Treatment Schedule Diagram 
Cycle 1: 
Cycle 2-7: 
Cycle A: 
Pembrolizumab 
Pembrolizumab 
Pembrolizumab 
200mg 
200mg 
200mg 
single agent 
+ Doxoribicin 
single agent 
Study Design Diagram 
Phase I 
3+3 design: 
Part 1: Doxorubicin 45 mg/m2  
Part 2: Doxorubicin 75 mg/m2  
Phase II 
2-stage design: 
Part 1: 20 patients (requires 2 responses) 
Part 2: 15 patients 
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3.0 OBJECTIVES & HYPOTHESES 
3.1 Primary Objectives & Hypotheses 
3.1.1 Objective: To assess the safety and tolerability of the combination of Pembrolizumab 
and Doxorubicin in patients with advanced soft tissue sarcoma (STS). 
Hypothesis: The combination of Doxorubicin and Pembrolizumab will be similar to the 
toxicity of standard Doxorubicin and Pembrolizumab therapy when these drugs are used 
a single agents. 
3.1.2 Objective: To assess the clinical response rate of advanced soft tissue sarcoma (STS) 
patients receiving the combination of Pembrolizumab and Doxorubicin. 
Hypothesis: The addition of Pembrolizumab to Doxorubicin will result in a 20% 
increase in the objective response rate (CR + PR) compared with historical controls. 
3.2 Secondary Objectives & Hypotheses 
Objective: To explore the clinical activity of Pembrolizumab in subjects with advanced STS 
with respect to the following endpoints: 
Time to response 
Duration of response 
Progression-free survival (PFS) 
Overall survival 
Hypothesis: Induction of a meaningful objective response rate with Pembrolizumab will be 
reflected in other clinical outcome parameters including duration of response, progression-
free survival, and overall survival. 
3.3 Exploratory Objective 
Objective: To compare response rates between patients with high levels of PD-L1 
expression with those who have PD-L I absent. 
Hypothesis: Patients with very strong PD-Ll expression will have more profound responses 
than those with weak or absent PD-Li expression. 
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4.0 BACKGROUND & RATIONALE 
4.1 Background 
Refer to the Investigator's Brochure (IB)/approved labeling for detailed background 
information on Pembrolizumab. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
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 Pdcdl) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). 
The structure of murine PD-1 has been resolved. PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM). Following T-cell stimulation, PD-1 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 CD3, PKCO 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 T-cell activation triggered through the T-cell 
receptor. PD-Li is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
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antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. 
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-Li 
serves to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor immune evasion and should be considered as an attractive target 
for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. KeytrudaTM  (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. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator's Brochure for Preclinical and Clinical data. 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal neoplasms together 
comprising 1% of all cancers and with a median overall survival of approximately 1 year in 
the metastatic setting. Biologically, STS are often divided into genetically "complex" tumors, 
having highly mutated genomes and complex karyotypes, and genetically "simple" tumors, 
which are often driven by a single translocation and in some cases express highly 
immunogenic self-antigens. 
Currently, the standard front line therapy for STS is single agent Doxorubicin that has a 
objective response rate (CR+PR) of 15% and results in a median progression free survival 
(PFS) of approximately 4.6 months (Santoro, Tursz et al. 1995, Judson 2013, Gelderblom, 
Blay et al. 2014). The oral tyrosine kinase inhibitor, pazopanib (Votrient), was approved by 
the FDA for second line treatment of STS based on the PALLETE study where an 
improvement in PFS of 3.2 months was observed compared with placebo(van der Graaf, 
Blay et al. 2012, Rajendra, Jones et al. 2013). There is currently no other approved therapy 
for STS though other standard cytotoxic chemotherapies including ifosfamide, gemcitabine/ 
docetaxel and DTIC are commonly used in clinical practice. PD-1 inhibition has been shown 
to improve outcomes in other difficult to treat cancers such as melanoma and lung 
cancer(Brahmer, Drake et al. 2010, Topalian, Hodi et al. 2012, Hamid, Robert et al. 2013). 
We have seen T-cell tumor infiltration in a variety of sarcoma subtypes and the amount of 
infiltrating T cells has been associated with shorter disease specific survival, supporting the 
idea that check point inhibition might be an effective strategy (Sorbye, Kilvaer et al. 2011). 
One recent study found PD-1+ lymphocytes in 65% of STS tumors and PDL-1 expression by 
IHC in 58% of STS tested (Kim, Moon et al. 2013). To better define the pattern of PDL-1 
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expression in specific STS subtypes, our tissue collaboration with Merck analyzed 81 FFPE 
sarcoma samples from the University of Washington Tissue Bank for PD-Li and PD-1 by 
IHC at Merck Research Laboratories. 90% of tumors tested positive for PD-1 staining and 
59% for PD-Li. Significantly higher expression levels were seen in higher grade tumors and 
pleomorphic undifferentiated sarcoma. 
There are currently no published reports regarding the use of checkpoint inhibitors in 
sarcoma. Two presentations were made at the 2016 ASCO meeting. In one study of twelve 
patients with uterine leiomyosarcoma no responses were seen. Another study looking at 40 
patients with several histologies saw 5 responses (4 pleomorphic undifferentiated sarcomas 
and 1 synovial sarcoma). These results demonstrate that checkpoint inhibition may have 
activity for some patients with soft tissue sarcoma but that combination therapies will really 
be necessary to make it broadly applicable. 
4.2.2 Rationale for Dose Selection/Regimen/Modification 
The safety of Pembrolizumab has been evaluated extensively as a single agent. An open-label 
Phase I trial (Protocol 001) was being conducted to evaluate the safety and clinical activity of 
single agent Pembrolizumab. 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 Pembrolizumab 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 Pembrolizumab program has shown that a lower dose of 
Pembrolizumab and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
PK data analysis of Pembrolizumab 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). This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q2W and Q3W dosing schedule. 
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 Pembrolizumab 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. Pembrolizumab 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 
Pembrolizumab 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 
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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. 
Although chemotherapy causes a temporary disruption in the immune response by inducing 
neutropenia and lymphopenia, chemotherapy also has the potential to bolster immunotherapy 
and create therapeutic synergy by directly removing barriers to the immune response such as 
regulatory T cells and myeloid derived suppressor cells (Ko, Kim et al. 2007, Hirschhorn-
Cymerman, Rizzuto et al. 2009). Furthermore, the anti-tumor cytotoxic effects of 
chemotherapy can lead to increased presentation of tumor antigens by dendritic cells 
resulting in a tumor specific T cell response (Hirschhorn-Cymerman, Rizzuto et al. 2009, 
Tesniere, Schlemmer et al. 2010). In this proposal, we will test whether the addition of 
immunotherapy can bolster the efficacy of front line Doxorubicin in patients with STS by 
using the PD-1 inhibitor Pembrolizumab. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
Historically, doxorubicin has been used in combination with Ifosfamide as front line 
therapy for patients with advanced sarcomas. However, the EORTC randomized patients to 
receive single agent doxorubicin or the combination with ifosfamide. Although the 
combination did lead to improved progression free survival, the trial found no significant 
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change in overall survival associated with the combination therapy and significantly 
increased toxicity associated with the combination. This study established single agent 
doxorubicin as standard front line therapy for patients with advanced sarcoma. In patients 
with advanced STS, doxorubicin has a response rate of 15% and results in a median 
progression free survival (PFS) of approximately 4.6 months (Santoro, Tursz et al. 1995, 
Judson 2013, Gelderblom, Blay et al. 2014). The primary objective of the phase II design is 
to compare the objective response rate (ORR) with historical rates. 
4.2.3.2 Biomarker Research 
We tested over 80 sarcoma tumors including both 
LMS and SS for expression of PD-Li and PD-1; we 
found some degree of PD-1 expressing cells in over 90% 
of tumors examined. Detectable PD-L1 was seen in a 
subset of each sarcoma subtype tested, including n=11 
(58%) of LMS and n=7 (47%) SS. PD-1 expressing 
lymphocytes were also see in a majority of tumors 
including n=16 (84%) LMS and n=15 (100%) SS. High 
(4+) or very high (5+) PD-L1 expression was seen in 10 
sarcoma including 3 LMS (Figure 2 A and B). Seven 
tumors had high or very high PD-1 expression including 
one SS, and two LMS. In contrast, even though 100% of 
the SS tumors had some PD-1 expression, none of the SS 
tumors had either 4+ or 5+ PD-1 expression. Only n=4 
(27%) of SS tumors had >2+ expression for PD-Ll. 
Higher-grade tumors were associated with higher levels of 
expression (p = 0.05). 
Fig.: A) High PD-1 staining in a high 
grade, metastatic sarcoma. B) Profuse 
membranous tumor cell staining for PD-
L1 in a leiomyosarcoma tumor. C) Graph 
showing intensity of staining for individual 
sarcoma subtypes. 
both PD-L1 (p = 0.03) and PD-1 
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5.0 METHODOLOGY 
5.1 Entry Criteria 
This trial is designed for both male and female patients 18 years of age with unresectable 
sarcoma not amenable to surgery or radiation with curative intent and an ECOG performance 
status of 0 or 1. We expect 9 patients will be treated on the phase I dose escalation portion of 
the trial (it is possible as few as 6 and as many as 12 patients could be treated on the phase I 
portion) and 35 additional patients will be treated on the phase II expansion. All patients 
meeting the eligibility criterion will be considered for enrollment. No exceptions to eligibility 
will be granted. 
5.1.1 Diagnosis/Condition for Entry into the Trial 
As is the standard practice in the Seattle Cancer Care Alliance Sarcoma Clinic, all patients 
must have had their pathology reviewed at the University of Washington sarcoma clinic. 
Certain sarcoma subtypes such as Osteosarcoma and Ewings sarcoma almost always receive 
anthracyclines in combination with other agents as part of their standard of care and therefore 
it would not make sense for those patients to participate in this study. Both patients with soft 
tissue sarcoma as well as patients with bone sarcomas (for example chondrosarcoma, 
leiomyosarcoma of the bone etc.) may be allowed on this trial as this is an anatomic 
distinction rather than a biologic or immunologic distinction. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
Be willing and able to provide written informed consent/assent for the trial. 
Be 18 years of age on day of signing informed consent. 
Have measurable disease based on RECIST 1.1. 
Have metastatic or unresectable sarcoma. 
Have a performance status of 0 to 1 on the ECOG Performance Scale. 
Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation. 
Table 1: Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute 
neutrophil 
(ANC) 
count 
,500 /mcL 
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Platelets 
00,000 / mcL 
Hemoglobin 
g/dL or 
.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment) 
Renal 
Serum creatinine OR 
.5 X upper limit of normal (ULN) OR 
Measured or calculated' 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrC1) 
l0 mL/min for subject 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) 92.5 X ULN OR 
 
95 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT) 
Activated Partial 
Thromboplastin Time (aPTT) 
9.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
9..5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. 
Female subjects 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 study medication (Reference Section 
5.7.2). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 
Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
Ejection Fraction >45% by either MUGA scan or echocardiogram. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
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Has prior treatment using an anthracycline. 
Has one of the following sarcoma subtypes where combining anthracyclines with 
other chemotherapies is established as the standard of care: Osteosarcoma, Ewings 
sarcoma, Embryonal Rhabdomyosarcoma, Alveolar Rhabdomyosarcoma. 
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
Has a known history of active TB (Bacillus Tuberculosis) 
Hypersensitivity to pembrolizumab or any of its excipients. 
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., _Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., •Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
Note: Subjects with Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy. 
Has 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. 
Has 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 trial 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 trial treatment. This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability. 
Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
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physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment. 
Has known history of, or any evidence of active, non-infectious pneumonitis. 
Has an active infection requiring systemic therapy. 
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, 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. 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or anti-
CTLA4. 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
Has received a live vaccine within 30 days of planned start of study therapy. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
5.2 Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2 Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequenc 
Y 
Route of 
Administratio 
n 
Regimen/ 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of 
each 3 week 
cycle 
Experimental 
Doxorubicin 
45 or 75 
Q3W 
IV infusion 
Day 1 of 
Standard 
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Drug 
Dose/ 
Potency 
Dose 
Frequenc 
y 
Route of 
Administratio 
n 
Regimen/ 
Treatment 
Period 
Use 
mg/m2  
each 3 week 
cycle 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered as a 30 minute IV infusion. However, given the 
variability of infusion pumps, a window of -5 minutes and +10 minutes will be permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
A Procedures Manual will contain specific instructions for Pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
Anti-emetics given to prevent and treat doxorubicin associated nausea and vomiting may be 
given according to the standard of care at the discretion of the treating clinician with the 
exception that corticosteroids are not recommended as their immunosuppressive effects may 
impact the efficacy of Pembrolizumab. While steroids are discouraged, they are not 
absolutely forbidden as there could be an individual situation where the benefits would be 
worthwhile (e.g. a specific case of very severe and refractory nausea). 
As stated in Section 2.5, a dose limiting toxicity (DLT) will be defined as a possibly-related, 
unexpected SAE of grade 3 or higher or any adverse event at least possibly related to either 
agent requiring discontinuation of either drug. 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 — 
Background and Rationale. 
Details on preparation and administration of Pembrolizumab are provided in the Pharmacy 
Manual. 
If a toxicity is clearly attributable to only one drug, the other may be continued per protocol. 
If a toxicity is clearly attributable to one agent and the dose adjustment or drug withdrawal is 
not required by the protocol, the treating physician may have the discretion to make dose 
adjustments as dictated by their clinical judgement. 
5.2.1.2 Dose Modification of Pembrolizumab 
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AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and intiation 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, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in 
Table 
3. 
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Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
General instructions: 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to 90 mg prednisone or equivalent per day within 12 weeks. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Monitor participants for signs and 
symptoms of pneumonitis 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Monitor participants for signs and symptoms 
of enterocolitis (ic, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). . 
Participants with _Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 
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AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4 
Permanently 
discontinue 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type I diabetes 
mellitus (TI DM) 
or 
Hyperglycemia 
Newly onset 
TI DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of f3-cell 
failure 
Withhold 
Initiate insulin replacement 
therapy for participants with 
T 1 DM 
Administer anti-hyperglycemic in 
participants with hyperglycemia 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated, 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue' 
Hyperthyroidism 
Grade 2 
Continue 
Treat with non-selective beta- 
blockers (eg, propranolol) or 
thionamides as appropriate 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue' 
Hypothyroidism 
Grade 2-4 
Continue 
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade I or 2 
Withhold 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
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All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
Based on type and severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue 
I. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to .Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T I DM). 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab  
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 
Table 4 Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Increase monitoring of vital signs as medically 
None 
Mild reaction; infusion 
indicated until the participant is deemed medically 
interruption not 
indicated; intervention 
not indicated 
stable in the opinion of the investigator. 
Grade 2 
Stop Infusion. 
Participant may be 
Requires therapy or 
Additional appropriate medical therapy may 
premcdicated 1.5h (± 30 
infusion interruption but 
include but is not limited to: 
minutes) prior to infusion of 
responds promptly to 
IV fluids 
with: 
symptomatic treatment 
Antihistamines 
Diphenhydramine 50 mg po 
(e.g., antihistamines, 
NSAIDs 
(or equivalent dose of 
NSAIDs, narcotics, IV 
Acetaminophen 
antihistamine). 
fluids); prophylactic 
Narcotics 
Acetaminophen 500-1000 mg 
medications indicated 
Increase monitoring of vital signs as medically 
po (or equivalent dose of 
for 
4 hrs 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
analgesic). 
If symptoms resolve within 1 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 participant 
should be premedicated for the next scheduled 
dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment 
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Grades 3 or 4 
Stop Infusion. 
No subsequent dosing 
Grade 3: 
Additional appropriate medical therapy may 
Prolonged (i.e., not 
include but is not limited to: 
rapidly responsive to 
Epinephrine** 
symptomatic medication 
IV fluids 
and/or brief interruption 
Antihistamines 
of infusion); recurrence 
NSAIDs 
of symptoms following 
Acetaminophen 
initial improvement; 
Narcotics 
hospitalization indicated 
Oxygen 
for other clinical 
Pressors 
sequelae (e.g., renal 
Corticosteroids 
impairment, pulmonary 
Increase monitoring of vital signs as medically 
infiltrates) 
indicated until the participant is deemed medically 
Grade 4: 
stable in the opinion of the investigator. 
Life-threatening; 
Hospitalization may be indicated. 
pressor or ventilatory 
**In cases of anaphylaxis, epinephrine should be 
support indicated 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov  
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
5.2.1.3 Dose Modification of Doxorubicin 
Doxorubicin is a cytotoxic chemotherapy that has a well-defined safety profile and will be 
given as per the standard of care. Doxorubicin will not be given while a patient's ANC is < 
1000 cells/m3 or if the platelet count is <75,000 cells/m3. When necessary, the next treatment 
cycle should be delayed until these counts have recovered to these levels. Transfusions of 
red blood cells and platelets are permitted as clinically indicated. If a patient has a grade 3 
febrile neutropenia, doxorubicin should be reduced to approximately 75% of the previous 
dose (first to 60mg/m2  then to 45 mg/m2). Dose reductions of doxorubicin are also required 
for patients having Grade 4 neutropenia lasting more than 1 week. For patients with grade 3 
febrile neutropenia or grade 4 neutropenia without fever lasting less than a week, dose 
reduction may be made at the discretion of the treating physician. Patients with grade 3 
fatigue and/or malaise, may have one dose reduction at the discretion of their treating 
physician. 
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Patients may not have more than 2 dose reductions of doxorubicin, and must come off 
doxorubicin should they continue to have prolonged cytopenias (>21 days) after their second 
dose reduction. If these patients are responding they may stay on Pembrolizumab as a single 
agent until progression. 
LFT abnormalities may also necessitate a dose reduction. For a bilirubin 1.2-1.5, dose 
reduction may be made at the discretion of the treating clinician. For bilirubin 1.5 -3, 50% 
dose reduction. For bilirubin 3.0-5.0, give no more than 25% of the prior dose and consider 
delaying the next cycle. 
EKG's will be collected periodically while a patient is receiving doxorubicin and any other 
times as the treating clinician deems necessary (see section 6.1). If clinically significant 
findings are observed on EKG, they should be evaluated as seen as appropriate by the 
treating clinician. An echocardiogram or MUGA scan will be performed prior to starting 
therapy for all patients. Should a second echocardiogram or MUGA be performed (this is 
required for patients on the phase I portion of the study), a drop in ejection fraction by more 
than 15% or to a total ejection fraction of less than 40% means that doxorubicin should be 
discontinued. While cardiac toxicity is an expected toxicity of doxorubicin, these events 
should be explicitly pointed out to the DSMB as frequent or severe occurrences could raise 
the possibility that pembrolizumab is worsening doxorubicin mediated cardiac toxicity. 
Dose delays of doxorubicin may be permitted for up to 3 weeks with PI approval for medical 
reasons not otherwise outlined in this section. The reason and length of the delay should be 
discussed with PI during the approval process. 
5.2.1.4 Mid-Cycle Labs for Patients on Doxorubicin 
As is our standard practice, all patients receiving doxorubicin will have a CBC and CMP 
drawn 10-14 days after their infusion. If these labs are drawn at an outside lab they must be 
faxed to the Seattle Cancer Care Alliance and reviewed by a nurse and the study team. A 
nurse will call the patient to inquire about any unexpected subjective toxicity. The patient's 
physician will be made aware of any unexpected toxicity and any critical lab values. 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each 21-day cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0). Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered as a 30 minute IV infusion every 3 weeks. Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible. 
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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). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
Doxorubicin is typically given over a 1-hour infusion but this could be stretched to 3 hours 
for relief of acute symptoms such as nausea. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 
5.3 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The investigator should discuss any questions regarding this 
with the Merck Clinical team. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician. 
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject's welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
Antineoplastic systemic chemotherapy or biological therapy 
Immunotherapy not specified in this protocol 
Chemotherapy not specified in this protocol 
Investigational agents other than pembrolizumab 
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Radiation therapy 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator's discretion. Because doxorubicin increases 
radiation related toxicity, the patient must have completed doxorubicin and be 
on the Pembrolizumab alone portion of the treatment to undergo radiation. 
Radiation must begin at least 1 week after the last pembrolizumab dose and 
complete 1 week prior to the following dose. Dose delays of up to 3 weeks are 
acceptable in order to achieve this. 
If the radiation is necessary as a result of progression, the patients should be 
treated as if they had progressed (e.g. they can continue pembrolizumab and 
have a confirmatory scan done after 2 cycles). 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology or for refractory 
doxorubicin-related nausea and vomiting. 
The use of physiologic doses of 
corticosteroids may be approved after consultation with the principal investigator and 
Merck. 
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. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guideline 
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 along with the dose modification 
guidelines in Section 5.2.1.2, [Table 3]. Where appropriate, these guidelines include the use 
of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose 
is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
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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 to pembrolizumab, the 
investigator does not need to follow the treatment guidance. Refer to Table 3 in Section 
5.2.1.2 for dose modification guidelines and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
While not an absolute protocol requirement, investigators are highly encouraged to use a 
cardioprotective agent such as dexrazoxane beginning at cycle 5 to doxorubicin. This will 
help to lower the cardiac risk if the patient progresses and chooses to receive additional 
doxorubicin along with olaratumab in a subsequent line of therapy. 
5.5 Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.5.2 Contraception 
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. Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive. Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is 
years of age and has 
not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study. The two birth control methods can be 
either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Subjects should start using birth control from study Visit 1 throughout the study period up to 
120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor-Investigator and to Merck. If there is any question 
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that a subject will not reliably comply with the requirements for contraception, that subject 
should not be entered into the study. 
5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study. 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 7.2.2. 
5.5.4 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. 
5.6 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw 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 considered withdrawn and no longer followed if they enroll onto hospice care. 
Specific details regarding discontinuation or withdrawal are provided in Section 7.1.4 — 
Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Unacceptable adverse experiences as described in Section 5.2.1.2 
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Intercurrent illness that prevents further administration of treatment 
Investigator's decision to withdraw the subject 
The subject has a confirmed positive serum pregnancy test 
Noncompliance with trial treatment or procedure requirements 
The subject is lost to follow-up 
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date offirst dose. Subjects 
who stop pembrolizumab after 24 months 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 7.1.5.5 
Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements). After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 30 days after the end of treatment as described in Section 7.2.3.1). Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up. After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.7 Subject Replacement Strategy 
The phase II expansion dose will treat up to 35 patients evaluable for response to therapy (20 
in the first stage, then if at least 2 responses are seen, an additional 15 patients). If patients 
become ineligible prior to starting therapy or for some other reason fail to be evaluable for 
response assessment, additional patients will be treated in their place. 
5.8 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
Quality or quantity of data recording is inaccurate or incomplete 
Poor adherence to protocol and regulatory requirements 
Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
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A 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
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J 
6.0 TRIAL FLOW CHART 
6.1 Study Flow Chart 
Trial Period: 
Screening 
Pembro 
Only 
Doxorubicin/Pembrolizumab Combination Pembrolizumab Only (repeat) End of Treatment 
Treatment 
Cycle/Title: 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
At time 
of Discon 
30 
days 
post 
discon 
Scheduling , 
Window 
(Days): 
see 
section 
7.1.5 
±3 
±3 
+3 
+3 
+3 
+3 
±3 
±3 
±3 
±3 
±3 
_ 
±7 
±7 
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Trial Period: 
Screening 
Pembro 
Only 
Doxorubicin/Pembrolizumab Combination Pembrolizumab Only (repeat) End of Treatment 
Treatment 
Cycle/Title: 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
At time 
of Discon 
30 
days 
post 
discon 
Scheduling 
Window 
(Days): 
see 
section 
7.1.5 
±3 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
+3 
+7 
±7 
Informed 
Consent 
X 
Inclusion/Exclu 
sion Criteria 
X 
Demographics 
and Medical 
History 
X 
Prior and 
Concomitant 
Medication 
Review 
X 
Trial Treatment 
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-• 
Trial Period: 
Screening 
Pembro 
Only 
Doxorubicin/Pembrolizumab Combination Pembrolizumab Only (repeat) 
End of Treatment 
Treatment 
Cycle/Title: 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
At time 
of Di scon 
30 
days 
post 
discon 
Scheduling 
Window 
(Days): 
see 
section 
7.1.5 
±3 
±3 
±3 
+3 
+3 
±3 
±3 
±3 
+3 
±3 
+3 
±7 
±7 
Administration 
Post-study 
anticancer 
therapy status 
X 
X 
Survival Status 
X 
X 
Review 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical 
Examination 
X 
Directed 
Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and 
XX 
X 
X 
X 
X 
X 
X 
X 
X 
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Trial Period: 
Screening 
Pembro 
Only 
Doxorubicin/Pembrolizumab Comb' nation 
Pembrolizumab Only (repeat) End of Treatment 
Treatment 
Cycle/Title: 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
At time 
of Discon 
30 
days 
post 
discon 
Scheduling 
Window 
(Days): 
see 
section 
7.1.5 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
Weight 
X 
X 
X 
X 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (Phase I 
portion) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG (Phase II 
portion) 
X 
X 
X 
X 
X 
Echo/MUGA 
(phase I) 
X 
X 
Echo/MUGA 
(phase II) 
X 
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Trial Period: 
Screening 
Pembro 
Only 
Doxorubicin/Pembrolizumab Combination 
Pembrolizumab Only (repeat) 
End of Treatment 
Treatment 
Cycle/Title: 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
At time 
of Discon 
30 
days 
post 
discon 
Scheduling 
Window 
(Days): 
see 
section 
7.1.5 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
Pregnancy Test 
— Urine or 
Serum (in 
appropriate 
study subjects) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/INR and 
aPTT 
X 
CBC with 
Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
Serum Chem 
Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
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L. 
Trial Period: 
Screening 
Pembro 
Only 
Doxorubicin/Pembrolizumab Comb.nation Pembrolizumab Only (repeat) 
End of Treatment 
Treatment 
Cycle/Title: 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
At time 
of Discon 
30 
days 
post 
discon 
Scheduling 
Window 
(Days): 
see 
section 
7.1.5 
+3 
±3 
±3 
±3 
±3 
±3 
±3 
+3 
+3 
±3 
±3 
+7 
+7 
T3, FT4 and 
TSH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor 
Imaging' 
X 
X 
X 
Archival Tissue 
Collection 
(slides) 
X 
Correlative 
Studies Blood 
Collection 
X 
X 
X 
X 
X 
X 
1: Tumor imaging may be performed with a +/- 1-week window. Scans will take place per the schedule even if there are treatment 
delays. 
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7.0 TRIAL PROCEDURES 
7.1 Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor-
Investigator and/or Merck for reasons related to subject safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and 
thus local regulations may require that additional informed consent be obtained from the 
subject. In these cases, such evaluations/testing will be performed in accordance with 'those 
regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject's dated signature or by the subject's legally 
acceptable representative's dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC's 
approval/favorable opinion in advance of use. The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject's willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
,form or addendum to the original consent form that captures the subject's dated signature or 
by the subject's legally acceptable representative's dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level. 
The informed consent will adhere to IRB requirements, applicable laws and regulations and 
Sponsor-Investigator requirements. 
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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee. 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. Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before 
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the first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up. 
7.1.1.6 Assignment of Screening Number 
The Sponsor-Investigator will assign each patient a de-identified screening number that will 
be used for data tracking purposes. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart 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 4.0 (see Section 11.2). Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial 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); see the separate ECI guidance document in Appendix 4 
regarding the identification, evaluation and management of potential irAEs. 
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs. 
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed during screening, 
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration. 
7.1.2.4 Vital Signs 
Vital signs will be taken at screening, prior to the administration of each dose of trial 
treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 6.0). 
Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure. 
Height will be measured at screening only. 
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7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 10.4) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart. 
7.1.2.6 Tumor Imaging and Assessment of Disease 
Radiology at the Seattle Cancer Care Alliance will perform RECIST. Patients will have a CT 
of the chest, abdomen and pelvis at each imaging visit. Patients whose RECIST evaluable 
disease is only outside the chest abdomen and pelvis (e.g. neck or extremities) must also have 
this disease imaging. For patients who have RECIST evaluable disease in their chest/ 
abdomen/ pelvis as well as outside this area, additional imaging may be performed as 
deemed appropriate or necessary by their treating clinician. 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
At the time of enrollment, all patients will have 12 slides (5 microns of tissue on a baked, 
charged slide) cut. These will be kept at 2-8 degrees Celsius until they are ready to be either 
to QualTek for PD-L1 IHC or Merck Research Laboratories. Other biomarkers such as PD-1 
expression, as well as potentially IHC for immune infiltrates and assessment of immune 
response related genes using an N-counter Nanostring assay. Additional archived tissue may 
also be requested for multiplex immunohistochemistry and gene expression assays. At time 
points specified in section 6.1, 30 mL PBMC and 10 mL serum will be frozen and delivered 
to the Pollack Laboratory at the Fred Hutchinson Cancer Research Center for flow cytometry 
and functional analysis. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5. 
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Table 5 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Hemoglobin 
Albumin 
Alkaline phosphatase 
Blood 
Glucose 
Serum f3-human chorionic 
gonadotropint 
(13-hCG)t 
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 thriiodothyronine (T3) 
Absolute Neutrophil Count 
Absolute Lymphocyte Count 
Carbon Dioxide I 
(CO2 or biocarbonate) 
results are noted 
Urine pregnancy test t 
Free tyroxine (T4) 
Thyroid stimulating hormone (TSH) 
PK 
Uric Acid 
Calcium 
Blood for correlative studies 
Chloride 
Glucose 
Phosphorus 
Potassium 
Sodium 
Magnesium 
Total Bilirubin 
Direct Bilirubin (If total 
bilirubin is elevated above the 
upper limit of normal) 
Total protein 
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Hematology 
Chemistry 
Urinalysis 
Other 
Blood Urea Nitrogen 
t Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy 
test will be required. 
I If considered standard of care in your region. 
A 
,2 
\
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Laboratory tests for screening should be performed within 14 days prior to the first dose of 
treatment. If within 3 days of Cycle 1 Day 1, the screening lab results may be utilized for 
Cycle 1 Day 1. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 
hours prior to dosing. Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to each dose of trial treatment. 
7.1.3.1 Pharmacokinetic/Pharmacodynamic Evaluations 
7.1.3.1.1 Blood Collection for Serum Pembrolizumab 
Given the prior extremely consistent pharmicokinetics of Pembrolizumab, no 
pharmicokinetic analysis will be performed in this study. 
7.1.3.1.2 Anti-Pembrolizumab Antibodies 
Given the lack of anti-pembrolizumab antibodies seen in prior trials, no assessment will be 
made for these in this study. 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events, which are present at the time of discontinuation/withdrawal, should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.5. After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
A subject will be considered withdrawn and no longer followed if they enroll onto hospice 
care. 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
The Sponsor-Investigator or a qualified designee will ensure that all inclusion and exclusion 
criteria have been met. Patients who initially fail screening may retake any test and enroll 
once they meet eligibility. 
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7.1.5.1.1 Screening Period 
Unless otherwise specified, all clinical assessments including lab work must be done within 
14 days of treatment initiation. Screening lab work may be utilized for Cycle 1 Day 1 lab 
work if done within 3 days of treatment initiation. Radiological assessment can be done 
within 28 days prior to first dose of study medication. Echocardiogram or MUGA scan may 
have been done up to 3 months of starting on study. 
7.1.5.2 Treatment Period 
Patients must be evaluated by a sarcoma provider prior to each infusion. In general, these 
visits will be the day of the infusion but could be up to 72 hours prior so long as labs are 
adequate. Visits where scan results will be reviewed should include an oncologist. 
7.1.5.3 Post-Treatment Visits 
Patients will be seen at the time of discontinuation and then again 30 days later. These visits 
may be conducted by an oncologist or one of the APP's. 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded. 
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-neoplastic therapy, whichever occurs first. SAEs that 
occur within 30 days of the end of treatment or before initiation of a new anti-cancer 
treatment, whichever is earlier, should also be followed and recorded. Subjects who are 
eligible for retreatment with pembrolizumab (as described in Section 7.1.5.5) may have up to 
two safety follow-up visits, one after the Treatment Period and one after the Second Course 
Phase. 
If a patient goes onto hospice, then they will no longer be followed and considered 
withdrawn from the study. 
7.1.5.3.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first. 
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7.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject 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 that is temporally associated with the 
use of the Merck's product, 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, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor-Investigator and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater ( 
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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If an adverse event(s) is associated with ("results from") the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck's product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (Ed), using the terminology "accidental or intentional 
overdose without adverse effect." 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor-Investigator and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor-Investigator and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial or within 90 days of completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. 
All subjects and female partners of male subjects who become pregnant must be followed to 
the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor-Investigator and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-
1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor-Investigator and to 
Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck's product that: 
Results in death; 
Is life threatening; 
Results in persistent or significant disability/incapacity; 
Results in or prolongs an existing inpatient hospitalization; 
Is a congenital anomaly/birth defect; 
Is a new cancer (that is not a condition of the study); 
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Is associated with an overdose; 
Is another important medical event 
Refer to Table 6 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time the consent is signed through 30 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck 
product, must be reported within 24 hours to the Sponsor-Investigator and within 2 working 
days to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor-Investigator and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number: +1-215-993-1220 
The Sponsor-Investigator will report significant new safety information associated with use 
of drugs in this trial (including serious, unexpected, suspected adverse reactions) to FDA in 
accordance with regulations under 21 CFR 312.32. Additionally investigators will submit a 
copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-
1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 661-6229). 
Events of clinical interest for this trial include: 
an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor-Investigator, 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 
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the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
7.2.4 Evaluating Adverse Events 
The Sponsor-Investigator or a qualified designee will evaluate all adverse events according to 
the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse 
event which changes CTCAE grade over the course of a given episode will have each change 
of grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
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Table 6 Evaluating Adverse Events 
An Sponsor-Investigator or qualified designee, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
tResults in death; or 
tIs 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 
tResults in a persistent or significant disability/incapacity (substantial disruption of one's ability to conduct 
normal life functions); or 
j 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 [including hospitalization for an elective procedure] for a preexisting condition 
which has not worsened does not constitute a serious adverse event.); or 
tIs 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) or 
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a 
serious adverse event. 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. 
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 
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jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a t). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and 
units 
Action 
taken 
Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product 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 the test drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between the Merck product and the AE; 
the greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely the Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), 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 the Merck product? 
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 
I Relationship The following components are to be used to assess the relationship between the test drug and the AE: 
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to Merck 
product 
(continued) 
(continued) 
Dechallenge Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) 
the AE resolved/improved despite continuation of the Merck product; or (3) the trial is a single-
dose drug trial); or (4) Merck product(s) is/are only used one time.) 
Rechallenge Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one 
time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS 
SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF 
REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding 
the Merck product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the 
following 
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to the Merck product. The temporal sequence of the AE onset 
relative to the administration of the Merck product is reasonable. The AE is more likely 
explained by the Merck product than by another cause. 
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No, there is not a 
reasonable possibility 
Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR there is another obvious cause of the 
AE. (Also entered for a subject with overdose without an associated AE.) 
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7.2.5 Sponsor-Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB, and investigators in 
accordance with all applicable global laws and regulations. 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 Statistical Analysis Plan Summary 
This is Phase I/II trial. The initial phase of the trial will use a "3+3" design. The phase II 
portion of the trial will use a two stage design and will not include patients treated in the 
phase I dose escalation for the efficacy analysis. 
8.2 Statistical Analysis Plan 
Phase I Design:  
The primary objective of the phase I component of this study is to evaluate the safety of 
Pembrolizumab given in combination with Doxorubicin among patients with advanced soft 
tissue sarcoma. The phase I component of this study will use a 3+3 design to evaluate the 45 
mg/m2  and 75 mg/m2  Doxorubicin dosing in combination with Pembrolizumab. Dose-
limited toxicities will be evaluated through the end of the first cycle combining 
Pembrolizumab with Doxorubicin. 
The study design is as follows: 
Initially enroll 3 patients into the 45 mg/m2  cohort 
If 2 of 3 experience a DLT, stop and conclude that Pembrolizumab may not be 
given safely with Doxorubicin at the protocol-specified dose levels. 
If I of 3 patients experiences a DLT, enroll 3 more patients. 
If less than 2 of 6 experiences a DLT then initiate enrollment to the 75 
mg/m2  cohort. 
If 2 or more experience a DLT, stop and conclude that Pembrolizumab 
may not be given safely with Doxorubicin at the protocol-specified dose 
levels. Should this occur, discussions will initiate with the DSMB and 
Merck about whether the protocol could be altered to make the regimen 
safe or whether the study should be halted. 
If 0 of 3 patients experience a DLT then initiate enrollment to the 75 mg/m2  
cohort 
If 45 mg/m2  is determined safe, enroll 3 patients into the 75 mg/m2  cohort 
If 2 of 3 experience a DLT stop and conclude that the MTD is 45 mg/m2 
If less than 2 of 3 patients experience a DLT, enroll 3 more patients. 
If less than 2 of 6 experience a DLT then conclude 75 mg/m2  is the MTD 
If 2 or more experience a DLT, stop and conclude that that the MTD is 45 
mg/m2  
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The maximum sample size for the phase I component is 12 patients. 
Phase II Design:  
The primary objective of the phase II design is to compare the objective response rate (ORR) 
with historical rates. Patients at the final phase I dose will not be included in the phase II 
analysis. Our null hypothesis estimates the overall response rate of single agent doxorubicin 
based on the EORTC randomized study of doxorubicin alone or in combination with 
Ifosfamide, the largest study using modern imaging and supportive care. A two-stage design 
with null hypothesis of 15% using a 1-sided 0.05 a level test has 85% power to detect an 
increase to 35%. This design requires a total of 35 patients, 20 in the 1 st  stage and 15 in the 
second stage. If 2 or more responses (CR or PR) are observed in the lst  stage, the study will 
continue accrual to the second stage, accruing 15 more patients. If at least 10 responses are 
seen out of the 35 patients (29%), then this will be considered evidence to rule out an ORR of 
15% or less. 
Secondary objectives include the estimation of the median PFS, time to and duration of 
response, and the frequency and severity of toxicities. With 51 patients, this design can 
estimate frequencies (and single time point estimates of PFS/OS) to within 14% with 95% 
confidence. The Kaplan-Meier method will be used to estimate median PFS and OS. 
Correlative Endpoints:  The study is not powered to detect specific hypotheses with regards 
to correlative endpoints, rather this data and analysis will help better identify patients having 
the potential to benefit from this therapy and aid in designing larger Phase III studies. 
Summary statistics will be used to for describing changes across time. In addition, the time 
course of biomarker outcomes will be investigated graphically by summary plots or 
individual patient plots. Categorical data analysis and logistic regression will be used to 
evaluate the associations between correlative measures and clinical outcome (eg, response, 
clinical benefit, time to progression, progression-free survival, and survival). If there is 
suggestion of meaningful trend, methods such as linear mixed models may be used to 
characterize the pattern of change over time. Kaplan-Meier methodology and Cox 
Proportional Hazards models will be used to evaluate time to event endpoints. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
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Table 7 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-
Investigator and/or designee are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not provided. 
9.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator's responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
9.6 Doxorubicin 
Clinical Doxorubicin will be used and standard practices regarding storing and 
handling the drug will apply. More detailed information can be found in the 
doxorubicin package insert. 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Institutional Review Board 
In accordance with federal regulations (21 CFR 312.66), an Institutional Review Board 
(IRB) that complies with regulations in 21 CFR 56 must review and approve this protocol 
and the informed consent form prior to initiation of the study. 
10.2 Consent 
The Principal Investigator or his associate must explain verbally and in writing the 
nature, duration, and purpose of the study and possible consequences of treatment. Patients 
must also be informed that they may withdraw from the study at any time and for any reason 
without jeopardizing their future treatment. In accordance with federal regulations (21 CFR 
312), all patients must sign the IRB-approved consent form. 
10.3 Termination of Study 
The Sponsor-Investigator reserves the right to terminate this study at any time. The FDA 
may also terminate the study. 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor-Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information. Common 
Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)  
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10.4 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
11.0 DATA AND SAFETY MONITORING PLAN 
Institutional support of trial monitoring will be in accordance with the 
FHCRC/University of Washington Cancer Consortium Institutional Data and Safety 
Monitoring Plan. Under the provisions of this plan, FHCRC Clinical Research Support 
(CRS) coordinates data and compliance monitoring conducted by consultants, contract 
research organizations, or FHCRC employees unaffiliated with the conduct of the study. 
Independent monitoring visits occur at specified intervals determined by the assessed risk 
level of the study and the findings of previous visits per the institutional DSMP. 
In addition, protocols are reviewed at least annually and as needed by the Consortium 
Data and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee 
(SRC) and the FHCRC/University of Washington Cancer Consortium Institutional 
Review Board (IRB). The review committees evaluate accrual, adverse events, stopping 
rules, and adherence to the applicable data and safety monitoring plan for studies actively 
enrolling or treating subjects. The IRB reviews the study progress and safety information 
to assess continued acceptability of the risk-benefit ratio for human subjects. Approval of 
committees as applicable is necessary to continue the study. 
The trial will comply with the standard guidelines ,set forth by these regulatory 
committees and other institutional, state and federal guidelines. 
During the phase I portion of the trial, a data safety monitoring board will meet regularly 
to oversee the trial. 
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Appendix A: 
Data Safety Monitoring Board Charter 
Title: A Trial of Pembrolizumab in Combination with Doxorubicin as Treatment for Patients 
with Advanced Soft Tissue Sarcomas 
Protocol number: 
Date: 
Table of Contents 
1. Introduction 
2. Primary Responsibilities of the DSMB 
3. Membership of the DMC 
Members 
Conflicts of Interest 
4. Timing and Purpose of the DSMB Meetings 
Organizational Meeting 
Early Safety/Trial Integrity Reviews 
Formal Interim Efficacy Analysis 
5. Procedures to Ensure Confidentiality 
6. Communication 
Closed Sessions 
Open Session 
Open and Closed Reports 
Minutes of the DSMB Meeting 
Recommendations to the PI 
7. Statistical Monitoring Guidelines 
8. Content of the DSMB's Open and Closed Reports 
1. Introduction 
This Charter is for the Data and Safety Monitoring Board (DSMB) for Protocol: 
A Trial of Pembrolizumab in Combination with Doxorubicin as Treatment for Patients with 
Advanced Sarcomas 
This Charter will define the primary responsibilities of the DSMB, its members, and purpose 
and timing of its meetings. The Charter will also provide the procedures for ensuring 
confidentiality and proper communication, the statistical monitoring guidelines to be 
implemented by the DSMB, and an outline of the content of Open Reports that will be 
provided to the DSMB. 
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Primary Responsibilities of the DSMB  
The DSMB will be responsible for safeguarding the interests of trial participants, and 
assessing the safety and efficacy of the interventions during the trial. This responsibility will 
be exercised by providing recommendations about stopping or continuing the trial. To 
contribute to enhancing the integrity of the trial, the DSMB may also formulate 
recommendations relating to the recruitment/retention of participants, their management, 
improving adherence to protocol-specified regimens, and the procedures for data 
management and quality control. 
The DSMB will be advisory to the principal investigator, Dr. Seth Pollack. The PI will be 
responsible for promptly reviewing the DSMB recommendations, to decide whether to 
continue or terminate the trial, and to determine whether amendments to the protocol or 
changes in study conduct are required. If an investigator does not agree with the DSMB 
recommendations then a memo justifying the reason for not complying with the 
recommendations must accompany the minutes. 
Membership 
a. Members 
The DSMB will consist of at least 3 independent clinicians and biostatisticians 
that, collectively, have experience in the management of patients with solid 
tumors and hematologic malignancies in the conduct and monitoring of clinical 
trials. A quorum will require at least 3 members, including the chair. 
Clinical Investigators: 
Ed Kim, M.D. 
Associate Professor 
Dept of Radiation Oncology 
Univ of Washington / Seattle Cancer Care Alliance 
(T) 206-598-1168, edykim(&,seattlecca.org  
Scott Tykodi, M.D. 
Assistant Professor /Assistant Member 
Division of Oncology 
Univ of Washington / FHCRC 
(T) 206-288-7763, stykodigfhcrc.org  
Ted Gooley Ph.D. (chair) 
Member 
Clinical Research Division 
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Fred Hutchinson Cancer Research Center 
(T) 206-667-6533, tgooley@fredhutch.org  
b. Conflicts of Interest 
No DSMB members have any conflicts of interest related to the study. Any 
DSMB member who has or develops a significant conflict of interest should 
resign from the DSMB. DSMB membership is for the duration of the clinical trial:  
If any members leave the DSMB during the course of the trial, the PI will 
promptly appoint their replacement. 
Timing and Purpose of the DSMB Meetings 
The DSMB will meet and review all AEs as is specified in section 2.1 Trial Design. 
The DSMB will also meet at least every 6 months during the phase I portion of the trial. 
During the phase II portion of the trial, the DSMB will meet every 6 months while the study 
is enrolling. Additionally, any toxicity defined as a DLT for the phase I portion will also 
trigger a meeting of the DSMB during the phase II portion of the trial. Should 2 of these 
events occur, enrollment must halt until the DSMB meets. 
DSMB reviews may be held in person, via teleconferencing, or via electronic mail. 
The purpose of the DSMB meetings is to review the conduct of the trial to date and assess 
safety and toxicity of the study intervention. The DSMB will review all grade 3 or greater 
NIH CTC v4.03 toxicities and SAEs and determine whether the study should be prematurely 
discontinued due to toxicity. Ad hoc meetings may be scheduled as needed. The FHCRC 
also has a Protocol Data Monitoring Committee (PDMC) that reviews the progress of the 
protocol with respect to the monitoring plan at the time of each annual renewal 
Confidentiality 
All patient information will be coded to maintain confidentiality. The DSMB will 
have responsibility for assessing and making recommendations to correct any possible abuses 
of disclosure. 
Communication 
Initial Review 
DSMB members are provided general study information by the study team; overall study 
progress, enrollment, or amendments at least 15 days prior to the regularly scheduled 
meeting. DSMB meetings will be open and may include the study investigators and DSMB 
members. The Open Session provides the DSMB an opportunity to query the study team 
about issues that have arisen during the review of the data. The DSMB will develop a 
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consensus on its list of recommendations, including whether the trial should continue. 
DSMB Meeting Minutes 
FHCRC Clinical Research Support (CRS) will provide staff to assist with minutes for the 
DSMB meeting. The FHCRC IRB and Regulatory Affairs Manager will be included on the 
distribution list. At the time of IRB annual renewal, DSMB minutes will be required, if not 
already provided. 
Statistical Monitoring Guidelines 
The DSMB will review all grade 3 or greater toxicities as defined by version 4.0 of 
NCI Common Toxicity Criteria and determine whether the study should be prematurely 
discontinued due to toxicity. Toxicity grading will be evaluated by the clinical investigators. 
Criteria for discontinuing of therapy in an individual patient are described in protocol section 
titled "Management of Toxicities and Complications". Criteria for discontinuing the trial is 
described in section titled "Data and Safety Monitoring". 
The type and grade of toxicities noted during therapy will be summarized for each dose level. 
All adverse events noted by the investigator will be tabulated according to the affected body 
system. Descriptive statistics will be used to summarize changes from baseline in clinical 
laboratory parameters. Tumor responses will be determined as specified above. 
Content of Reports for the DSMB 
Study number and title. Brief summary of the study design. 
Protocol amendments 
Status of accrual. If accrual is slower than expected, a plan for increasing 
enrollment. 
Compliance 
Analyses of primary and secondary endpoints 
Analyses of adverse events and overall safety data. A listing of SAEs by 
subject and by body system. 
Analysis of lab values 
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APPENDIX B: 
ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
*As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E. 7'., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
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Appendix C: Literature Cited 
Brahmer, J. R., C. G. Drake, I. Wollner, J. D. Powderly, J. Picus, W. H. Sharfman, E. 
Stankevich, A. Pons, T. M. Salay, T. L. McMiller, M. M. Gilson, C. Wang, M. Selby, J. M. 
Taube, R. Anders, L. Chen, A. J. Korman, D. M. Pardo11, I. Lowy and S. L. Topalian (2010). 
"Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid 
tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates." J Clin 
Oncol 28(19): 3167-3175. 
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